Insulin and Oral Hypoglycemic Drugs

Insulin and oral
hypoglycemic drugs
Diabetes Mellitus
 A group of diseases characterized by high levels of
blood glucose resulting from defects in insulin
production, insulin action, or both
 194 million people worldwide
 90% cases are Type 2
CLASSIFICATION
 TYPE 1 (IDDM,10%)

Deficiency of insulin secretion

Genetic predisposition and possible links to
viral infections and environmental factors
 Possible autoimmune process with
destruction of beta pancreatic cells
 Require insulin supplementation, prone to
develop DKA ( 酮症酸中毒）
CLASSIFICATION
 TYPE 2 (NIDDM,90%)

Resistance to action of insulin on target organs

Decrease in insulin production

Increased risk with obesity high fat, high caloric
diets

Stronger genetic predisposition

Variety of initial presentations: HHNKS ,
nephropathy, retinopathy, neuropathies

Disease can be delayed or prevented with life
style changes
CLINICAL FEATURES
 Polyuria
 Polydipsia
 Polyphagia
 Weight loss
TYPE 1 DM-- acute, severe

TYPE 2 DM-- chronic, less severe
Therapy of Diabetes Mellitus
 Diet
 Exercise
 Insulin and its enhancers
 Oral hypoglycemic drugs
Insulin and its action enhancers
Structure of insulin
Insulin
1. Pharmacological effects
(1) Carbohydrate metabolism: reducing blood glucose levels by glucose
oxidation and glycolysis , glycogenolysis , glycogen synthesis ,
gluconeogenesis 
(2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids ,
ketone bodies 
(3) Protein metabolism: active transport of amino acids , incorporation of

amino acids into protein , protein catabolism 
(4) HR , myocardial contractility , renal blood flow 
Mechanism of insulin actions

Interacting with insulin receptor
Insulin
(1) Carbohydrate metabolism: reducing blood glucose levels by glycose
oxidation and glycolysis , glycogenolysis , glycogen synthesis ,
gluconeogenesis 
(2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids ,
ketone bodies 
(3) Protein metabolism: active transport of amino acids , incorporation of

amino acids into protein , protein catabolism 
(4) HR , myocardial contractility , renal blood flow 
Mechanism of insulin actions

Interacting with insulin receptor
Interaction
between insulin
and its receptor
IRS: insulin receptor
substrate
tyr: tyrosine
P: phosphate
Insulin
2. Clinical uses
(1) Type 1 diabetes mellitus
(2) Type 2 diabetes mellitus: failure to other drugs or diet

control
(3) Diabetic complications: diabetic ketoacidosis ,

hyperosmotic nonketotic coma
(4) Critical situations of diabetic patients: fever, severe

infection, pregnancy, trauma, operation
(5) Others: intracellular lack of K+

3. Preparations
Properties Preparations Onset Peak duration
Rapid Lispro, aspart 5-15min 30- 2-5h
60min
Fast Regular insulin 0.5-1h 2-4h 5-7h
Fast Novolin R, Humulin R 0.5-1h 2-4h 5-7h
Intermediate Neutral protamine hagedorn 1-2h 8-12h 24h
(NovolinN, Humulin N)
Long Protamine zinc insulin 4-8h 14-20h 24-36h

suspension
Long Glargine 1-2h no 20-24h
Rapid Acting Insulin Analogues
 Current agents include lispro , aspart , and glulisine
 Remain monomeric after injection, resulting in rapid
absorption, and relatively rapid onset and offset.
 Onset of action is 5-15 minutes, with peak action at
30-60 minutes and duration of ~2-5 hours.
 Advantages include:

increased convenience- can take just prior to meal.

better postprandial glycemic control.
 Disadvantages include:

short duration of action- can be problematic in Type 1
diabetic without basal insulinization, as with bedtime
NPH.

more expensive than regular insulin (~double the
cost).
3. Preparations
60min

suspension
Regular Insulin
 Referred to as clear or unmodified insulin.
 Onset of action 30-60 minutes, Peak action
2-4 hours, Duration of action: 5-7 hours.
 Advantages:

Inexpensive

Long track record of safety.
 Disadvantages:

Need to take doses 30-45 minutes prior to eating a meal.
 Effect is not truly rapid… it is delayed which can result in
postprandial hyperglycemia, late hypoglycemia.
3. Preparations
60min

suspension
Glargine (Lantus )
 Long acting insulin analogue.
 Onset is ~90 minutes, and it is virtually
peakless.
 Duration is 20-24 hours.
 Provides ~flat basal insulinization.
 More expensive
 Cannot be mixed with other insulins.
The Medical Letter, Vol 43, August 6, 2001

Mixed insulin
 70-30: human monocomponent insulin 30% , Human
Insulin Isophane Suspension 70%.
 50-50: human monocomponent insulin 50% , Human

