Treatment of Type 1 Diabetes

• exogenous insulin to control hyperglycemia, avoid

ketoacidosis, and maintain acceptable levels of glycosylated
hemoglobin (HbA1c)
• [Note: HbA1c is a marker of overall glucose control and is
used to monitor diabetes in clinical practice. The rate of
formation of HbA1c is proportional to the average blood
glucose concentration over the previous 3 months. A higher
average glucose results in a higher HbA1c]

Ayman Khdair, Ph.D. 3

 Treatment of Type 1 Diabetes

• The goal of insulin therapy in type 1 diabetes is to maintain

– blood glucose as close to normal as possible
– and to avoid wide fluctuations in glucose
• The use of home blood glucose monitors facilitates frequent
self-monitoring and treatment with insulin.

Ayman Khdair, Ph.D. 4

 Treatment of Type 2 Diabetes

Goals of treatment
• maintain blood glucose within normal limits
• and to prevent the development of long-term complications
• Non pharmacologic factors help control type 2 diabetes
– Weight reduction, exercise, and dietary modification
– decrease insulin resistance and correct hyperglycemia in some
patients with type 2 diabetes
• However, most patients require pharmacologic intervention
with oral glucose-lowering agents
• As the disease progresses, β-cell function declines, and insulin
therapy is often needed to achieve satisfactory glucose levels

Ayman Khdair, Ph.D. 5

 Insulin and Insulin Analogs

• Insulin is a polypeptide hormone consisting of two peptide

chains that are connected by disulfide bonds
• It is synthesized as a precursor (proinsulin) that undergoes
proteolytic cleavage to form insulin and C-peptide, both of
which are secreted by the β cells of the pancreas
• Because insulin undergoes significant hepatic and renal
extraction, plasma insulin levels may not accurately reflect
insulin production
• Thus, measurement of C-peptide provides a better index of
insulin levels

Ayman Khdair, Ph.D. 7

 Insulin and Insulin Analogs

• Natural Insulin secretion is regulated by

– (mainly) blood glucose levels
– certain amino acids
– other hormones, and autonomic mediators
• Mechanism of glucose triggered insulin secretion
• β cells takes glucose by glucose transporters  glucose is
phosphorylated by glucokinase (acts as a glucose sensor) 
increases in intracellular Ca2+  pulsatile insulin exocytosis

Ayman Khdair, Ph.D. 8

 Insulin and Insulin Analogs

• Exogenous insulin is administered to replace absent insulin

secretion in type 1 diabetes or to supplement insufficient
insulin secretion in type 2 diabetes

Ayman Khdair, Ph.D. 9

Reasons for variation in PK of synthetics insulin

• Human insulin is produced by recombinant DNA technology

– using strains of Escherichia coli or yeast that are genetically altered to
contain the gene for human insulin
• Modification of the amino acid sequence of human insulin
produces insulins with different pharmacokinetic properties
– onset and duration of activity

Ayman Khdair, Ph.D. 10

Reasons for variation in PK of synthetics insulin

• External factors affect onset and duration of action

• Dose, injection site, blood supply, temperature, and physical
activity
• Orally, insulin is degraded
• Insulin is mainly used SC
• In emergency hyperglycemia, regular insulin is administered
intravenously
• Inhaled insulin failed and was withdrawn

Ayman Khdair, Ph.D. 11

Reasons for variation in PK of synthetics insulin

• Continuous subcutaneous insulin infusion (also called the

insulin pump) is another method of insulin delivery
– eliminating multiple daily injections of insulin  more convenient
• The pump is programmed to deliver a basal rate of insulin
• In addition, it allows the patient to deliver a bolus of insulin to
cover mealtime carbohydrate intake and compensate for high
blood glucose

Ayman Khdair, Ph.D. 12

 Adverse effects of exogenous insulin

• Hypoglycemia is the most serious and common adverse

reaction
• weight gain
• local injection site reactions
– Lipodystrophy (local atrophy or hypertrophy of subcutaneous fatty
tissue at the site of injections)
– can be minimized by rotation of injection sites
• Diabetics with renal insufficiency may require a decrease in
insulin dose

Ayman Khdair, Ph.D. 13

 Adverse effects of exogenous insulin

• Tachycardia
• Confusion
• Diaphoresis
• Increased appetite
• Shakiness
• Blurred vision
• Weakness and fatigue
• Hypersensitivity

Ayman Khdair, Ph.D. 14

 Insulin Preparations and Treatment

• Rapid-acting
• Short-acting
• Intermediate-acting
• long-acting
– It is important that clinicians exercise caution when adjusting insulin
treatment, paying strict attention to the dose and type of insulin

Ayman Khdair, Ph.D. 15

Rapid-acting and short-acting insulin preparations

• regular insulin (peak insulin at 50-120 minutes post injection)

– E.g. Humalin R® and Novloin R ®
• insulin lispro (rapid-acting) (peak at 30-90 minutes)
– Humalog ®
• insulin aspart (rapid-acting) (peak at 30-90 minutes)
– Novolog ®
• Insulin glulisine (rapid-acting) (peak at 30-90 minutes)
– Apidra ®
• and inhaled insulin (not available)

