3 s2.0 B9780128158449000075 Main

C H A P T E R
7
The pancreatic islets
Case study: type 1 diabetes mellitus

Patient is a 25-year-old female without significant past insulin. Insulin is a hormone needed to allow glucose
medical history who presented to the emergency room to enter cells to produce energy. The exact cause of
with 7 days of polyuria, polydipsia, dry mouth, polypha- type 1 diabetes is unknown. Usually, the body’s own
gia, 10 lb weight loss, blurry vision, and diffuse abdomi- immune system mistakenly destroys the insulin-
nal pain. On physical examination, her body mass index producing islets of Langerhans in the pancreas. Type 1
was normal at 20. She was afebrile but tachycardic (heart diabetes has no cure. Treatment focuses on managing
rate 120) and blood pressure was 100/65. She had a fruity blood sugar levels with insulin, diet, and lifestyle to
odor to her breath and had a tender but nonsurgical prevent complications. Until the discovery of insulin,
abdomen. Laboratory evaluation revealed a serum glu- type 1 diabetes was a lethal disease. In 1869 Paul
cose of 550, anion gap was elevated at 25 (normal ,12), Langerhans, a medical student in Berlin, Germany, dis-
arterial pH was low at 7.1 (normal arterial pH 7.357.45), covered the later known islets of Langerhans but their
and positive serum and urine ketones. Her hemoglobin role became evident only in 1901 when Eugene
A1c was elevated at 9.5%. Based on her clinical presenta- Lindsay Opie established the link between the islets of
tion and biochemical evaluation, she was diagnosed with Langerhans and diabetes. Over the following two dec-
diabetic ketoacidosis and was started on intravenous ades, several attempts were made to isolate insulin
fluids and insulin. After 12 h, her hyperglycemia and from the pancreatic tissue. In 1916 Nicolae Paulescu, a
metabolic acidosis were corrected. She was able to eat Professor of Physiology at the University of Medicine
and was transitioned to subcutaneous long acting and and Pharmacy in Bucharest, Romania, developed an
mealtime insulin. Once her blood sugars were well con- aqueous pancreatic extract that normalized hyperglyce-
trolled on the insulin regimen, she was discharged home. mia when was administered to a diabetic dog. In 1921
Outpatient laboratory evaluation revealed low C-peptide Frederick Banting in collaboration with J.J.R. Macleod,
of 0.3 ng/mL (normal range 0.83.85 ng/mL) and ele- Charles H. Best and James B. Collip at the University
vated titers of glutamic acid decarboxylase 65 antibodies of Toronto, Canada, were able to isolate an extract
(2.7 U/mL, normal ,1 U/mL), IA-2 antibodies (1.8 U/ from the pancreatic islets. A year later, Leonard
mL, normal ,0.8 U/mL), and antiinsulin antibodies Thompson, a 14-year-old very sick Canadian diabetic
(2.3 U/mL, normal ,0.4 U/mL) confirming a diagnosis patient, was given the first injection of insulin. Banting
of type 1 diabetes mellitus. and MacLeod were awarded the Nobel Prize in
Type 1 diabetes mellitus, once known as juvenile Physiology or Medicine in 1923 for the discovery of
diabetes or insulin-dependent diabetes, is a chronic insulin (Fig. 7.1). Banting and MacLeod shared the
condition in which the pancreas produces little or no award money with Best and Collip.
Goodman’s Basic Medical Endocrinology.

DOI: https://doi.org/10.1016/B978-0-12-815844-9.00007-5 203 © 2022 Elsevier Inc. All rights reserved.
204 7. The pancreatic islets
(cont’d)
FIGURE 7.1 The four people who made insulin possible. From left: Frederick Banting, J.J. R. MacLeod, Charles H. Best and James B.
Collip.
In the clinic: diabetes mellitus

Introduction usually more severe than those of patients without aci-
dosis. In addition to polyuria, polydipsia, and weight
Diabetes mellitus is a disease that occurs when the
loss, patients with ketoacidosis may present symptoms
blood glucose is elevated. In diabetes the pancreas does
caused by the acidosis such as fruity-smelling breath,
not make insulin or the body does not use the insulin
abdominal pain, and change in mental status, including
well (insulin resistance). The two most common types of
drowsiness and lethargy. On clinical exam, patient with
diabetes are type 1 and type 2 diabetes. In type 1 diabe-
diabetic ketoacidosis appears sick and dehydrated. Signs
tes the body does not make insulin because the immune
include hypotension, tachycardia and tachypnea, hypo-
system destroyed the pancreatic beta cells that secreted
thermia, Kussmaul breathing, ileus, acetone breath, and
insulin. Type 1 diabetes is usually diagnosed in children
altered sensorium. Type 2 diabetes patients can present
and young adults, although it can appear at any age.
with extreme hyperglycemia and hyperosmolality but
People with type 1 diabetes need to take insulin every
without or with minimum ketosis. This condition is
day to stay alive. Type 2 is the most common type of
called hyperglycemic hyperosmolar state. Patients pre-
diabetes. In this type the body does not make enough
senting with hyperglycemic hyperosmolar state are very
insulin or there is resistance to it. Type 2 diabetes can
dehydrated and present with more significant changes
develop at any age but is most common in middle-aged
in mental status than patients with diabetic ketoacidosis.
and older people. Usually, type 2 diabetes is being asso-
ciated with being overweight or obese, which causes
Diagnosis
insulin resistance.
Diabetes mellitus is diagnosed based on one of the
Signs and symptoms following criteria:
The most common presentation of new onset diabetes 1. fasting plasma glucose $ 126 mg/dL (7 mmol/L) on
is with hyperglycemia without acidosis. Patients present more than one occasion;
with polyuria, polydipsia, weight loss, fatigue, and blur- 2. random plasma glucose $ 200 mg/dL (11.1 mmol/L)
ry vision. Less commonly patients present with diabetic in a patient with classic symptoms of hyperglycemia;
ketoacidosis, which is more frequently seen in type 1 3. plasma glucose $ 200 mg/dL (11.1 mmol/L)
rather than type 2 diabetes. Symptoms are similar but measured 2 h after an oral glucose tolerance test; and
Goodman’s Basic Medical Endocrinology

The pancreatic islets 205
(cont’d)
4. hemoglobin A1c $ 6.5% (using an assay that is noninsulin antidiabetic medications which work through
certified by the National Glycohemoglobin different mechanisms, including biguanides, sulfonylur-
Standardization Program) eas, glinides, thiazolidinedione, glucagon-like protein-1
(GLP-1) agonists, dipeptidyl peptidase-4 inhibitors,
Unless patient has unequivocal symptoms of hyper-
sodiumglucose cotransporter 2 inhibitors, and alpha-
glycemia, the diagnosis of diabetes mellitus should be
glucosidase inhibitors.
confirmed by repeat testing.
Management Prognosis
The goal of treatment in diabetes is to control hyper- Diabetes mellitus is a chronic disease. Diabetes-
glycemia and prevent micro- and macrovascular diabe- related complications include microvascular complica-
tes complications. As type 1 diabetes is caused by lack tions (retinopathy, nephropathy, and neuropathy) and
of insulin production due to the destruction of pancre- macrovascular complications (heart attack, stroke, and
atic beta cells, all patients with type 1 diabetes should peripheral artery disease). As good glycemic control has
receive insulin. Insulin is a hormone administered by been shown to decrease the risk of diabetes-related com-
injection or via insulin pump into subcutaneous fat tis- plications, in particular, microvascular disease, the goal
sue. Different types of insulin are available, including of treatment is to control hyperglycemia while not
long acting, intermediate acting, short/rapid acting, and exposing patients to severe hypoglycemia. A reasonable
premixed preparations. As in type 2 diabetes, there is treatment goal for most patients is a hemoglobin A1c
often time some residual insulin production; these 6%7%; however, the target should be individualized
patients can be treated with oral agents, insulin, or a especially for older patients who in general should have
combination of these agents. There are several classes of a higher hemoglobin A1c target.
The pancreatic islets The principal pancreatic hormones are insulin and
glucagon, whose opposing effects on the liver regulate
The pancreas (Fig. 7.2) has both an exocrine and an hepatic storage, production, and release of energy-rich
endocrine function. Exocrine secretions of the pancreas fuels. Insulin is an anabolic hormone that promotes
are digestive enzymes and will not be covered further. sequestration of carbohydrate, fat, and protein in storage
The endocrine portion secretes hormones (Table 7.1). depots throughout the body. Its powerful actions are
FIGURE 7.2 The pancreas in the abdominal cavity lies behind the stomach. In this illustration the liver is not shown. It would lie above
the right kidney. The regions of the pancreas are also shown. The pancreas gets some of its arterial blood from the splenic artery which is
unlabeled but is visible as a series of curves just above the neck, body, and tail of the pancreas and from branches of the superior mesenteric
artery. Source: From Figure 69.1 in S. Standring. (2016), Gray’s anatomy (41st ed.) (p. 1179). Elsevier.

TABLE 7.1 The endocrine hormones produced by the islet cells in the pancreas.
Percentage Fine structure of Hormone and
Cell of total Location granules molecular weight Function
β Cell 70 Scattered 300 nm in diameter; Insulin 6000 Da Decreases blood glucose levels
throughout islet dense core granule
(but surrounded by a wide Amylin, B3200 Da Inhibits gastric emptying and glucagon
release from α cells
concentrated in electron-lucent halo
center)
α Cell 20 Islet periphery 250 nm in diameter; Glucagon, 3500 Da Increases blood glucose levels
dense core granule with
a narrow electron-lucent
halo
δ Cell 5 Scattered 350 nm in diameter; Somatostatin, 1640 Da Paracrine: inhibits hormone release from
D throughout islet electron-lucent endocrine pancreas and enzymes from
D1 homogeneous granule Vasoactive intestinal exocrine pancreas
peptide, 3800 Da
Endocrine: reduces contractions of
alimentary tract and gallbladder smooth
muscles
Induces glycogenolysis; regulates
smooth muscle tonus and motility of
gut; controls ion and water secretion by
intestinal epithelial cells
G cell 1 Scattered 300 nm in diameter Gastrin, 2000 Da Stimulates production of hydrochloric
throughout islet acid by parietal cells of stomach
PP cell (F cell) 1 Scattered 180 nm in diameter Pancreatic polypeptide Inhibits exocrine secretions of pancreas
throughout islet 4200 Da
ε Cell (Epsilon 1 Scattered ? Ghrelin Induces the sensation of hunger and
cell) throughout islet modulates receptive relaxation of the
smooth muscle fibers of the muscularis
externa of the gastrointestinal tract
From Table 18.1 from Histology (4th ed.), by Leslie P. Gartner. Elsevier, 2017, p. 480.
exerted principally on skeletal muscle, liver, and adipose Morphology of the endocrine pancreas
tissue, whereas the effects of glucagon are restricted to
the liver, which responds by forming and secreting The 12 million islets of the human pancreas range
energy-rich water-soluble fuels: glucose, acetoacetic acid, in size from about 50 to about 500 mm in diameter and
and β-hydroxybutyric acid. Interplay of these two hor- contain from 50 to 300 endocrine cells (Fig. 7.3).
mones contributes to constancy in the availability of met- Collectively, the islets make up only 1%2% of the
abolic fuels to all cells. Somatostatin is also an islet pancreatic mass. They are highly vascular, with each
hormone and was discussed in Chapter 6, Hormones of cell seemingly, in direct contact with a capillary. Blood
the Gastrointestinal Tract, as was pancreatic polypep- is supplied by the pancreatic artery and eventually
tide. Ghrelin, produced by epsilon cells, is discussed in drains into the portal vein, which thus delivers the
Chapter 8, Hormonal Regulation of Fuel Metabolism. entire output of pancreatic hormones to the liver.
Glucagon acts in concert with other fuel-mobilizing Blood entering each islet through one or more arter-
hormones to counterbalance the fuel-storing effects of ioles flows through an anastomosing network of
insulin. Insulin, on the other hand, acts alone, and pro- capillaries before forming a vein and exiting at the
longed survival is not possible in its absence. opposite pole. The blood then flows through the acini.
Inadequacy of insulin due to insufficient production The transition from arterioles to capillaries in the islets
results in the disease called diabetes mellitus type 1; a and acini and then back to a venule forms the insuloa-
second disease, diabetes mellitus type 2, results pri- cinar portal system. The islets then have some control
marily from decreased end organ sensitivity to insulin over the digestive enzyme secretions of the acini
(insulin resistance). (Figs. 7.4 and 7.5).