Insulin Isophane Suspension 50%.
 Onset:0.5h, peak 2-12h, duration:16-24h. 30min

before breakfast.
Insulin
4. Adverse effects
(1) Hypersensitivity: treated with H1 receptor antagonist,
glucocorticoids, replaced by human or high purity insulin
(2) Hypoglycemia: (sweating, hunger, weakenss,

tachycardia, blurred vision, headache, coma, shock, etc.),
drink glucose contained water, or treated with 50% glucose
(3) Lipoatrophy: localized in injection sites
(4) Insulin resistance:
Acute: stress etc. induced, need large dose of insulin
Chronic: need >200U/d and no complication
Insulin
4. Adverse effects
(5) Increase body weight
(6) Ametropic eye
(7) Edema
Insulin action enhancers
(oral hypoglycemic drugs)
Thiazolidinediones (TDs)
Biguanides
Thiazolidinediones (TDs)
Rosiglitazone
Pioglitazone
Troglitazone
Rosiglitazone
Pioglitazone
Selective agonists for nuclear peroxisome proliferator-
activated receptor- (PPAR).
(1) Fat cells differentiate to a lot of small fat cells, and
increase GLUT-4 expression
(2) Increase signal transmission of insulin (Rosiglitazone
increase insulin receptors)
(3) Decrease leptin, IL-6 and TNF-alpha expression in fat
cells
(4) increase GLUT1,4 transcription and expression
(5) Inhibit VEGF mediated angiogenesis, to prevent the
complications.
(6) Increase adiponectin level, recover the function of B
cells
(1) Lowering insulin resistance
(2) Lipid metabolism regulation: TG, free fat acid, LDL 
(3) Antihypertensive effects
(4) Effect on vascular complications in type 2 patients
(5) Recover the function of B cells
2. Clinical uses
Used for treatment of insulin-resistant
diabetic patients or type 2 patients
3. Adverse effects
Edema, headache, myalgia, GI reactions,
hepatic damage (troglitazone)
Biguanides
Metformin
Phenformin
Biguanides
1. Pharmacilogical effects
increasing glucose uptake in fat tissues and
anaerobic glycolysis in skeletal muscles
decreasing glucose absorption in gut,
gluconeogenesis, and glucagon release.
2. Clinical uses

mild insulin-independent patients with obesity

3. Adverse effects
severe lactic acidosis (less for metformin),
malabsorption of vitamin B12 and folic acid
Other oral hypoglycemic drugs
Oral insulin secretagogues
Sulfonylureas
Repaglinide
Incretin (GLP-1) Mimetics
Dipeptidylpeptidase IV (DPP-IV) Inhibitors
Oral hypoglycemic drugs
Sulfonylureas
Tolbutamide (D860)
Chlorpropamide
Glibenclamide
Glipizide
Gliclazide
Sulfonylureas
(1)Hypoglycemic effect:
blocking ATP-sensitive K+ channel: Ca2+ inflow , insulin
release , stimulating insulin secretion
increase the binding of insulin and its receptors (still effective
after long-term use to recover insulin level)
glucose utilization, glycogen and fat synthesis, insulin
receptor number and affinity , insulin metabolism↓
(2) Antidiuretic effect
(3) Effect on coagulation function

Action of sulfonylureas
Sulfonylureas
Hypoglycemic effect:
blocking ATP-sensitive K+ channel: Ca2+ inflow , insulin
release , stimulating insulin secretion,
increase the binding of insulin and its receptors (still effective
after long-term use to recover insulin level)
glucose utilization, glycogen and fat synthesis, insulin
receptor number and affinity , insulin metabolism↓
(2) Antidiuretic effect (chlorpropamide): effect of

antiuretic hormone (ADH) 
(3) Effect on coagulation function (gliclazide)

Sulfonylureas
2. Clinical uses
(1) Insulin-indenpedent diabetic patients (type 2):

alone or combined with insulin
(2) Diabetes insipidus : Chlorpropamide

Sulfonylureas
3. Adverse effects
(1) GI reactions
(2) CNS reactions
(3) Hypoglycemia: especially in elderly, hepatic or
renal insufficiencies
(4) Others: cholestatic jaundice, hepatic damage
(Chlorpropamide), leukopenia.
Sulfonylureas
4. Drug interactions
(1) Potentiation of hypoglycemic effects

replacement in plasma protein binding: salicylic acid, sulfates,
indomethacin, penicillin, warfarin, etc.
inhibition of hepatic microsomal enzymes: chloramphenicol,
warfarin
(2) Attenuation of hypoglycemic effects

induction of hepatic microsomal enzymes: phenytoin,
phenobarbital, etc.
interactions in pharmacodynamics: glucocorticoids, thiazides,
etc.
Repaglinide ( 餐时血糖调节剂 )
 Pharmacological effects
 Repaglinide lowers blood glucose by stimulating the release of
insulin from the pancreas.
 It achieves this by closing ATP-dependent potassium channels
in the membrane of the beta cells. This depolarizes the beta
cells, opening the cells' calcium channels, and the resulting
calcium influx induces insulin secretion
 Protect beta cell
 Clinical uses
 Type2 DM, diabetic nephropathy, elder DM patient
 less hypoglycemia
 Mechanism of Action:
 Act as an incretin enhance insulin secretion in response
to an oral glucose load.
 Suppress post-prandial glucagon secretion