Ayman Khdair, Ph.D. 17

Rapid-acting and short-acting insulin preparations

Regular insulin
• is a short-acting, soluble, crystalline zinc insulin
Rapid-acting insulin
• Modification of the amino acid sequence of regular insulin
produces analogs that are rapid-acting insulin
• This modification results in more rapid absorption, a quicker
onset, and a shorter duration of action after subcutaneous
injection

Ayman Khdair, Ph.D. 18

Rapid-acting and short-acting insulin preparations

• Rapid- or short-acting insulins are administered to mimic the

prandial (mealtime) release of insulins and to control
postprandial glucose
• They may also be used in cases where swift correction of
elevated glucose is needed
• Rapid- and short-acting insulins are usually used in
conjunction with a longer-acting basal insulin that provides
control of fasting glucose

Ayman Khdair, Ph.D. 19

Rapid-acting and short-acting insulin preparations

• Regular insulin should be injected subcutaneously 30 minutes

before a meal
• Rapid-acting insulins are administered in the 15 minutes
before a meal or within 15 to 20 minutes after starting a meal
• Rapid-acting insulin suspensions are commonly used in
external insulin pumps, and they are suitable for IV
administration, although regular insulin is most commonly
used when the IV route is needed.

Ayman Khdair, Ph.D. 20

 Intermediate-acting insulin

• Neutral protamine Hagedorn (NPH) insulin is an intermediate-

acting insulin formed by the addition of zinc and protamine to
regular insulin
– Also called insulin isophane.]
• The combination with protamine forms a complex that is less
soluble, resulting in delayed absorption and a longer duration of
action
• NPH insulin is used for basal (fasting) control in type 1 or 2 diabetes
and is usually given along with rapid- or short-acting insulin for
mealtime control
• NPH insulin should be given only subcutaneously (never IV), and it
should not be used when rapid glucose lowering is needed (for
example, diabetic ketoacidosis)
Ayman Khdair, Ph.D. 21
Recommended combination of different types of insulin
 Long-acting insulin preparations

• The isoelectric point of insulin glargine is lower than that of

human insulin, leading to formation of a precipitate at the
injection site that releases insulin over an extended period
• It has a slower onset than NPH insulin and a flat, prolonged
hypoglycemic effect with no peak

Ayman Khdair, Ph.D. 25

 Long-acting insulin preparations

• Insulin detemir has a fatty acid side chain that enhances

association to albumin
• Slow dissociation from albumin results in long-acting
properties similar to those of insulin glargine

Ayman Khdair, Ph.D. 26

 Long-acting insulin preparations

• Insulin degludec remains in solution at physiologic pH, with a

slow release over an extended period
• It has the longest half-life of the long-acting insulins
• As with NPH insulin, insulin glargine, insulin detemir, and
insulin degludec are used for basal control and should only be
administered subcutaneously
• Long-acting insulins should not be mixed in the same syringe
with other insulins (alters pharmacodynamic profile)

Ayman Khdair, Ph.D. 27

 Insulin combinations

• Various premixed combinations of human insulins, such as

70% NPH insulin plus 30% regular insulin or 50%/50%
– E.g. Humulin 70/30
– E.g. Novolog 70/30
• Use of premixed combinations decreases the number of daily
injections but makes it more difficult to adjust individual
components of the insulin regimen.

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Standard treatment versus intensive treatment

• Standard insulin therapy involves twice daily injections

• Intensive treatment utilizes three or more injections daily
with frequent monitoring of blood glucose levels
• The ADA recommends a target mean blood glucose level of
154 mg/dL or less (HbA1c ≤ 7%) for most patients  intensive
treatment is more likely to achieve this goal

Ayman Khdair, Ph.D. 29

Standard treatment versus intensive treatment

• Disadvantages of intensive regimen

– The frequency of hypoglycemic episodes, coma, and seizures is higher
with
• Advantages of intensive regimen
– significant reduction in microvascular complications of diabetes such
as retinopathy, nephropathy, and neuropathy
• Intensive therapy should not be recommended for patients
with long-standing diabetes, significant microvascular
complications, advanced age, and those with hypoglycemic
unawareness

Ayman Khdair, Ph.D. 30

 Synthetic Amylin Analog

• Amylin is a hormone that is cosecreted with insulin from β

cells following food intake
• It delays gastric emptying, decreases postprandial glucagon
secretion, and improves satiety
• Pramlintide is a synthetic amylin analog that is indicated as an
adjunct to mealtime insulin therapy in patients with type 1
and type 2 diabetes
• SC immediately before meals

Ayman Khdair, Ph.D. 31

 Synthetic Amylin Analog

• The dose of mealtime insulin should be decreased by 50% to

avoid a risk of severe hypoglycemia
Adverse effects
• nausea, anorexia, and vomiting
• Pramlintide may not be mixed in the same syringe with insulin
• should be avoided in patients with diabetic gastroparesis
(delayed stomach emptying), cresol hypersensitivity, or
hypoglycemic unawareness.

Ayman Khdair, Ph.D. 32