Morphology of the endocrine pancreas 207
FIGURE 7.3 Rat islets of Langerhans. The islets are surrounded by acini that secrete digestive enzymes. Note the extensive blood vessel
network in (A). In (B) the beta cells have been stained for insulin and in (C) the alpha cells have been stained for glucagon. Note that the alpha
cells are organized around the periphery of each islet, while the beta cells are centrally located. In humans the alpha and beta cells are ran-
domly scattered throughout each islet. Source: From Figure 39.5 in Koeppen B. M., & Stanton B. A. (2018). Berne and levy physiology (7th ed.) (p.
704). Elsevier.
FIGURE 7.4 Blood flow through the islets and acini

and demonstrating the insuloacinar portal system. By this
system the islets may exert some control over nearby acini.
More distal acini are supplied with blood from branches of
the splenic artery. Source: From Figure 19-15 from
Kierszenbaum A. L., & Tres L. L. (2020). Histology and cell
biology: An introduction to pathology (5th ed.) (p. 653).
Elsevier.
This pattern of blood flow in human islets differs and beta cells are distributed randomly throughout the
from the classic description of islet blood flow derived islet (Fig. 7.6).
from studies in rodents. The same is true of the loca- The islets are richly innervated with both sympa-
tion of alpha and beta cells. In rodents the alpha cells thetic and parasympathetic fibers that terminate on or
are on the periphery of the islet, while the beta cells near the secretory cells. Parasympathetic preganglionic
are in the center (Fig. 7.3), but in humans, the alpha fibers arise from cell bodies in the dorsal motor

Histologically, the islets consist of three major and

Pancreas
at least two minor cell types. Beta cells, which synthe-
Common size and secrete insulin, make up about 60% of a typi-
bile duct cal islet. Alpha cells are the source of glucagon and
comprise perhaps as much as 30% of islet tissue. Delta
cells, which are considerably less abundant, produce
Pancreatic somatostatin.
duct F cells, which secrete pancreatic polypeptide, may
also appear in the exocrine part of the pancreas. A fifth
cell type, epsilon cells, that secretes ghrelin has been
Duodenum identified in both fetal and adult islets. In humans,
these cells and the F cells occupy the perimeters of
islets, with alpha cells, whereas beta cells are more
centrally located (Figs. 7.3 and 7.4) and are situated
 cells  cells produce along the lengths of capillaries. In humans as well as
produce somatostatin Blood flows rodents the close contacts between the different cell
glucagon from the center
to the periphery
types is thought to favor paracrine communication and
may have a role in regulating islet cell function.
 cells
produce
insulin Glucagon
Biosynthesis, secretion, and metabolism

F cells Glucagon is a simple unbranched peptide chain that
produce consists of 29 amino acids and has a molecular weight
pancreatic
polypeptide
of about 3500 Da. Its amino acid sequence has been
remarkably preserved throughout evolution of the ver-
tebrates. The glucagon gene, which is located on chro-
Islet of Langerhans mosome 2, is expressed primarily in alpha cells, L-cells
of the intestinal epithelium, and discrete brain areas. It
FIGURE 7.5 The blood flow within an islet and the different cell
types. The blood flows from the center of the islet toward the is secreted from a preproglucagon peptide (Fig. 7.8).
periphery. Epsilon cells are not illustrated. Source: Redrawn from Glucagon formation and its relation to other pro-
Figure 51.1 from Barrett E. J. (2017). Chapter 51: The endocrine pancreas. ducts of the same gene and to other hormones and
In W. F. Boron, & E. L. Boulpaep (Eds.) Medical physiology (3rd ed.) (p. neuropeptides are discussed in Chapter 6, Hormones
1036). Elsevier.
of the Gastrointestinal Tract. Glucagon is packaged,
stored in membrane-bound granules, and secreted by
exocytosis like other peptide hormones. It circulates
nucleus of the vagus and synapse with postganglionic without binding to carrier proteins and has a half-life
cholinergic and peptidergic neurons in pancreatic gan- in blood of about 5 minutes. Glucagon concentrations
glia buried within the pancreas. Sympathetic fibers in peripheral blood are considerably lower than in
originate in the hypothalamus and terminate on cell portal venous blood. This difference reflects not only
bodies in the intermediolateral column of the spinal greater dilution in the general circulation but also the
cord. The preganglionic fibers to the pancreas pass fact that about 25% of the secreted glucagon is
through the sympathetic chain and without synapsing destroyed during passage through the liver. The kid-
and travel in the greater splanchnic nerve to synapse ney is another important site of degradation, and a
in the celiac or superior mesenteric ganglia. The post- considerable fraction of circulating glucagon is
ganglionic fibers from these ganglia end in the pan- destroyed by plasma peptidases.
creas but it has not been determined if they synapse
directly on individual cells (Fig. 7.7).
These neurons release norepinephrine and several
Physiological actions of glucagon
neuropeptides. The islets also contain a rich comple- The physiological role of glucagon is to stimulate
ment of sensory fibers. Pain fibers return to the spinal hepatic production and secretion of glucose and to a
cord via the sympathetic fibers in the greater splanch- lesser extent, ketone bodies, which are derived from
nic nerve. fatty acids (Fig. 7.9).

Glucagon 209
FIGURE 7.6 Cytoarchitecture of a typical human pancreatic islet as revealed in immunostained confocal scanning microscopic images.
Endocrine cells are closely but randomly associated with vascular cells. Most (A) insulin- (red) and glucagon- (green), and (B) somatostatin-
(cyan) immunoreactive cells are in close proximity to vascular cells immunoreactive for smooth muscle cell actin (blue). Endocrine cells are
aligned along the blood vessels in a random order. Source: From Cabrera, O., Berman, D. M., Kenyon, N. S., Ricordi, C., Berggren, P. O., &
Caicedo, A. (2006). The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proceedings of the National Academy
of Sciences of the United States of America, 103, 23342339, with permission.
Under normal circumstances, liver and possibly pan- target genes. Glucagon may also increase intracellular con-
creatic beta cells are the only targets of glucagon action centrations of calcium by a mechanism that depends
(Fig. 7.10). upon activation of protein kinase A. Increased intracellu-
A number of other tissues, including fat, and heart lar calcium may reinforce some cAMPmediated actions
express glucagon receptors and can respond to gluca- of glucagon, particularly on glycogenolysis.
gon experimentally, but considerably higher concentra-
tions of glucagon are needed than are normally found
in peripheral blood. Glucagon stimulates the liver to
release glucose and produces a prompt increase in
Glucose production
blood glucose concentration. Glucose that is released To understand how glucagon stimulates the hepato-
from the liver is obtained from breakdown of stored cyte to release glucose, we must first consider some of
glycogen (glycogenolysis) and new synthesis (gluco- the biochemical reactions that govern glucose metabo-
neogenesis). Because the principal precursors for glu- lism in the liver. Biochemical pathways that link these
coneogenesis are amino acids, especially alanine, reactions are illustrated in Fig. 7.11.
glucagon also increases hepatic production of urea It is important to recognize that not all enzymatic
(ureagenesis) from the amino groups taken off the reactions are freely reversible under conditions that
amino acids (two amine groups are combined with prevail in living cells. Phosphorylation and dephos-
CO2 to form urea). Glucagon also increases production phorylation of substrates usually require separate
of ketone bodies (ketogenesis) by directing metabolism enzymes. This arrangement sets up substrate cycles
of long-chain fatty acids toward oxidation and away that would spin futilely in the absence of some regula-
from esterification and export as lipoproteins. tory influence exerted on either or both opposing reac-
Concomitantly, glucagon may also promote break- tions. These reactions are often strategically situated at
down of hepatic triacylglycerols to yield long-chain or near branch points in metabolic pathways and can
fatty acids, which, along with fatty acids that reach the therefore direct flow of substrates toward one fate or
liver from peripheral fat depots, provide the substrate another.
for ketogenesis. Regulation is achieved both by modulating the
All the effects of glucagon appear to be mediated by activity of enzymes already present in cells and by
cyclic adenosine monophosphate (cAMP) (see Chapter 1: increasing or decreasing rates of enzyme synthesis
Introduction). In fact, it was studies of the glycogenolytic and therefore the amounts of enzyme molecules.
action of glucagon that led to the discovery of cAMP and Enzyme activity can be regulated allosterically by
its role as a second messenger. Activation of protein changes in conformation produced by interactions
kinase A by cAMP results in phosphorylation of enzymes, with substrates or cofactors, or covalently by phos-
which increases or decreases their activity, or phosphory- phorylation and dephosphorylation of regulatory sites
lation of the transcription factor cAMP response element- in the enzymes themselves. Changing the activity of
binding protein, which usually increases transcription of an enzyme requires only seconds, whereas many

FIGURE 7.7 (A) The structure of one of the more than one million islets in the human pancreas. Blue cells are beta cells, red are alpha
cells, green are somatostatin-forming cells, and orange are F cells. Not shown are epsilon cells. This image depicts the beta cells as being in
the center with the alpha cells in the periphery. As was indicated, in humans, the alpha and beta cells are distributed randomly throughout
the islet; (B) (boxed inset) a beta cell showing direct vagal stimulation. Black arrows show the direction of insulin synthesis; (C) (boxed inset)
the relationship between an alpha cell (red) and a delta cell (green). The neural modulation is via the vagus nerve. Source: From Figure 60.10
from S. Standring (2016). Gray’s anatomy (41st ed.) (p. 1186). Elsevier.
minutes or even hours are needed to change the surfaces of hepatocyte (see Chapter 1: Introduction)
amount of an enzyme. activates protein kinase A, which catalyzes phosphory-
lation, and hence activation, of an enzyme called phos-
phorylase kinase (Fig. 7.12).
Glycogenolysis This enzyme, in turn, catalyzes phosphorylation
cAMP formed in response to the interaction of glu- of another enzyme, glycogen phosphorylase, that
cagon with its G proteincoupled receptors on the cleaves glycogen stepwise to release glucose-1-

Glucagon 211
FIGURE 7.8 The synthesis of different mole-
cules from the preproglucagon molecule and
whether they are active or inactive. GLUC,
Glucagon; GLP, glucagon-like peptide, GRPP,
glucagon-related polypeptide. Source: From
Figure 39.10 in Koeppen B. M., & Stanton B. A.
(2018). Berne and levy physiology (7th ed.) (p. 708).
Elsevier.
itself, leaving dephosphorylation and delivery into

the blood as the major pathway open to newly depo-
lymerized glucose.
Gluconeogenesis
Precursors of glucose enter the gluconeogenic path-
way as 3- or 4-carbon compounds. Glucagon directs
their conversion to glucose by accelerating their con-
densation to fructose phosphate while simultaneously
blocking their escape from the gluconeogenic pathway
(cycles III and IV in Fig. 7.7). cAMP controls produc-
tion of a potent allosteric regulator of metabolism
called fructose-2,6-bisphosphate. This compound,
when present even in tiny amounts, activates phospho-
fructokinase and inhibits fructose-1,6-bisphosphatase,
thereby directing flow of substrate toward glucose
breakdown rather than glucose formation (Fig. 7.13).
Fructose-2,6-bisphosphate, which should not be con-
fused with fructose-1,6-bisphosphate, is formed from
fructose-6-phosphate by the action of an unusual bifunc-
tional enzyme that catalyzes either phosphorylation of
fructose-6-phosphate to fructose-2,6-bisphosphate or
FIGURE 7.9 Integrated regulation of blood glucose showing the dephosphorylation of fructose-2,6-bisphosphate to
effect of glucagon, insulin, and catecholamines (norepinephrine and fructose-6-phosphate, depending on its own state of phos-
epinephrine) on blood glucose. Source: From Figure 39.11 in Koeppen
B. M., & Stanton B. A. (2018). Berne and levy physiology (7th ed.) (p.
phorylation. This enzyme is a substrate for protein kinase
709). Elsevier. A and behaves as a phosphatase when it is phosphory-
lated. Its activity in the presence of cAMP rapidly depletes
the hepatocyte of fructose-2,6-bisphosphate, and substrate
phosphate. Glucose-1-phosphate is the substrate for therefore flows toward glucose production.
glycogen synthase which catalyzes the incorporation The other important regulatory step in gluconeogen-
of glucose into glycogen. Glycogen synthase is also a esis is phosphorylation and dephosphorylation of
substrate for protein kinase A and is inactivated pyruvate (cycle IV in Fig. 7.7). It is here that 3- and 4-
when phosphorylated. Thus by increasing the forma- carbon fragments enter or escape from the gluconeo-
tion of cAMP, glucagon simultaneously promotes genic pathway. The cytosolic enzyme that catalyzes
glycogen breakdown and prevents recycling of glu- dephosphorylation of phosphoenol pyruvate (PEP)
cose to glycogen. cAMPdependent phosphorylation was inappropriately named pyruvate kinase before it
of enzymes that regulate the glycolytic pathway at was recognized that direct phosphorylation of pyru-
the level of phosphofructokinase and acetyl coen- vate does not occur under physiological conditions,
zyme A (CoA) carboxylase (see later) minimizes con- and that this enzyme acts only in the direction of
sumption of glucose-6-phosphate by the hepatocyte dephosphorylation (Fig. 7.14).