Increase insulin secretion in a glucose-dependent manner
 Increase somatostatin secretion which inhibit glucagon
release

Delay gastric emptying

Centrally suppress appetite
 Preserve beta cell mass by reducing apoptosis and
increased neogenesis (animal models).
Keating, Drugs. 65(12):1681-92, 2005.
Riddle and Drucker. Diabetes Care 2006; 29:435-49.
 Exenatide (Byetta) is first
incretin mimetic on market.
 Synthetic version of salivary protein found in the Gila monster53%
overlap with human GLP-1.
Exenatide
GLP-1
Human HA
A E G T F TSD V S SY
SYLL E GQA
GQ AAKE VK GRR -NH2
K E F I A W LVK
Site of DPP-IV Inactivation

 Must be taken as a BID injection w/in 60 mins prior to meal
 Major side effects: nausea, vomiting, diarrhea. Increases the risk of
Acute pancreatitis.
 Use not recommended in severe renal impairment.
 Not recommended as monotherapy

To be used as add on therapy with SU, metformin, or TZD’s

Increases the risk of Hypoglycemia when added to SU treatment.
 Major advantage is weight loss (~5 kg) as well as maintained effect (?
preserved beta cell function).
 Efficacy: decreases A1C ~1.0%.
Keating, Drugs 2005 65(12):1681-92

Dipeptidylpeptidase IV (DPP-IV) Inhibitors
 Mechanism of Action:

Acts to prevent breakdown of intrinsic GLP-1, thereby increasing
portal GLP-1 levels
 Sitagliptin (Januvia) is first DPP-IV inhibitor on market.
 Effective as monotherapy or when used in conjunction
with metformin or a thiazolidinedione.
 Efficacy: decreases A1C ~0.8%.
Riddle and Drucker. Diabetes Care 2006; 29:435-49.

-Glucosidase inhibitors （葡萄糖苷酶抑制
药）
Acarbose 阿卡波糖
Reducing intestinal absorption of starch ( 淀粉 ),

dextrin ( 糊精 ), and disaccharides ( 二糖 ) by
inhibiting the action of intestinal brush border
-glucosidase
Pramlintide acetate ( 醋酸普兰林肽 )
• an analogue of amylin, a small peptide hormone that is released

into the bloodstream by the β-cells of the pancreas along with
insulin, after a meal.
• delay glucose absorption, inhibit secretion of glucagon
• Symlin has been approved by the FDA, for use by Type 1 and
Type 2 Diabetics who use insulin. Symlin allows patients to use
less insulin, lowers average blood sugar levels, and blood sugar
after eating.
• Apart from insulin analogs, symlin is the only drug approved by

the FDA to lower blood sugar in type 1 diabetics since insulin in
the early 1920s
Aldose reductase inhibitor
Epalrestat
Treatment of Diabetic Neuropathy

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Insulin and oral

TYPE 1 DM-- acute, severe

(3) Protein metabolism: active transport of amino acids , incorporation of

(4) HR , myocardial contractility , renal blood flow 

Mechanism of insulin actions

(3) Protein metabolism: active transport of amino acids , incorporation of

(4) HR , myocardial contractility , renal blood flow 

Mechanism of insulin actions

(2) Type 2 diabetes mellitus: failure to other drugs or diet

(3) Diabetic complications: diabetic ketoacidosis ,

(4) Critical situations of diabetic patients: fever, severe

(5) Others: intracellular lack of K+

Long Protamine zinc insulin 4-8h 14-20h 24-36h

Long Protamine zinc insulin 4-8h 14-20h 24-36h

Long Protamine zinc insulin 4-8h 14-20h 24-36h

The Medical Letter, Vol 43, August 6, 2001

 50-50: human monocomponent insulin 50% , Human

 Onset:0.5h, peak 2-12h, duration:16-24h. 30min

(2) Hypoglycemia: (sweating, hunger, weakenss,

(6) Ametropic eye

2. Clinical uses

Oral insulin secretagogues

(2) Antidiuretic effect

(3) Effect on coagulation function

(2) Antidiuretic effect (chlorpropamide): effect of

(3) Effect on coagulation function (gliclazide)

(1) Insulin-indenpedent diabetic patients (type 2):

(2) Diabetes insipidus : Chlorpropamide

(1) Potentiation of hypoglycemic effects

(2) Attenuation of hypoglycemic effects

Site of DPP-IV Inactivation

Keating, Drugs 2005 65(12):1681-92

Riddle and Drucker. Diabetes Care 2006; 29:435-49.

Reducing intestinal absorption of starch ( 淀粉 ),

• an analogue of amylin, a small peptide hormone that is released

• delay glucose absorption, inhibit secretion of glucagon

• Apart from insulin analogs, symlin is the only drug approved by

Aldose reductase inhibitor

Treatment of Diabetic Neuropathy

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