Bile canaliculus FIGURE 7.10 The effect of glucagon on the liver cell (hepato-
cyte). The liver is the main target for glucagon. Source: Redrawn
Liver from Figure 51-12 from Barrett E. J. (2017). Chapter 51: The endocrine
pancreas. In W. F. Boron, & E. L. Boulpaep (Eds.), Medical physiol-
ogy (3rd ed.) (p. 1052). Elsevier.
Blood
sinusoid
Hepatocyte
Blood PKA
phosphorylates
Extracellular key enzymes in
space glycolysis and
Fatty acids (of Disse) gluconeogenesis
Glucagon AC cAMP PKA

receptor
ATP
G protein
GLUT2
Glycogen
Glucose-1 phosphate
Glycogen synthesis Glycogenolysis
Hepatocyte
cytosol Glucose Glucose-6 phosphate
Fructose-6 phosphate
Fructose-1,6 bisphosphate
Phosphoenolpyruvate
Pyruvate
Glycolysis Gluconeogenesis
Acetyl CoA
Malonyl Fatty acids

CoA CoA Citric
acid
Carnitine cycle
carrier protein
Lipid metabolism
Ketone bodies
Mitochondrion
Pyruvate kinase is another substrate for protein reactions shown in Fig. 7.9. Inhibiting pyruvate kinase
kinase A and is powerfully inhibited when phosphory- may be the single most important effect of glucagon
lated, but the inhibition can be overcome allosterically on the gluconeogenic pathway. On a longer time scale,
by fructose-6-bisphosphate. Thus activation of protein glucagon inhibits the synthesis of pyruvate kinase.
kinase A has the duel effect of decreasing pyruvate Phosphorylation of pyruvate requires a complex series
kinase activity directly and of decreasing the abun- of reactions in which pyruvate must first enter mito-
dance of its activator, fructose-1,6-bisphosphate, by chondria where it is carboxylated to form oxaloacetate.

Glucagon 213
FIGURE 7.12 Role of protein kinase A (cyclic AMP-dependent

protein kinase) in glycogen metabolism.
FIGURE 7.13 Regulation of fructose-1,6-bisphosphate metabo-

lism by protein kinase A (cyclic AMPdependent protein kinase).
Formation of fructose-1,6-bis phosphate is accelerated by the metabo-
lite fructose-2,6-bisphosphate, which stimulates phosphofructokinase
and inhibits fructose-1,6-phosphatase. Protein kinase A lowers the
concentration of fructose-2,6-bisphosphate by catalyzing phosphory-
FIGURE 7.11 Biochemical pathways of glucose metabolism in lation of the bifunctional enzyme 6 phosphofructose-2 kinase/fruc-
hepatocytes. Reactions that are accelerated in the presence of gluca- tose-2,6-bisphosphatase, which promotes its phosphatase activity.
gon are shown in green. Broken red arrows indicate reactions that The resulting decrease in fructose-2,6-bisphosphate concentration
are inhibited by protein kinase A catalyzed phosphorylation. The removes the stimulation of phosphofructokinase, and the inhibition
hexose-monophosphate shunt is indirectly inhibited. Roman numer- of fructose-1,6-phosphatase, and drives substrate flow from fructose-
als indicate substrate cycles. 1,6-bisphosphate to fructose-1-phosphate.
Lipogenesis and ketogenesis

Entry of pyruvate across the mitochondrial membrane
is accelerated by glucagon, but the mechanism for this The alternate fate of pyruvate in mitochondria is
effect is not known. Oxaloacetate is converted to cyto- decarboxylation to form acetyl CoA (Fig. 7.15).
solic PEP by the catalytic activity of PEP carboxyki- This 2-carbon acetyl unit is the building block of fatty
nase. Synthesis of this enzyme is accelerated by acids and eventually finds its way back to the cytosol
increased cAMP. where fatty acid synthesis (lipogenesis) takes place.

synthesis promotes fatty acid oxidation and conse-

quently ketogenesis (ketone body formation)
(Fig. 7.11). Long-chain fatty acid molecules that reach
the liver can be either oxidized or esterified and
exported to adipose tissue as the triacylglycerol. To be
esterified, fatty acids must remain in the cytosol, and
to be oxidized they must enter the mitochondria.
Long-chain fatty acids can cross the mitochondrial
membrane only when linked to carnitine. Carnitine
acyltransferase, the enzyme that catalyzes this linkage,
is powerfully inhibited by malonyl CoA.
FIGURE 7.14 Regulation of PEP formation by PKA (cyclic Malonyl CoA thus has two distinct and crucial
AMPdependent protein kinase). PKA catalyzes the phosphoryla- roles: it is both an indispensable metabolite for fatty
tion and, hence, inactivation of pyruvate kinase whose activity limits acid synthesis and an allosteric regulator of the
the conversion of PEP to pyruvate. PEP, Phosphoenol pyruvate;
enzyme that permits fatty acids to be oxidized. When
PKA, protein kinase A.
hepatic concentrations of malonyl CoA are high, coin-
cident with fatty acid synthesis, fatty acid oxidation is
inhibited. Conversely, when its concentration is low,
fatty acids readily enter mitochondria and are oxidized
to acetyl CoA. Because long-chain fatty acids typically
contain 16 and 18 carbons, each molecule that is oxi-
dized yields eight or nine molecules of acetyl CoA.
The ketone bodies, β-hydroxybutyrate and acetoace-
tate, are formed from condensation of two molecules
of acetyl CoA and the subsequent removal of the CoA
moiety.
By blocking the formation of malonyl CoA, gluca-
gon sets the stage for ketogenesis, but the actual rate
of ketone production is determined by the abundance
of long-chain fatty acids that are available for oxida-
tion. Most fatty acids oxidized in liver are derived
from the plasma free fatty acids (FFA) released from
adipose tissue. In addition, glucagon, through its stim-
FIGURE 7.15 Protein kinase A (cyclic AMPdependent protein ulation of cAMP production, may also activate a lipase
kinase) indirectly stimulates ketogenesis by decreasing the formation in liver and thereby make fatty acids available from
of malonyl CoA, thus removing a restriction on accessibility of fatty the breakdown of hepatic triacylglycerols. The meta-
acids to intramitochondrial oxidative enzymes. CoA, Coenzyme A. bolic effects of glucagon are summarized in Table 7.2.
Lipogenesis is the principal competitor of gluconeogen-

Ureagenesis
esis for 3-carbon precursors. The first committed step in Whenever carbon chains of amino acids are used as
fatty acid synthesis is the carboxylation of acetyl CoA to substrate for gluconeogenesis, amino groups must be
form malonyl CoA. Acetyl CoA carboxylase, the disposed of in the form of urea, which thus becomes a
enzyme that catalyzes this reaction, is yet another sub- by-product of gluconeogenesis. By promoting gluco-
strate for protein kinase A and is powerfully inhibited neogenesis, therefore, glucagon also increases the for-
when phosphorylated. Inhibition of fatty acid synthesis mation of urea (ureagenesis). Carbon skeletons of most
not only preserves substrate for gluconeogenesis but amino acids can be converted to glucose, but because
also prevents oxidation of glucose by the hexose mono- of peculiarities of peripheral metabolism alanine is
phosphate shunt pathway (Fig. 7.11). NADP, which is quantitatively the most important glucogenic amino
required for shunt activity, is reduced in the initial reac- acid. By accelerating conversion of pyruvate to glucose
tions of this pathway and can be regenerated only by (see earlier), glucagon indirectly accelerates transami-
transferring protons to the elongating fatty acid chain. nation of alanine to pyruvate. Glucagon also acceler-
Fatty acid synthesis and oxidation constitute ates ureagenesis by increasing transport of amino acids
another substrate cycle and another regulatory site for across hepatocyte plasma membranes by an action that
cAMP action. The same reaction that inhibits fatty acid requires synthesis of new RNA and protein. In

Glucagon 215
TABLE 7.2 The effect of glucagon on glucose, fat, ketone, and
protein metabolism.
Glucagon effect on glucose metabolism

Stimulation of liver glycogenolysis
Increase of gluconeogenesis
Glucagon effect on fat metabolism
Stimulation of lipolysis
Enhancement of hepatic oxidation of fatty acids
Glucagon effect on ketone body metabolism

Stimulation of ketone body formation
FIGURE 7.16 Stimulatory and inhibitory signals for glucagon
Glucagon effect on protein metabolism
secretion.
Stimulation of amino acid uptake by the liver providing substrate
for gluconeogenesis (ureagenesis)
Tract), and FFA also exert inhibitory influences on glu-
cagon secretion (Fig. 7.16).
Hypoglycemia is detected not only at the level of
addition, glucagon also promotes the synthesis of the islet, but this life-threatening circumstance also is
some urea cycle enzymes. The metabolic effects of glu- detected by glucose-sensing neurons in the hypothala-
cagon are summarized in Table 7.2. mus, which alert autonomic centers to activate both
sympathetic and parasympathetic responses.
Parasympathetic nerve endings within the islets
Regulation of glucagon secretion release their neurotransmitters, acetylcholine and VIP
(vasoactive intestinal peptide) and perhaps PACAP
The concentration of glucose in blood is the most (pituitary adenylate cyclase activating peptide), and
important determinant of glucagon secretion in normal norepinephrine and NPY (neuropeptide Y) are
individuals. When the plasma glucose concentration released from sympathetic nerve fibers. These peptides
exceeds 200 mg/dL, glucagon secretion is maximally are described in Chapter 6, Hormones of the
inhibited. Inhibitory effects of glucose are proportion- Gastrointestinal Tract. Alpha cells express receptors
ately less at lower concentrations and disappear when for all these neurotransmitters and increase their secre-
its concentration falls below 50 mg/dL. Except imme- tion of glucagon in response to both parasympathetic
diately after a meal rich in carbohydrate, the blood and sympathetic stimulation. The sympathetic
glucose concentration remains constant at around response to hypoglycemia also stimulates the adrenal
90 mg/dL. This set point for glucose concentration medulla to secrete epinephrine and norepinephrine
thus falls well within the range over which glucagon (see Chapter 4: The Adrenal Glands). These adrenome-
secretion is regulated, so alpha cells can respond to dullary hormones not only reinforce the glycogenolytic
fluctuations in blood glucose with either an increase or actions of glucagon on the liver but also further stimu-
a decrease in glucagon output. It is possible that alpha late alpha cells to secrete glucagon.
cells directly sense glucose concentrations, but molecu- Glucagon secretion also is evoked by a meal rich in
lar mechanisms conferring such monitoring ability amino acids. Alpha cells may respond directly to
await discovery. Alternatively, changes in glucagon increased blood levels of certain amino acids, particu-
secretion may be controlled by insulin released from larly arginine, which also increases insulin secretion.
adjacent beta cells, whose well-documented capacity to In addition, digestion of protein-rich foods triggers the
monitor blood glucose concentrations is discussed release of cholecystokinin (CCK) and GIP (glucose-
later. Insulin inhibits glucagon secretion and is dependent insulinotropic peptide) from cells in the
required for expression of inhibitory effects of glucose. duodenal mucosa (see Chapter 6: Hormones of the
A precipitous decline in insulin secretion in response Gastrointestinal Tract). CCK is a secretagogue for islet
to hypoglycemia may trigger glucagon release. In per- hormones as well as pancreatic enzymes and GIP may
sons suffering from insulin deficiency (see later), gluca- stimulate secretion of glucagon as well as insulin. Both
gon secretion is deranged and may be brisk despite of these gastrointestinal hormones alert alpha cells to
high blood glucose concentrations or may fail to an impending influx of amino acids. The resulting
increase in response to hypoglycemia. Somatostatin, increased secretion of glucagon not only prepares the
GLP-1 (see Chapter 6: Hormones of the Gastrointestinal liver to dispose of excess amino acids by

gluconeogenesis but also signals the liver to release 5′ UTR 3′ UTR

glucose and thus counteracts the potentially hypogly- B A
C mRNA-encoding
cemic effects of insulin, whose secretion is simulta- preproinsulin
Ribosome
neously increased by amino acids (see later).
3′
5′
Proinsulin
mRNA
Insulin
C H C peptide
S
HS SH
Biosynthesis, secretion, and metabolism SH A
SH
N S S C
SH
Insulin is composed of two unbranched peptide Insulin N
S S B
chains joined together by two disulfide bridges
S S
(Fig. 7.17). ER
The single gene that encodes the 110-amino acid
preproinsulin molecule consists of three exons and
two introns and is located on chromosome 11. After
removal of the leader sequence in the endoplasmic Converting
reticulum, the proinsulin molecule undergoes fold- enzymes S S C
ing and disulfide bond formation before it is trans- N
S S
ferred to the Golgi apparatus where it is packaged in
S S
secretory granules and stored complexed with zinc. Golgi
Processing of the single-chain proinsulin molecule to
form the two-chained mature insulin takes place in
the secretory granules where a 31-residue peptide,
called the connecting peptide (C peptide), is excised
Cleavage
by stepwise actions of two endopeptidase enzymes
called prohormone convertases 2 and 3. The C pep- S S C
tide therefore accumulates within granules in equi- N
S S Cleavage
molar amounts with insulin. When insulin is S S
secreted, the entire contents of secretory vesicles are
trans-Golgi
disgorged into extracellular fluid (Fig. 7.18).
Consequently, the C peptide and any remaining
proinsulin and processing intermediates enter the cir- Secretory granule
culation along with insulin. When secretion is rapid, C peptide
proinsulin may comprise as much as 20% of the circu-
lating peptides detected by insulin antibodies, but it +
contributes little biological activity. Although several A
biological actions of the C peptide have been B
S S
described, no physiological role for the C peptide has S S
yet been established. S S
The insulin storage granule contains a variety of
Insulin
proteins that are also released whenever insulin is
secreted. Most of these proteins are thought to main-
tain optimal conditions for storage and processing of
FIGURE 7.17 Synthesis and processing of the insulin molecule.
insulin, but some may also have biological activity. UTR, 50 untranslated region which refers to the gray area. Source:
One such protein, called amylin, has a synergistic Redrawn from Figure 51-2 from Barrett E. J. (2017). Chapter 51: The endo-
effect to the action of insulin in various tissues. In crine pancreas. In W. F. Boron, & E. L. Boulpaep (Eds.). Medical physiol-
addition, the amylin causes decreased gastric empty- ogy (3rd ed.) (p. 1037). Elsevier, 2017.
ing, inhibits the digestive secretions, and, as a result,
reduces the food intake. The precursor molecule proa- degradation is receptor-mediated internalization by an
mylin may contribute to the amyloid that accumulates endosomic mechanism. Degradation may take place
in and around beta cells in states of insulin hypersecre- following fusion of endosomes with lysosomes. The
tion and may contribute to islet pathology. liver is the principal site of insulin degradation and
Insulin is cleared rapidly from the circulation with a inactivates from 30% to 70% of the insulin that reaches
half-life of 46 minutes. The first step in insulin it in hepatic portal blood. Insulin degradation in the

Insulin 217
Glucose Leucine
GLUT 2 transporter
1 Glucose enters the cell Extracellular space
via a GLUT 2 transporter,
which mediates
facilitated diffusion of
glucose into the cell Glycolysis β cell
cytosol
Glucokinase
2 The increased glucose influx stimulates
glucose metabolism, leading to an
increase in [ATP]i′ [ATP]i / [ADP]i′ Glucose-6-phosphate
[NADH]i / [NAD+]i′ or [NADPH]i /
[NADP+]i
ATP
Pyruvate
3 The increased [ATP]i′ [ATP]i / [ADP]i′
[NADH]i / [NAD+]i′ or [NADPH]i /
[NADP+]i inhibits the KATP channel
Citric
4 Closure of this K+ channel causes Vm to K+ acid
CCK
become more positive (depolarization) cycle acetylcholine
H2 O
Mitochondrion
CO2
Kir 6.2 Gq
KATP ATP
SUR1
Depolarization Phospholipase C
PLC
5 The depolarization activates a
voltage-gated Ca2+ channel in
ER PIP2
the plasma membrane
IP3
[Ca2+]
Ca2+
DAG
Voltage-gated
Ca2+ channel Protein kinase C
PKC
[Ca2+]i
6 The activation of this Ca2+ channel Protein kinase A
promotes Ca2+ influx and thus Other modulators of
Secretory
increases [Ca2+]i′ which also evokes secretion act via the
granules
Ca2+ -induced Ca2+ release PKA adenyl cyclase-cAMP-
protein kinase A pathway
Adenyl and the phospholipase
cyclase
C-phosphoinositide
ATP pathway
cAMP
7 The elevated [Ca2+]i leads to
Gα
exocytosis and release into the s
blood of insulin contained
within the secretory granules Gαi AC Gα s
β-Adrenergic agonists
Insulin Somatostatin Glucagon
galanin
α-adrenergic agonists
FIGURE 7.18 A detailed summary of the synthesis of insulin. Source: Redrawn from Figure 51.4 from Barrett E. J. (2017). Chapter 51: The endo-
crine pancreas. In Medical Physiology (3rd ed.) by Walter F. Boron and Emile L. Boulpaep. Elsevier, 2017, p. 1040.

liver appears to be a regulated process governed by

changes in availability of metabolic fuels and changing
physiological circumstances. The liver may thus regu-
late the amount of insulin that enters the systemic cir-
culation. The kidneys account for destruction of about
half the circulating insulin following receptor-
mediated uptake both from the glomerular filtrate and
from postglomerular blood plasma. Normally, little or
no insulin is found in urine. The remainder is
degraded in muscle and other insulin-sensitive tissues
throughout the body. Proinsulin has a half-life that is
at least twice as long as insulin and is not converted to
insulin outside the pancreas. The kidney is the princi-
pal site of degradation of proinsulin and the C peptide.
Because little degradation of the C peptide occurs in
the liver, its concentration in blood is useful for esti-
mating the rate of insulin secretion and evaluation of FIGURE 7.19 Idealized glucose tolerance tests in normal and dia-
betic subjects. Subjects are given a standardized solution of glucose
beta cell function.
to drink and blood samples are taken at the indicated times thereaf-
ter. An impairment of glucose disposition results in a greater than
normal and prolonged increase in blood glucose concentration.
Physiological actions of Insulin
Effects of insulin deficiency do not rise above 180 mg/dL. In the diabetic or “predi-
In many areas of endocrinology, basic insights into abetic,” blood glucose levels rise much higher and take
the physiological role of a hormone can be gained a longer time to return to basal levels (Fig. 7.19).
from examining the consequences of its absence. In
such studies, secondary or tertiary effects may over- Glycosuria
shadow the primary cellular lesion but nevertheless Normally, renal tubules have adequate capacity to
ultimately broaden our understanding of cellular transport and reabsorb all the glucose filtered at the
responses in the context of the whole organism. glomeruli so that little or none escapes in the urine.
Insights into the physiology of insulin and the physio- When the serum glucose concentration rises above
logical processes it affects directly and indirectly were 180 mg/dL (10 mmol/L), the renal threshold for glu-
gained originally from clinical observations. cose is exceeded, which leads to increased urinary glu-
Consideration of some of the classic signs of this dis- cose excretion (glycosuria).
ease therefore provides a good starting point for dis-
cussing the physiology of insulin. Polyuria
Polyuria is defined as excessive production of urine.
Hyperglycemia Because more glucose is present in the glomerular fil-
In the normal individual the concentration of glu- trate than can be reabsorbed by proximal tubules,
cose in blood is maintained at around 90 mg/dL of some remains in the tubular lumen and exerts an
plasma (5 mM). Blood glucose in diabetics is higher, osmotic hindrance to water and salt reabsorption in
sometimes reaching levels of more than 1000 mg/dL. this portion of the nephron, which normally reabsorbs
Diabetics have particular difficulty removing excess about two-thirds of the glomerular filtrate. The abnor-
glucose from their blood. Normally, after ingestion of mally high volume of fluid that remains cannot be
a meal rich in carbohydrate, excess glucose disappears reabsorbed by more distal portions of the nephrons,
rapidly from plasma, and there is only a small and with the result that water excretion is increased
transient increase in blood glucose. The diabetic, how- (osmotic diuresis). Increased flow through the nephron
ever, is intolerant of glucose, and the ability to remove increases urinary loss of sodium and potassium as
it from plasma is severely impaired. Oral glucose toler- well.
ance tests, which assess the ability to dispose of a glu-
cose load, are used diagnostically to evaluate existing Polydipsia
or impending diabetic conditions. A standard load of Dehydration results from the copious flow of urine
glucose is given by mouth and the blood glucose con- and stimulates thirst, a condition called polydipsia, or
centrations are measured periodically over several excessive drinking. The untreated diabetic is character-
hours. In normal subjects, blood glucose peak values istically thirsty and consumes large volumes of water

Insulin 219
to compensate for water lost in urine. Polydipsia is
often the first symptom that is noticed by the patient
or parents of a diabetic child.
Polyphagia
By mechanisms that likely stem from insulin’s role
in regulating food intake (see Chapter 8: Hormonal
Regulation of Fuel Metabolism), appetite is increased
in what seems to be an effort to compensate for uri-
nary loss of glucose. The condition is called polypha-
gia (excessive food consumption).
Weight loss
Despite increased appetite and food intake, how-
ever, insulin deficiency reduces all anabolic processes
and accelerates catabolic processes. Accelerated protein
degradation, particularly in muscle, provides substrate
for gluconeogenesis. Insulin is the most potent antili-
polytic hormone. Insulin deficiency increases the activ-
ity of hormone sensitive lipase (HSL), which causes
lipolysis of the fat stores. FFA and glycerol are
released into the circulation causing hyperlipidemia.
The fatty acids are transported to the liver where they
FIGURE 7.20 The effect of insulin on blood glucose and the
are oxidized. After oxidation, they can enter the keto-
counterregulatory factors glucagon and catecholamines (norepineph-
genic metabolic pathway to form ketone bodies (acet- rine and epinephrine) that increase blood glucose. Source: From
oacetate, β-hydroxybutyrate, and acetone). Ketones can Figure 39.11 from Koeppen B. M., & Stanton B. A. (2018). Berne and
be used as source of energy when glucose is not avail- levy physiology (7th ed.) (p. 709). Elsevier.
able. Acetoacetate and β-hydroxybutyrate are true
acids and their accumulation in diabetic ketoacidosis
leads to an anion gap metabolic acidosis. Effects on glucose metabolism
Insulin affects glucose production and glucose utili-
Effects of insulin excess zation (Fig. 7.20).
The effect of insulin excess on glucose metabolism Insulin acts directly to limit hepatic glucose output
is hypoglycemia. Insulin lowers blood glucose in two by inhibiting the glycogenolytic enzyme glycogen
ways: it increases uptake of glucose by muscle and phosphorylase. Insulin also acts indirectly to suppress
adipose tissue and decreases the glucose output by the hepatic gluconeogenesis through several mechanisms,
liver. There is no absolute blood glucose cutoff that including decrease in the flow of gluconeogenic pre-
should be used to define hypoglycemia. In patients cursors and FFA to the liver (Fig. 7.21), inhibition of
with diabetes, hypoglycemia is defined as an episode glucagon secretion, in part by direct inhibition of the
of low blood sugar with or without symptoms that glucagon gene in the pancreatic alpha cells, and
exposes the patient to harm (usually blood glucose change in neural input to the liver.
,6070 mg/dL). In individuals without diabetes, it is Insulin stimulates glucose uptake by skeletal muscle
best to use Whipple’s triad to define hypoglycemia: (1) and fat. In these tissues, glucose transport across cell
symptoms consistent with hypoglycemia; (2) documen- membranes is mediated by glucose transporter 4
ted low plasma glucose when symptoms are present; (GLUT 4) which is located in the cytoplasm. Insulin
and (3) alleviation of symptoms by administering glu- signal causes translocation of GLUT 4 to the cell mem-
cose or glucagon. Hypoglycemia causes neurogenic brane, where it facilitates glucose entry into these tis-
and neuroglycopenic symptoms. The neurogenic sues. When blood glucose is normal, most insulin-
symptoms include tremor, palpitations, anxiety (adren- mediated glucose uptake occurs in muscle and less in
ergic symptoms), sweating, hunger, and paresthesias the adipose tissue. But adipose tissue can indirectly
(cholinergic symptoms). The neuroglycopenic symp- promote glucose utilization via insulin-mediated inhi-
toms are cognitive impairment, behavioral and motor bition of lipolysis. This occurs through the mechanism
abnormalities, loss of consciousness, seizure, and of competing substrates. When the availability of FFA
coma. as a fuel source is low, glucose uptake and metabolism

FIGURE 7.21 Effect of insulin on hepatic glucose production.

Insulin suppresses hepatic glucose production directly by inhibiting
gluconeogenesis and the breakdown of glycogen to glucose and indi-
rectly by inhibiting lipolysis by adipose tissue and inhibiting the pro-
duction of glucagon by the islet alpha cells. Source: From Figure 31-5
in Polonsky K. S., & Burant C. F. (2016). Chapter 31: Type 2 diabetes mel-
litus. In S. Melmed, K. S. Polonsky, P. R. Larsen, & H. M. Kronenberg FIGURE 7.22 Carbohydrate and lipid metabolism in adipose tis-
(Eds.), Williams textbook of endocrinology (13th ed.) (p. 1396). sue. Reactions enhanced by insulin (green arrows) are as follows: (1)
Elsevier. transport of glucose into adipose cell; (2) conversion of excess glu-
cose to glycogen; (3) decarboxylation of pyruvate; (4) initiation of
fatty acid synthesis; and (5) uptake of fatty acids from circulating
in the muscle is increased. Insulin also promotes glu- lipoproteins. Breakdown of triacylglycerols is inhibited by insulin
cose disposal within cells through its effects on glyco- (dashed red arrows). Esterification of fatty acids to triacylglycerols fol-
gen synthesis and glucose breakdown (glycolysis). lows from availability of α-glycerol phosphate.
Insulin increases the activity of glycogen synthase in
several tissues, including adipose tissue, muscle, and access to the lipid droplet by its coating of perilipin. In
liver. This action of insulin does not result in net glyco- response to stimulation, cAMP is formed and activates
gen synthesis unless glycogen phosphorylase is protein kinase A, which catalyzes phosphorylation of
strongly inhibited. Insulin stimulates the rate of glycol- both HSL and perilipin. The resulting association of
ysis in skeletal muscle and adipose tissue by increasing activated HSL with the lipid droplet dramatically
the activity of two key enzymes in the glycolytic path- increases the breakdown of triacylglycerols to fatty
way, hexokinase, and 6-phosphofructokinase. acids that can either escape from the adipocyte and
become the FFA of blood or be reesterified to
Effects on adipose tissue triacylglycerol.
Storage of fat in adipose tissue depends on multiple Fatty acid esterification requires a source of glycerol
insulin-sensitive reactions, including: (1) synthesis of that is phosphorylated in its α-carbon; free glycerol
long-chain fatty acids from glucose; (2) synthesis of cannot be used. Because adipose tissue lacks the
triacylglycerols from fatty acids and glycerol (esterifi- enzyme α-glycerol kinase, all of the free glycerol that
cation); (3) breakdown of triacylglycerols to release is produced by lipolysis escapes into the blood. The
glycerol and long-chain fatty acids (lipolysis); and (4) α-glycerol phosphate used for esterification of fatty
uptake of fatty acids from the lipoproteins of blood. acids is derived primarily from phosphorylated 3-
The relevant biochemical pathways are shown in carbon intermediates formed from oxidation of glu-
Fig. 7.22. cose. However, when glucose is in short supply, as in
Lipolysis and esterification are central events in the fasting, some α-glycerol phosphates can also be
physiology of the adipocyte. Fat, in the form of triacyl- formed from plasma lactate or alanine in a process of
glycerols, is stored in a single large droplet coated by a glyceroneogenesis that depends on the availability of
protein called perilipin. The rate of lipolysis depends the enzyme PEP carboxykinase.
largely, but not exclusively, on the activity of an As its name implies, HSL is activated by lipolytic
enzyme called HSL that catalyzes the breakdown of hormones that stimulate the formation of cAMP and
triacylglycerols into fatty acids and glycerol. In the thereby promote its phosphorylation and the phos-
absence of stimulation, lipolysis proceeds at a low basal phorylation of perilipin by protein kinase A. Insulin
rate, while HSL resides in the cytoplasm and is denied accelerates the degradation of cAMP by activating the

Insulin 221
enzyme cAMP phosphodiesterase and thus interferes There are at least five isoforms of GLUT expressed
with activation of lipolysis. Simultaneously, insulin in various cell types. The liver has GLUT 2 (Fig. 7.25).
increases the rate of fatty acid esterification by acceler- In addition to GLUT 1, which is present in the
ating glucose oxidation, which increases the availabil- plasma membrane of most cells, insulin-sensitive cells
ity of α-glycerol phosphate. The net result of these such as adipocytes contain pools of intracellular mem-
actions is preservation of triacylglycerol stores at the branous vesicles that are rich in GLUT 4 (Fig. 7.26).
expense of plasma FFA, whose concentration in blood Insulin increases the number of glucose transporters
plasma promptly falls. Decreases in FFA concentra- on the adipocyte surface by stimulating the transloca-
tions are seen with doses of insulin that are too low to tion of GLUT 4containing vesicles toward the cell
affect blood glucose and appear to be the most sensi- surface and fusion of their membranes with the adipo-
tive response to insulin. cyte plasma membrane (Fig. 7.26).
Because glucose does not readily diffuse across the Insulin accelerates synthesis of fatty acids by
plasma membrane, its entry into adipocytes and most increasing the uptake of glucose and by activating at
other cells depends on carrier-mediated transport. least two enzymes that direct the flow of glucose car-
Insulin increases cellular uptake and metabolism of bons into fatty acids. Insulin increases conversion of
glucose by accelerating transmembrane transport of pyruvate to acetyl CoA, which provides the building
glucose and structurally related sugars. This process blocks for long-chain fatty acid synthesis and stimu-
starts with the insulin receptor that has a cytosolic lates carboxylation of acetyl CoA to malonyl CoA,
tyrosine kinase domain (Fig. 7.23). which is the initial and rate-determining reaction in
This action depends upon the availability of glucose fatty acid synthesis. In humans, adipose tissue is not
transporters in the plasma membrane. Glucose trans- an important site of fatty acid synthesis, particularly in
porters (abbreviated GLUT) are large proteins that Western cultures where the diet is rich in fat. Fat
weave in and out of the membrane 12 times to form stored in adipose tissue is derived mainly from dietary
stereospecific channels through which glucose can dif- fat and tri-glycerides synthesized in the liver. Fat des-
fuse down its concentration gradient Fig. 7.24). tined for storage reaches adipose tissue in the form of
low density lipoproteins and chylomicrons. Uptake of
fat from lipoproteins depends on cleavage of ester
bonds in triacylglycerols by the enzyme lipoprotein
The cysteine-rich lipase to release fatty acids. Lipoprotein lipase is syn-
domain binds insulin thesized and secreted by adipocytes and adheres to the
endothelium of adjacent capillaries. Insulin promotes
Glycosylation site synthesis of lipoprotein lipase and thus facilitates the
transfer of fatty acids from lipoproteins to triacylgly-
S S cerol storage droplets in adipocytes.

S S Effects on muscle
S S
Insulin increases uptake of glucose by muscle and
directs its intracellular metabolism toward the forma-
tion of glycogen (Fig. 7.27).
Because muscle comprises nearly 50% of body mass,
uptake by muscle accounts for the majority of the glu-
 cose that disappears from blood after injection of insu-
lin. As in adipocytes, glucose utilization in muscle is
limited by permeability of the plasma membrane.
Insulin accelerates entry of glucose into muscle by
mobilizing GLUT 4containing vesicles by the same
Tyrosine kinase domain Phosphorylation sites mechanism that is operative in adipocytes. Metabolism
of glucose begins with conversion to glucose-6-
phosphate catalyzed by either of the two isoforms of
FIGURE 7.23 Insulin combines with its receptor on the cell mem- the enzyme hexokinase that are present in muscle.
brane of a typical cell. This activates tyrosine kinase which sets off a Insulin not only increases the synthesis of hexokinase II,
series of reactions (see Fig. 7.24) which ends up inserting one of the
but it also appears to enhance the efficiency of hexoki-
GLUT transporters into the cell membrane. Glucose is transported
on the GLUT into the cell. Source: Redrawn from Figure 51.5 from nase II activity by promoting its association with the
Barrett E. J. (2017). Chapter 51: The endocrine pancreas. In W. F. Boron, outer membrane of mitochondria, which optimizes its
& E. L. Boulpaep (Eds.) Medical physiology (3rd ed.) (p. 1042). Elsevier. access to ATP. In the basal state, glucose is

FIGURE 7.24 Glucose uptake by a cell that has been activated by insulin. The tyrosine kinase in the insulin receptor sets off a chain reac-
tion that results in GLUT 4 being incorporated into the cell membrane. Glucose can then slide down the concentration gradient into the cell
via GLUT 4 (upper left). GS, Glycogen synthetase; GSK-3, glycogen synthetase kinase 3; IF, initiation factor; PDK, phosphatidylinositol-
dependent kinase; IRS, insulin-receptor substrates; SHC, Src homology C terminus. Source: From Figure 51.6 from Barrett E. J. (2017). Chapter 51:
The endocrine pancreas. In W. F. Boron, & E. L. Boulpaep (Eds.) Medical physiology (3rd ed.) (p. 1043). Elsevier.

Insulin 223
FIGURE 7.25 The effect of insulin on a liver cell. Note that GLUT 2 is the transporter in liver. Insulin has a direct effect on the liver as it
receives blood directly from the pancreas via the hepatic portal system. Source: From Figure 51-8 Barrett E. J. (2017). Chapter 51: The endocrine
pancreas. In W. F. Boron, & E. L. Boulpaep (Eds.) Medical physiology (3rd ed.) (p. 1046). Elsevier.
phosphorylated almost as rapidly as it enters the cell, increased when it is dephosphorylated. The degree of
and hence the intracellular concentration of free glucose phosphorylation of glycogen synthase is determined by
is only about one-tenth to one-third that of extracellular the balance of kinase and phosphatase activities. Insulin
fluid. Glucose-6-P is an allosteric inhibitor of hexokinase shifts the balance in favor of dephosphorylation in part
and an allosteric activator of glycogen synthase. by inhibiting the enzyme, glycogen synthase kinase 3
Stimulation of glycogen synthesis by insulin and (GSK-3), and in part by activating a phosphatase.
glucose-6-phosphate protects hexokinase from the Dephosphorylation of glycogen synthase not only
inhibitory effect of glucose-6-phosphate when entry of increases its activity directly but also increases its
glucose into the muscle cell is rapid. Glycogen synthase responsiveness to stimulation by its substrate, glucose-
activity is low when the enzyme is phosphorylated and 6-P. Hence, the powerful effects of insulin on muscle

FIGURE 7.26 Effect of insulin on adipocytes, here being shown located in the greater omentum, the apron-like structure that covers the
abdominal surface. Source: From Figure 51-10 Barrett E. J. (2017). Chapter 51: The endocrine pancreas. In W. F. Boron, & E. L. Boulpaep (Eds.)
Medical physiology (3rd ed.) (p. 1049). Elsevier.
glycogen synthesis are achieved by the complementary by phosphofructokinase, whose activity is precisely
effects of increased glucose transport, increased glucose regulated by a combination of allosteric effectors,
phosphorylation, and increased glycogen synthase including ATP, ADP, and fructose-2,6-bisphosphate.
activity. This complex enzyme behaves differently in intact cells
The alternative fate of glucose-6-P, metabolism to and in the broken cell preparations typically used by
pyruvate in the glycolytic pathway, is also increased biochemists to study enzyme regulation. Because con-
by insulin. Access to the glycolytic pathway is guarded flicting findings have been obtained under a variety of

Insulin 225
FIGURE 7.27 Effect of insulin on muscle cells. Source: From Figure 51-9 Barrett E. J. (2017). Chapter 51: The endocrine pancreas. In W. F.
Boron, & E. L. Boulpaep (Eds.) Medical physiology (3rd ed.) (p. 1048). Elsevier.
experimental circumstances, no general agreement has insulin also increases all aspects of glucose metabolism
been reached on how insulin increases phosphofructo- in muscle as an indirect consequence of its action on
kinase activity. In contrast to the liver the isoform of the adipose tissue to decrease FFA production. When insu-
enzyme that forms fructose-2,6-bisphosphate in muscle lin concentrations are low, increased oxidation of fatty
is not regulated by cAMP. The effects of insulin are acids decreases oxidation of glucose by inhibiting the
likely to be indirect. decarboxylation of pyruvate and the transport of glu-
It should be noted that oxidation of fat profoundly cose across the muscle cell membrane. In addition,
affects the metabolism of glucose in muscle and that products of fatty acid oxidation appear also to inhibit

across the plasma membrane accompanied by sodium

ions by a process of secondary active transport that is
driven by the favorable electrochemical gradient for
sodium. The sodium gradient is preserved by the opera-
tion of the sodium/potassium ATPase in the plasma
membrane. Each cycle of this “sodium pump” extrudes
three ions of sodium into the extracellular space in
exchange for two ions of potassium. Insulin increases
sodium pumping activity by recruiting pump molecules
to the plasma membrane and by promoting their phos-
phorylation. Because more positively charged ions (Na 1 )
are extruded than enter (K 1 ), the cell interior becomes
more negative with respect to the extracellular fluid, and
the electrochemical driving force for sodium-coupled
amino acid uptake is increased. The effects of insulin on
the sodium pump are of considerable clinical importance.
Because normal plasma potassium concentrations are
FIGURE 7.28 Effects of insulin on protein turnover in muscle. quite low (B4 mM/L), transfer of even small amounts
Reactions stimulated by insulin are shown in green. The dashed red into muscle may produce relatively large decreases in
arrows indicate reactions inhibited by insulin. plasma concentrations and may lead to cardiac arrhyth-
mias and other problems.
Protein synthesis requires the attachment of mRNA to
hexokinase, but recent studies have called into ques- ribosomes. Insulin stimulates phosphorylation and hence
tion the relevance of earlier findings that fatty acid oxi- the activity of the eukaryotic initiation factor 4 (eIF4),
dation may inhibit phosphofructokinase. Insulin not which plays a pivotal role in the binding of mRNA to
only limits the availability of fatty acids but also inhi- ribosomes. Initiation of the synthesis of any particular
bits their oxidation. Insulin increases the formation of protein begins with the engagement of methionine-
malonyl CoA, which blocks entry of long-chain fatty loaded transfer RNA with the start codon in its mRNA.
acids into the mitochondria as described for liver This engagement depends on the eukaryotic initiation
(Fig. 7.23). These effects are discussed further in factor 2 (eIF2), which is inactive when phosphorylated.
Chapter 8, Hormonal Regulation of Fuel Metabolism. One of the enzymes that catalyzes its phosphorylation is
Protein synthesis and degradation are ongoing pro- GSK, which, as already mentioned, is inhibited by insu-
cesses in all tissues and in the nongrowing individual lin. By inactivating GSK, insulin accelerates dephosphor-
are completely balanced so that on average there is no ylation of eIF2. Elongation of the nascent protein
net increase or decrease in body protein (Fig. 7.28). requires the stepwise translocation of the ribosome along
Insulin intercedes in protein turnover at several the mRNA after the addition of each amino acid. This
levels and has both rapid and delayed effects. One of process is governed by elongation factors that insulin
the hallmarks of insulin deficiency is the massive also activates by inhibiting the kinase that catalyzes their
breakdown of muscle protein. Protein degradation phosphorylation. On a longer time scale, insulin
begins with the attachment of ubiquitin to the protein increases synthesis of ribosomal RNA.
molecules destined for breakdown. Ubiquitinated pro-
teins enter the proteasomes and are cleaved to small Effects on liver
fragments that subsequently are hydrolyzed to their Insulin reduces outflow of glucose from the liver
amino acid constituents in the lysosomes. Insulin and promotes its storage as glycogen. It inhibits glyco-
reduces the protein degrading activity of the ubiqui- genolysis, gluconeogenesis, ureagenesis, and ketogene-
tinproteasomal system by decreasing expression of sis, and it stimulates the synthesis of fatty acids and
ubiquitin conjugating enzymes and by modulating the proteins. These effects are accomplished by a combina-
protease activity of its components. tion of actions that change the activity of some hepatic
Protein synthesis is a complex process that begins with enzymes and rates of synthesis of other enzymes.
adequate supplies of amino acids to charge the transfer Hence, not all the effects of insulin occur on the same
RNA molecules that deliver them to the protein synthetic timescale. Although we use the terms “block” and
apparatus. Insulin stimulates the transport of amino acids “inhibit” to describe the actions of insulin, it is impor-
from blood into muscle cells by recruiting carrier mole- tant to remember that these verbs are used in the rela-
cules to the plasma membrane in a manner analogous to tive and not the absolute sense. Rarely would
the recruitment of GLUT 4. Amino acids are transported inhibition of an enzymatic transformation be absolute.

Insulin 227
FIGURE 7.29 Changes in insulin and glucagon in plasma and carbohydrate metabolism in normal subjects following ingestion of a liquid
meal rich in carbohydrate. Although secretion of both insulin and glucagon was stimulated, insulin increased about 25-fold, while glucagon
increased only 3-fold so that the ratio of glucagon to insulin fell dramatically. Plasma glucose increased transiently, but release of glucose
from the liver fell precipitously, and liver glycogen increased. Source: From Taylor, R., Magnusson, I., Rothman, D. L., Cline, D.W., Caumo, A.,
Cobelli, C., & Shulman, G. L. (1996). Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose
homeostasis after a mixed meal in normal subjects. Journal of Clinical Investigation 97, 126132, with permission.
In addition, all the hepatic effects of insulin are rein- hepatocytes depends upon the high-capacity insulin-
forced indirectly by actions of insulin on muscle and insensitive glucose transporter, GLUT 2. Because the
fat to reduce the influx of substrates for gluconeogene- movement of glucose is passive, net uptake or release
sis and ketogenesis (Figs. 7.25 and 7.29). depends upon whether the concentration of free glu-
The actions of insulin on hepatic metabolism are cose is higher in extracellular or intracellular fluid. The
always superimposed on a background of other regu- intracellular concentration of free glucose depends on
latory influences exerted by metabolites, glucagon, and the balance between phosphorylation and dephosphor-
a variety of other regulatory agents. The magnitude of ylation of glucose (Fig. 7.30, cycle II). The two enzymes
any change produced by insulin thus is determined that catalyze phosphorylation are hexokinase, which
not only by the concentration of insulin but also by the has a high affinity for glucose and other 6-carbon
strength of the opposing or cooperative actions of sugars, and glucokinase, which is specific for glucose.
these other influences. Rates of secretion of both insu- The kinetic properties of glucokinase are such that
lin and glucagon are dictated by physiological phosphorylation increases proportionately with glu-
demand. Because of their antagonistic influences on cose concentration over the entire physiological range.
hepatic function, however, it is the ratio rather than In addition, glucokinase activity is regulated by glu-
the absolute concentrations of these two hormones that cose. When glucose concentrations are low, much of
determines the overall hepatic response (Fig. 7.30). the glucokinase is bound to an inhibitory protein that
sequesters it within the nucleus. An increase in glucose
concentration releases glucokinase from its inhibitor
Glucose production and allows it to move into the cytosol where glucose
In general, liver takes up glucose when the circulat- phosphorylation can take place.
ing concentration is high and releases it when the Phosphorylated glucose cannot pass across the
blood level is low. Glucose transport into or out of hepatocyte membrane. Dephosphorylation of glucose

and phosphorylation by glucokinase is only one source

of glucose-6-P. Glucose-6-P is also produced by glyco-
genolysis and gluconeogenesis. Insulin not only inhi-
bits these processes, but it also drives them in the
opposite direction. Most of the hepatic actions of insu-
lin are opposite to those of glucagon, discussed earlier,
and can be traced to inhibition of cAMP accumulation.
Rapid actions of insulin largely depend on changes in
the phosphorylation state of enzymes already present
in hepatocytes. Insulin decreases hepatic concentra-
tions of cAMP by accelerating its degradation by
cAMP phosphodiesterase and may also interfere with
cAMP formation and perhaps, activation protein
kinase A. The immediate consequences can be seen
in Fig. 7.28 and are in sharp contrast to the changes in
glucose metabolism produced by glucagon shown in
Fig. 7.11. Insulin promotes glycogen synthesis and
inhibits glycogen breakdown. These effects are accom-
plished by the combination of interference with
cAMPdependent processes that drive these reactions
in the opposite direction (Fig. 7.12); inhibition of glyco-
gen synthase kinase, which, like protein kinase A, inac-
tivates glycogen synthase; and by activation of the
phosphatase that dephosphorylates both glycogen
synthase and phosphorylase. The net effect is that
glucose-6-P is incorporated into glycogen.
By lowering cAMP concentrations, insulin decreases
the breakdown and increases the formation of
fructose-2,6-phosphate, which potently stimulates
phosphofructokinase and promotes the conversion of
glucose to pyruvate. Insulin affects several enzymes in
the PEP substrate cycle (Fig. 7.30, cycle IV) and in so
doing directs substrate flow away from gluconeogene-
sis and toward lipogenesis (Fig. 7.31).
With relief of inhibition of pyruvate kinase, PEP
can be converted to pyruvate, which then enters mito-
chondria. Insulin activates the mitochondrial pyru-
vate dehydrogenase enzyme complex that catalyzes
decarboxylation of pyruvate to acetyl CoA. Insulin
also indirectly accelerates this reaction by decreasing
FIGURE 7.30 Effects of insulin on glucose metabolism in hepato-
the inhibition imposed on it by fatty acid oxidation.
cytes. Green arrows indicate reactions that are increased, and dashed Decarboxylation of pyruvate to acetyl CoA irrevers-
red arrows indicate reactions that are decreased. ibly removes these carbons from the gluconeogenic
pathway and makes them available for fatty acid syn-
thesis. The roundabout process that transfers acetyl
requires the activity of glucose-6-phosphatase. Insulin carbons across the mitochondrial membrane to the
suppresses synthesis of glucose-6-phosphatase and cytoplasm, where lipogenesis occurs, requires con-
increases synthesis of glucokinase, thereby decreasing densation with oxaloacetate to form citrate. Citrate is
net output of glucose while promoting net uptake. transported to the cytosol and cleaved to release ace-
This response to insulin is relatively sluggish and con- tyl CoA and oxaloacetate. It might be recalled from
tributes to long-term adaptation rather than to minute- earlier discussion that oxaloacetate is a crucial inter-
to-minute regulation. The rapid effects of insulin to mediate in gluconeogenesis and is converted to PEP
suppress glucose release are exerted indirectly through by PEP carboxykinase. Insulin bars the flow of this
decreasing the availability of glucose-6-phosphate, lipogenic substrate into the gluconeogenic pool by
hence starving the phosphatase of substrate. Uptake inhibiting synthesis of PEP carboxykinase. The only

Insulin 229
fate left to cytosolic oxaloacetate is decarboxylation to
pyruvate.
Finally, insulin increases the activity of acetyl CoA
carboxylase, which catalyzes the rate determining reac-
tion in fatty acid synthesis. Activation is accomplished
in part by relieving cAMPdependent inhibition and in
part by promoting the polymerization of inactive subu-
nits of the enzyme into an active complex. The resulting
malonyl CoA not only condenses with acetyl CoA to
form long-chain fatty acids but also prevents oxidation
of newly formed fatty acids by blocking their entry into
mitochondria (Fig. 7.27). On a longer timescale, insulin
increases the synthesis of acetyl CoA carboxylase.
It may be noted that hepatic oxidation of either glu-
cose or fatty acids increases delivery of acetyl CoA to
the cytosol, but ketogenesis results only from oxidation
of fatty acids. The primary reason is that lipogenesis
usually accompanies glucose utilization and provides
an alternate pathway for disposal of acetyl CoA. There
is also a quantitative difference in the rate of acetyl CoA
production from the two substrates: 1 mol of glucose
yields only 2 mol of acetyl CoA compared to 8 or 9 mol
FIGURE 7.31 Effects of insulin on lipogenesis in hepatocytes.
for each mole of fatty acids. The effects of insulin on
Green arrows indicate reactions that are increased, and the dashed
red arrow indicates a reaction that is decreased. (1) Pyruvate kinase, glucose, fat, ketone, and protein metabolism are sum-
(2) pyruvate dehydrogenase, (3) acetyl CoA carboxylase, and (4) fatty marized in Table 7.3 and a comparison of the metabolic
acid synthase. effects of insulin and glucagon is outlined in Table 7.4.
TABLE 7.3 The effects of insulin on glucose, fat, ketone, and protein metabolism.
Insulin effects on glucose metabolism
Inhibition of glycogenolysis
Inhibition of gluconeogenesis
Stimulation of glucose transport into fat and muscle

Increase of glycolysis in fat and muscle
Stimulation of glycogen synthesis
Insulin effects on fat metabolism
Increase clearance from circulation of triglyceride-rich chylomicrons via lipoprotein lipase
Stimulation of reesterification of free fatty acids into triglycerides within fat cells
Inhibition of lipolysis of triglyceride stores by inhibiting hormone-sensitive lipase

Insulin effects on ketone body metabolism
Reduction of circulating ketone bodies by decreasing the supply of free fatty acids to the liver (decrease of lipolysis)
Inhibition of ketogenesis in the liver
Enhancement of peripheral clearance of ketone bodies
Insulin effects on protein metabolism
Stimulation of protein synthesis

Inhibition of protein breakdown (proteolysis)
Inhibition of urea formation

TABLE 7.4 Comparison of the metabolic effects of insulin and substrates (IRS-1, IRS-2, IRS-3, and IRS-4). These rela-
glucagon. tively large proteins contain multiple tyrosine phos-
Insulin Glucagon phorylation sites and act as scaffolds upon which
other proteins are assembled to form large signaling
Glycogen synthesis m k complexes. IRS-1 and IRS-2 appear to be present in all
Glycolysis m k insulin target cells, whereas IRS-3 and IRS-4 have
Glycogenolysis k m
more limited distributions. Despite their names the IRS
proteins are not functionally limited to transduction of
Gluconeogenesis k m the insulin signal but participate in expression of the
Lipogenesis m k effects of other hormones and growth factors.
Lipolysis k m
Moreover, they are not the only substrates for the insu-
lin receptor kinase.
Ketogenesis k m Two other scaffold proteins called Shc and Cbl serve
Protein synthesis m k a similar function. A variety of other proteins that are
tyrosine phosphorylated by the insulin receptor kinase
have also been identified. Proteins recruited to the
insulin receptor and IRS proteins may have enzymatic
Mechanism of insulin action activity or they may have a coupling function by pro-
The many changes that insulin produces at the viding binding sites for recruiting other proteins. The
molecular level—membrane transport, enzyme activa- assemblage of proteins initiates signaling cascades that
tion, gene transcription, and protein synthesis—have ultimately express the various actions of insulin
been described. The molecular events that link these described earlier.
changes to the interaction of insulin and its receptor are One of the most important of the proteins that is
still incompletely understood, although much progress activated is phosphatidylinositol-3 (PI3) kinase. PI3
has been made in recent years. More than a hundred kinase plays a critical role in activating many down-
different molecules have already been identified as par- stream effector molecules, including protein kinase B
ticipants in the complex panoply of events entrained by (also called AKT), which mediates the effects of insulin
the activated insulin receptor. Transduction of the insu- on glycogen synthesis and GLUT 4 translocation. Like
lin signal is not accomplished by a linear series of bio- the IRS proteins, PI3 kinase also is activated by a vari-
chemical changes, but rather multiple intracellular ety of other hormones, cytokines, and growth factors
signaling pathways are activated simultaneously and whose actions do not necessarily mimic those of insu-
may intersect at one or more points before the final lin. The uniqueness of the response to insulin probably
result is expressed. reflects the unique combination of biochemical conse-
The insulin receptor is a tetramer composed of two α- quences produced by the simultaneous activity of mul-
and two β-glycoprotein subunits that are held together tiple signaling pathways and the particular set of
by disulfide bonds that link the α subunits to each other effector molecules expressed in insulin target cells.
and to the β subunits (Fig. 7.23). The α and β subunits of Insulin is known to regulate expression of more than
insulin are encoded in a single gene that contains 22 150 genes, but the functions of many of the proteins
exons. The α subunits are completely extracellular and encoded by these genes and how the receptor commu-
contain the insulin-binding domain. The β subunits span nicates with these regulatory proteins is under extensive
the plasma membrane and contain tyrosine kinase activ- study. Fig. 7.32 presents a simplified map of some of
ity in the cytosolic domain. Binding to insulin is thought the signaling pathways that produce the cellular
to produce a conformational change that relieves each β responses to insulin.
subunit from the inhibitory effects of the α subunit,
allowing it to phosphorylate itself and other proteins at
tyrosine residues. Autophosphorylation of the kinase
Regulation of insulin secretion
domain is required for full activation. Tyrosine phos- As might be expected of a hormone whose physio-
phorylation of the receptor also provides docking sites logical role is promotion of fuel storage, insulin secre-
for other proteins that participate in transducing the hor- tion is greatest immediately after eating and decreases
monal signal. Docking on the phosphorylated receptor during between-meal periods (Fig. 7.33).
may position proteins optimally for phosphorylation by Coordination of insulin secretion with nutritional
the receptor kinase. state as well as with fluctuating demands for energy
Among the proteins that are phosphorylated on production is achieved through stimulation of beta cells
tyrosine residues by the insulin receptor kinase are by metabolites, hormones, and neural signals. Because
four cytosolic proteins called insulin receptor insulin plays the primary role in regulating storage and

Insulin 231
FIGURE 7.32 Simplified model of insulin signaling pathways. The insulin receptor proteins (IRS 1,2,3,4), Cbl, Shc, and the β subunits of
the insulin receptor are phosphorylated on tyrosine residues by the insulin receptor kinase and serve as anchoring sites for cytosolic proteins
that form signaling cascades. Proteins shown in blue boxes are serine/threonine kinases. Specific isoforms and/or subunits are not shown nor
are the relevant phosphatases. Cbl, Cacitas B lineage lymphoma protein; ERK, extracellular receptor kinase; GSK, glycogen synthase kinase;
mTOR, mammalian target of rapamycin; PDE, phosphodiesterase; PDK, phosphoinositide-dependent kinase; PI3K, phosphoinositol-3-kinase;
PKB, protein kinase B; RAS, Ras oncogene, a small G-protein; Shc, Src homology containing protein; α PKC, α isoform of protein kinase C.
mobilization of metabolic fuels, the beta cells must be In the normal individual, its concentration in blood
constantly apprised of bodily needs, not only with is maintained within the narrow range of about 70 or
regard to feeding and fasting, but also to the changing 80 mg/dL after an overnight fast to about 150 mg/dL
demands of the environment. Energy needs differ immediately after a glucose-rich meal. When blood
widely when an individual is at peace with the sur- glucose increases, insulin secretion increases propor-
roundings and when (s)he is fighting for survival. tionately. At low concentrations of glucose, adjust-
Maintaining constancy of the internal environment is ments in insulin secretion are influenced most heavily
achieved through direct monitoring of circulating meta- by other stimuli (see next) that act as amplifiers or
bolites by beta cells themselves. This input can be over- inhibitors of the effects of glucose. The effectiveness of
ridden or enhanced by hormonal or neural signals that these agents therefore decreases as glucose concentra-
prepare the individual for rapid storage of an influx of tion decreases.
food or for massive mobilization of fuel reserves to per-
mit a suitable response to environmental demands.
Other circulating metabolites
Amino acids are important stimuli for insulin secre-
Glucose tion. The transient increase in plasma amino acids after
Glucose is the most important regulator of insulin a protein-rich meal is accompanied by increased secre-
secretion (Fig. 7.34). tion of insulin. Arginine, lysine, and leucine are the

FIGURE 7.33 Changes in the concentrations of plasma glucose, IRG, and IRI throughout the day. Values are the mean 6 SEM (n 5 4). IRG,
immunoreactive glucagon; IRI, immunoreactive insulin. Source: From Tasaka, Y., Sekine, M., Wakatsuki, M., Ohgawara, H., & Shizume, K. (1975).
Levels of pancreatic glucagon, insulin and glucose during twenty-four hours of the day in normal subjects. Hormone and Metabolic Research 7, 205206.
FIGURE 7.34 Insulin secretion by isolated human pancreatic islets in response to increasing concentrations of glucose. (A) Stimulus:response
curve. The threshold for increased secretion in vivo may be somewhat higher than between 1 and 3 mM/L shown here. (B) Insulin secretion in
response to a sudden rise in glucose concentration has two phases: an early transient spike followed by a sustained plateau. Source: Drawn from the
data of Henquin, J. C., Dufrane, D., & Nenquin, M. (2006). Nutrient control of insulin secretion in isolated normal human islets. Diabetes, 55, 34703477.
most potent amino acid stimulators of insulin secretion. are adequate. Failure to increase insulin secretion when
Insulin secreted at this time may facilitate storage of die- glucose is in short supply prevents hypoglycemia that
tary amino acids as protein and prevents their diversion might otherwise occur after a protein meal that contains
to gluconeogenesis. Amino acids are effective signals for little carbohydrate. Fatty acids and ketone bodies may
insulin release only when blood glucose concentrations also increase insulin secretion, but only when they are

Insulin 233
present at rather high concentrations. Because fatty acid
mobilization and ketogenesis are inhibited by insulin,
their ability to stimulate insulin secretion provides a
feedback mechanism to protect against excessive mobili-
zation of fatty acids and ketosis.
Hormonal and neural control

In response to carbohydrate in the lumen, the intes-
tinal mucosa secretes at least two hormones, called
incretins, that reach the pancreas through the general
circulation and stimulate the beta cells to release insu-
lin even though the increase in blood glucose is still
quite small (see Fig. 6.35). Incretins are thought to act
by amplifying the stimulatory effects of glucose. This
FIGURE 7.35 Metabolic, hormonal, and neural influences on
anticipatory secretion of insulin prepares tissues to insulin secretion.
cope with the coming influx of glucose and dampens
what might otherwise be a large increase in blood
sugar. Various gastrointestinal hormones, including directly evoke a secretory response, basal insulin secre-
gastrin, secretin, CCK, glucagon-like peptide (GLP-1), tion is increased when it is present in excess, and beta
and glucose-dependent insulinotropic peptide (GIP), cells become hyperresponsive to signals for insulin
can evoke insulin secretion when tested experimen- secretion. Excessive secretion of growth hormone or
tally, but of these hormones, only GLP-1 and GIP cortisol decreases tissue sensitivity to insulin and pro-
appear to be physiologically important incretins. vokes compensatory increases in both basal and stimu-
Secretion of insulin in response to food intake is lated secretion. These hormones can produce transient
also mediated by a neural pathway. The taste or smell or even permanent diabetes when beta cells are over-
of food or the expectation of eating may increase insu- taxed (see Chapter 8: Hormonal Regulation of Fuel
lin secretion during this cephalic phase of feeding. Metabolism). In high concentrations, glucocorticoids
Parasympathetic fibers in the vagus nerve stimulate may directly inhibit insulin synthesis and secretion
beta cells by releasing acetylcholine or the neuropep- and may even cause beta cell apoptosis, but paradoxi-
tide VIP. Activation of this pathway is initiated at inte- cally, perhaps, insulin secretion is reduced when corti-
grative centers in the brain and involves input from sol or growth hormone are deficient. The adipose
sensory endings in the mouth, stomach, small intes- hormone leptin (see Chapter 8: Hormonal Regulation
tine, and portal vein. An increase in the concentration of Fuel Metabolism) also inhibits insulin gene expres-
of glucose in portal blood is detected by glucose sen- sion. Factors that regulate insulin secretion are shown
sors in the wall of the portal vein and the information in Fig. 7.35.
is relayed to the brain via vagal afferent nerves. In
response, vagal efferent nerves stimulate the pancreas Cellular events
to secrete insulin and the liver to take up glucose.
Insulin secretion is virtually shut off by epinephrine Beta cells increase their rates of insulin secretion
or norepinephrine delivered to beta cells by either the within a few seconds of exposure to increased concen-
circulation or sympathetic neurons. This inhibitory trations of glucose and can shut down secretion as rap-
effect is seen not only as a response to low blood glu- idly. Secretion in response to a sudden increase in
cose but may occur even when the blood glucose level glucose takes place in two distinct phases (Fig. 7.32B):
is high. It is mediated through α2-adrenergic receptors an initial short-lived burst followed by a lower, but
on the surface of beta cells. Physiological circum- sustained rate that lasts as long as the glucose concen-
stances that activate the sympathetic nervous system tration is elevated. Insulin secreted in the first phase is
thus can shut down insulin secretion and thereby released from storage granules that are already primed
remove the major restraint on mobilization of meta- and docked at fusion sites on the plasma membrane
bolic fuels needed to cope with an emergency. (see Chapter 1: Introduction). These granules are part
Secretory activity of beta cells is also enhanced by of the “readily releasable pool” that may account for
growth hormone and prolactin by mechanisms that are about 5% of the granules stored in the beta cell. The
not yet understood. During pregnancy and lactation second phase of secretion represents the rate of replen-
the capacity for insulin secretion is greatly enhanced ishment of the readily releasable pool by storage gran-
(see Chapter 14: Hormonal Control of Pregnancy and ules from the larger “reserve pool” located deeper in
Lactation). Although growth hormone does not the cytosol and the requisite docking at specific sites

on the membrane, priming, and ultimately fusion and KATP channels are octamers composed of four pore-
hormone release. In normal beta cells the reserve pool forming subunits bound to four regulatory subunits
is large enough to sustain maximal rates of secretion called sulfonylurea receptors (SUR). The SUR subunits
for prolonged periods without a need for de novo syn- are so named for their role in the action of a class of
thesis, but signals that increase secretion also activate drugs, the sulfonylureas, that stimulate insulin secre-
insulin gene expression and ensure that the reserve tion. These channels are activated (opened) by
pool is replenished. MgADP, which binds to the regulatory subunits, and
The event that triggers insulin secretion is an influx inhibited (closed) by ATP, which binds to the pore-
of extracellular calcium through voltage-sensitive forming subunits. When blood glucose concentrations
channels. Secretion of insulin in both phases depends are low, the effects of ADP predominate even though
upon increased intracellular calcium and is amplified its concentration in beta cell cytoplasm is less than a
by processes that are sensitive to the availability of third that of ATP. When glucose concentrations
extracellular glucose, hormonally induced cAMP and increase, accelerated oxidation of glucose increases the
other second messengers, and to both intracellular and rate of phosphorylation of ADP to ATP. As a result,
extracellular lipids and other metabolites. Normal beta the inhibitory effects of ATP become dominant
cells secrete insulin in a pulsatile manner with each (Fig. 7.36).
pulse coinciding with a transient increase in cytosolic Closure of the KATP channels results in accumula-
calcium. The cellular mechanisms that govern these tion of positive charge in the cells and causes the mem-
complex events are the subject of intense investigation brane to depolarize. Voltage-sensitive calcium
motivated by the growing need to develop therapeutic channels open when the depolarizing membrane
approaches to correct beta cell dysfunction in type 2 potential reaches about 250 mV. Influx of positively
diabetes. charged calcium produces a transient reversal of the
The question of how the concentration of glucose is membrane potential. This increase in cytosolic calcium
monitored and translated into rates of insulin secretion inhibits voltage-sensitive calcium channels and acti-
has not been answered completely, but many of the vates calcium-sensitive and voltage-sensitive potas-
important steps are known. The beta cell has specific sium channels allowing potassium to exit and the cell
receptors for hormones and neurotransmitters that to repolarize briefly. Calcium may exit the cells via the
augment or inhibit secretion, but it does not have spe- action of calcium ATPases (calcium pumps) in the
cific receptors for glucose. To stimulate insulin secre- plasma membrane. Electrical recording of these events
tion, glucose must be metabolized by the beta cell, reveals a pattern of voltage changes that resembles an
indicating that some consequence of glucose oxidation, action potential. Oscillations in membrane potential
rather than glucose itself, is the critical determinant. thus produced are accompanied by oscillations in cyto-
Glucose enters the cells on two transporters, GLUT 1 solic calcium concentrations and bursts of insulin
and GLUT 2, which have a high capacity, but rela- secretion. The frequency and duration of electrical dis-
tively low affinity for glucose. At plasma concentra- charges in beta cells increase as glucose concentrations
tions at or above about 100 mg/dL, glucose enters the increase.
beta cell primarily on GLUT 2 at a rate that is deter- The role of calcium is not limited to triggering insu-
mined by its concentration and not by the capacity of lin release from storage granules that are poised to
transporters. Glucose can potentially cross the cell fuse with the plasma membrane. The increase in cyto-
membrane 100 times faster than it can be phosphory- solic calcium also stimulates further release of calcium
lated. Glucokinase, which catalyzes the rate determin- from endoplasmic reticulum stores by a process
ing reaction for glucose metabolism, has the requisite known as calcium-induced calcium release. Calcium
kinetic characteristics to behave as a glucose sensor. has multiple roles in mobilizing and priming storage
Mutations that affect its function result in decreased granules to replenish the readily releasable pool.
insulin secretion in response to glucose and may be Acting in conjunction with calmodulin, calcium also
severe enough to cause a form of diabetes. Increased activates adenylyl cyclase and cAMP formation. cAMP
metabolism of glucose results in increased phosphory- stimulates insulin secretion at multiple steps in the
lation of adenosine diphosphate (ADP) to form adeno- exocytotic pathway by activating both protein kinase
sine triphosphate (ATP). A and a guanine nucleotide exchange factor (EPAC,
Glucose metabolism and calcium influx are linked see Chapter 1: Introduction) that, in turn, activates
by their mutual relationship to cellular concentrations small G-protein regulators of granule translocation and
of ATP and ADP. In resting beta cells, efflux of potas- fusion with the plasma membrane.
sium through open ATP-sensitive potassium channels The increase in cytosolic calcium is mirrored by an
(KATP) offsets the slow influx of positive charge and increase in calcium within mitochondria whose role in
maintains the membrane potential at about 270 mV. amplifying insulin secretion extends beyond supplying

Insulin 235
FIGURE 7.36 Triggering of insulin secretion by glucose. (A) “Resting” beta cell (blood glucose ,100 mg/dL). ADP/ATP ratio is high
enough so that ATP-sensitive potassium channels (KATP) are open, and the membrane potential is about 70 mV. VSCC and CSKC are closed.
(B) Beta cell response to increased blood glucose. Increased entry and metabolism of glucose decreases the ratio of ADP/ATP, and KATP chan-
nels close. VSCC are activated; calcium enters and stimulates insulin secretion. Mitochondrial metabolites formed in response to glucose and
calcium amplify secretion. Influx of calcium inhibits VSCC and activates calcium-sensitive and voltage-sensitive potassium channels, thereby
allowing the cell membrane to repolarize and calcium channels to close. Calcium is extruded by membrane calcium ATPase. Persistence of
high glucose results in repeated spiking of electrical discharges and oscillation of intracellular calcium concentrations. CSKC, Calcium-
sensitive potassium channels; VSCC, voltage-sensitive calcium channels.
the requisite ATP. Increased intramitochondrial cal- contribute to both the triggering and amplifying aspects
cium increases the activity of pyruvate dehydrogenase of insulin secretion remain subjects of active
and other dehydrogenases that are critical for generat- investigation.
ing metabolites that modulate insulin secretion. In addition to stimulating insulin secretion, glucose
Pyruvate is the major product of glycolysis and may is the most important stimulator of insulin synthesis.
be decarboxylated by the pyruvate dehydrogenase Both glucose and cAMP increase transcription of the
complex to form acetyl CoA or carboxylated to form insulin gene, and glucose stabilizes the mRNA tran-
oxaloacetate within the mitochondria. These two pro- script. The mRNA template for insulin turns over
ducts can then combine to form citrate, which, upon slowly and has a half-life of about 30 hours.
transfer to the cytosol, serves as a precursor of malonyl Hyperglycemia prolongs its half-life more than two-
CoA and other metabolic regulators of islet cell fold, while hypoglycemia accelerates its degradation.
metabolism. In addition, glucose increases translation of the proin-
Unstimulated beta cells derive the bulk of their sulin mRNA by stimulating both the initiation and
energy from the oxidation of long-chain fatty acids, but elongation reactions. Concurrently, glucose also upre-
malonyl CoA blocks access of fatty acid CoA to intrami- gulates production of the convertase enzymes that pro-
tochondrial sites of oxidation and switches beta cells to cess proinsulin to insulin.
use glucose as their primary fuel. Long-chain fatty acids
that accumulate in the cytosol amplify insulin secretion Effects of incretins
through their effects on secretory granule trafficking GIP and GLP-1 (see Chapter 6: Hormones of the
and the activities of enzymes and ion channels. Fatty Gastrointestinal Tract) are secreted by K and L cells of
acids are also converted to more complex lipids that the intestinal mucosa in response to luminal nutrients.
appear to have additional signaling functions. Other They activate specific G proteincoupled receptors on
metabolites derived from citrate and amino acids or beta cells to accelerate glucose-dependent insulin
arising from mitochondrial transformations that secretion in a manner that blunts the increase in

to the effects of calcium and promote both secretion of

insulin from the readily releasable pool and its replen-
ishment from the reserve pool.
On a longer timescale, GLP-1 in conjunction with glu-
cose increases transcription of the insulin gene and stabi-
lizes its mRNA transcript. Prolonged stimulation with
GLP-1 increases islet cell mass by stimulating prolifera-
tion of beta cells and by inhibiting apoptosis. Some data
indicate that GLP-1 may also stimulate beta cell develop-
ment from precursor stem cells. GLP-1 receptor agonists
are a novel class of antihyperglycemic medications used
in management of type 2 diabetes. All the actions of
GLP-1 are shared by GIP, but receptors for GIP tend to
be downregulated by hyperglycemia.
Effects of other hormones and neurotransmitters

Acetylcholine and CCK, whose receptors are coupled
through Gαq to phospholipase C, stimulate insulin
secretion by way of the IP3/DAG second messenger sys-
tem. IP3 stimulates release of calcium from intracellular
storage sites and thus augments the influx of extracellu-
lar calcium triggered by metabolism of glucose. In addi-
tion, activated protein kinase C enhances aspects of the
secretory process that are both dependent and indepen-
dent of calcium. Receptors for norepinephrine and
FIGURE 7.37 Major acute cellular actions of incretins. GLP-1 and
somatostatin are coupled to the inhibitory guanine
GIP acting through G peptidecoupled receptors activate adenylyl
cyclase to increase intracellular concentrations of cAMP. cAMP nucleotide-binding protein Gi and block insulin secre-
increases the activity of protein kinase A or binds to a GTP exchange tion primarily by inhibiting adenylyl cyclase and lower-
factor to increase cytosolic calcium and enhance the effects of cal- ing cAMP. Through the effects on ion channels, the βγ
cium of insulin secretion. cAMP, Cyclic AMP; ER, endoplasmic retic- subunits of the somatostatin receptor may also cause the
ulum; GIP, glucose-dependent insulinotropic peptide; GLP-1,
plasma membrane to hyperpolarize and hence prevent
glucagon-like peptide 1; GTP, guanosine triphosphate; KATP, ATP-
sensitive potassium channels; KV, voltage-sensitive potassium chan- activation of voltage-sensitive calcium channels.
nels; RP, reserve pool of secretory granules; VSCC, voltage-sensitive
calcium channels. See text for details.
Somatostatin
plasma glucose concentration produced by intestinal
absorption. Stimulation of beta cells by these agents Although somatostatin produced in delta cells is the
may account for as much as 60% of the insulin secreted third most abundant of the pancreatic islet hormones,
each day. Activation of GLP-1 and GIP receptors and the physiological importance of pancreatic somato-
the subsequent production of cAMP enhance glucose- statin is not understood. Its major role may be as a
dependent insulin secretion at multiple sites in the sti- paracrine regulator of insulin and glucagon secretion.
mulationsecretion pathway (Fig. 7.37). Somatostatin originally was isolated from hypotha-
At the level of the plasma membrane, lamic extracts that inhibited the secretion of growth
cAMPdependent phosphorylation of channel proteins hormone. It is found in many secretory cells (delta
facilitates closure KATP in response to ATP and cells) outside of the pancreatic islets, particularly in the
impedes opening of the voltage-sensitive K channels lining of the gastrointestinal tract (see Chapter 6:
that contribute to repolarization. At the same time, Hormones of the Gastrointestinal Tract), and is widely
cAMPdependent phosphorylation partially activates distributed in many neural tissues where it presum-
the voltage sensitive calcium channels and prolongs ably functions as a neurotransmitter. Measurable
their open state. Together these effects magnify the increases in somatostatin concentration can be found
influx of calcium produced by increases in plasma glu- in peripheral blood after ingestion of a meal rich in fat
cose. cAMPdependent release of calcium from intra- or protein, with the vast majority secreted by intestinal
cellular stores further augments the increase in cells rather than islet cells. It is cleared rapidly from
cytosolic calcium. In addition to increasing cytosolic the blood and has a half-life of only about 3 minutes.
calcium, the incretins sensitize the secretory apparatus Further discussion of somatostatin is found in

Suggested readings 237
Chapter 2, Pituitary Gland, Chapter 6, Hormones of Polonsky, K. S., & Burant, C. F. (2017). Type 2 diabetes mellitus. In S.
the Gastrointestinal Tract, and Chapter 11, Hormonal Melmed, K. S. Polonsky, P. R. Larson, & H. M. Kronenberg
(Eds.), Williams textbook of endocrinology (13th ed., pp. 13861450).
Control of Growth. Philadelphia, PA: Elsevier.
Summary Advanced information

Downie, M. L., Ulrich, E. H., & Noone, D. G. (2018). An update on
The pancreas is divided into two parts: an exocrine hypertension in children with type 1 diabetes. Canadian Journal of
part for the digestion of food and an endocrine part for Diabetes, 42(2), 199204. Available from https://doi.org/10.1016/
j.jcjd.2018.02.008.
the regulation of blood glucose and potassium, the results
Nambam, B., & Haller, M. J. (2016). Updates on immune therapies in
of digestion. The interaction of pancreatic hormones with type 1 diabetes. European Endocrinology, 12(2), 8995. Available
other hormones and the imbalance when this interaction from https://doi.org/10.17925/EE.2016.12.02.89.
is not good is discussed in the last part of this chapter. Shibao, C. A., Celedonio, J. E., Tamboli, R., Sidani, R., Love-Gregory,
L., Pietka, T., . . . Flynn, C. R. (2018). CD36 modulates fasting and
preabsorptive hormone and bile acid levels. The Journal of Clinical
Suggested readings Endocrinology & Metabolism. Available from https://doi.org/
10.1210/jc.2017-01982, jc.2017-01982-jc.02017-01982.
Basic foundations Turton, J. L., Raab, R., & Rooney, K. B. (2018). Low-carbohydrate
Atkinson, M. A. (2017). Type 1 diabetes mellitus. In S. Melmed, K. S. diets for type 1 diabetes mellitus: A systematic review. PLoS One,
Polonsky, P. R. Larson, & H. M. Kronenberg (Eds.), Williams textbook 13(3), e0194987. Available from https://doi.org/10.1371/journal.
of endocrinology (13th ed., pp. 14511483). Philadelphia, PA: Elsevier. pone.0194987.
Brownlee, M., Aiello, L. P., Cooper, M. E., Vinik, A. I., Plutzky, J., & Vella, A. (2016). Gastrointestinal hormones and gut endocrine
Boulton, A. J. M. (2017). Complications of diabetes mellitus. In S. tumors. In S. Melmed, K. S. Polonsky, P. R. Larson, & H. M.
Melmed, K. S. Polonsky, P. R. Larson, & H. M. Kronenberg Kronenberg (Eds.), Williams textbook of endocrinology (13th ed.,
(Eds.), Williams textbook of endocrinology (13th ed., pp. 14841581). pp. 17011723). Philadelphia, PA: Elsevier.
Philadelphia, PA: Elsevier. You, C.-j, Liu, D., Liu, L.-l, & Li, G.-z (2018). Correlation between
Marino, C. R., & Gorelick, F. S. (2017). Pancreatic and salivary acute stroke-induced white matter lesions and insulin resistance.
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(3rd ed., pp. 879898). Philadelphia, PA: Elsevier. md.0000000000009860.

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C H A P T E R

Case study: type 1 diabetes mellitus

Goodman’s Basic Medical Endocrinology.

In the clinic: diabetes mellitus

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

FIGURE 7.4 Blood flow through the islets and acini

Goodman’s Basic Medical Endocrinology

Histologically, the islets consist of three major and

Biosynthesis, secretion, and metabolism

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

itself, leaving dephosphorylation and delivery into

Goodman’s Basic Medical Endocrinology

Glucagon AC cAMP PKA

Malonyl Fatty acids

Goodman’s Basic Medical Endocrinology

FIGURE 7.12 Role of protein kinase A (cyclic AMP-dependent

FIGURE 7.13 Regulation of fructose-1,6-bisphosphate metabo-

Lipogenesis and ketogenesis

Goodman’s Basic Medical Endocrinology

synthesis promotes fatty acid oxidation and conse-

Lipogenesis is the principal competitor of gluconeogen-

Goodman’s Basic Medical Endocrinology

Glucagon effect on glucose metabolism

Glucagon effect on ketone body metabolism

Goodman’s Basic Medical Endocrinology

gluconeogenesis but also signals the liver to release 5′ UTR 3′ UTR

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

liver appears to be a regulated process governed by

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

FIGURE 7.21 Effect of insulin on hepatic glucose production.

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

across the plasma membrane accompanied by sodium

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

and phosphorylation by glucokinase is only one source

Goodman’s Basic Medical Endocrinology

Stimulation of glucose transport into fat and muscle

Inhibition of lipolysis of triglyceride stores by inhibiting hormone-sensitive lipase

Stimulation of protein synthesis

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Hormonal and neural control

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

Goodman’s Basic Medical Endocrinology

to the effects of calcium and promote both secretion of