Pharmacotherapy of Diabetes Mellitus

Insulin

15 June 2010

Cell type Hormone Function

Alpha [A] cells Glucagon Hyperglycemic factor

Beta [B] Cells Insulin, Pro insulin, Amylin

Anabolic hormone

Delta[D] Cells Somatostatin Universal inhibitor of secretion

G Cells Gastrin Stim.Gastric secretion

F cell[PP cell] Panc.Polypeptide Digestion

THE ENDOCRINE PANCREAS1 million islets of Langerhans

4 hormone-producing cells

What is DM?

Diabetes mellitus

Elevated blood glucose

Associated with absent or inadequate pancreatic insulin secretion

With or without concurrent impairment of insulin action.

Expert Committee, 2003

Type 4 Type 3

Diabetes mellitus -TYPES TYPE 1

• IDDM

• Loss of  beta cells → deficiency of insulin

“Juvenile diabetes” majority cases

in children.

TYPE 2

• NIDDM

• Due to insulin resistance

• [or reduced insulin sensitivity]

• Combined with reduced insulin secretion 

• TYPE 3

• Drug induced or other causes

• TYPE 4

• Gestational diabetes mellitus 

Proinsulin

INSULIN

Two peptide chains A & B of

21 and 30 amino acids linked by disulfide

bridges

Insulin Biosynthesis

[110AA] Preproinsulin (in RER)

↓

[110-24AA] Proinsulin (Golgi Apparatus)

↓

[51AA] Insulin + C Peptide[-35AA]

↓

Stored in granules of cells

Basal rate: 1U/h, during meals

Control:Insulin Release• Chemical

Glucose

Incretins• Hormonal

GH Corticosteroids, Thyroxine

Glucagon ↑Somatostatin ↓

• Neural

Adrenergic-a2↓

Adrenergic-b2↑

Muscarinic[Vagal] ↑

Counter

regulatory

First phase- Within 2 minutesDelayed phase

Insulin release from the pancreatic Beta cell by Glucose

Role of ATP sensitive K+ channels (KATP)

Hyperglycemia

↓

Intracellular ATP

↓

Blockade of KATP

↓

Outflow of K+

↓

Depolarization of β cells

↓

Ca2+ influx

↓

Insulin Release

Degradation of Insulin

• Endogenous:– Liver – 60%, Kidney: 35-40%

• Exogenous:– Liver – 40%, Kidney- 60%

•  Plasma half-life: 5-6 min.

Insulin receptor substrate

2 covalently linked heterodimers

Insulin receptor

The binding of an insulin molecule

Mutual phosphorylation of tyrosin recidues

Activated Tyrosin kinases Further phosphorylates down stream proteins[IRS]

•Translocation of glucose transporters (especially GLUT 4) to the cell membrane with increase in glucose uptake; •Increased glycogen synthase activity and increased glycogen formation; •Multiple effects on protein synthesis, lipolysis, and lipogenesis; and •Activation of transcription factors that enhance DNA synthesis and cell growth and division.

Insulin receptors

• Glucocorticoids lower the affinity of insulin receptors for insulin;

• Growth hormone in excess increases this affinity slightly.

• Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance

Glucose transporters[GLUT]

Blood

Absorption

Glycogenolysis

GluconeogenesisIN LIVER

Processes add glucose[Hyperglycemia]

Processes utilize glucose[Hypoglycemia]

Protein Synth. In MusclesLipogenesis

Peripheralutilization

[-]Insulin

[-]

Insulin

[+]

Insulin

[+]

Insulin

[+]In

sulin

Endocrine effects of Insulin

Endocrine effects of Insulin….

Endocrine effects of Insulin….

Over view of Insulin action

Source and insulin preperations

Species A Chain B Chain

8th AA 10th AA 30th AA

Human THR ILEU THR

Pork THR ILEU ALA

Beef ALA VAL ALA

Analogs

Conventional prep.•Impurities•Antigenic

•Less expensive

1. Highly purified porkInsulins

• Monocomponent insulins

2. Human insulins• Recombninant DNA Technology[E.Coli, Yeast]

3. Insulin analoguesChanging or replacing AA sequences1. Lispro2. Aspart3. Glulisine4. Glargine 5. Detemir

•Replaced by1.Highly purified pork

Insulins2.Human insulins

3.Insulin analogues

Genetic engineeringto produce human insulin

Insulin preparations

• Rapid acting insulins:– Insulin lispro

– Insulin aspart

– Insulin glulisine

• *Short acting insulins:– Regular insulin

• *Intermediate acting insulins:– Lente insulin[Insulin

Zinc suspension

– NPH insulin [Isophane Insulin suspension]

*Long-acting insulins:– Ultralente insulin

– Protamine Zinc Insulin (PZI)

– Insulin Glargine

– Insulin detemir

*Premixed insulins:– 70% NPH + 30% Regular

– 50% NPH + 50% Regular

– 75% NPH + 25% Lispro

*Animal or human

Analogues

Analogues

Insulin preparationsRapid acting

• More physiologic prandial insulin replacement - their rapid onset and early peak action - closely mimic normal endogenous prandial insulin secretion than does regular insulin,

• Can be taken immediately before the meal without sacrificing glucose control.

• Their duration of action is rarely more than 4–5 hours, which decreases the risk of late postmeal hypoglycemia.

• Lowest variability of absorption [Monomers]• Preferred insulins for use in continuous subcutaneous

insulin infusion [CSII] devices.

Insulin preparationsRapid acting

Lispro

Insulin preparationsRapid acting

Aspart

Insulin preparationsRapid acting

Glulysine

Insulin preparationsShort acting

• Recombinant DNA techniques, purified porcine• Effect appears within 30 minutes - peaks between 2 and

3 hours after s.c injection -lasts 5–8 hours. • Prandial hyperglycemia and risk of late hypoglycemia

[30-45 mts before meals]• Only preperation for i.v.use.

Insulin preparations Intermediate actingLente insulin[Insulin Zinc suspension]NPH insulin [Isophane Insulin suspension]

–Onset-1-2 h

–Peak-6-12h

–Duration-18-24

–Dose related action profile

–Long acting analogs are preferred

Long actingInsulin preparations

–Onset-1-2 h

–Peak less

–Duration-18-24

THRThriiii

THR Myristic acidGlargine

Detemir

Type Appearance Onset Peak Duration

Rapid/Short

Regular soluble Clear 0.5–0.7 1.5–4 5–8

Lispro Clear 0.25 0.5–1.5 2–5

Aspart Clear 0.25 0.6–0.8 3–5

Glulisine Clear - - - 0.5–1.5 1–2.5

Intermediate 1–2

NPH (isophane) Cloudy 1–2 6–12 18–24

Lente Cloudy 6–12 18–24

Long

Ultralente Cloudy 4–6 16–18 20–36

Protamine zinc Clear 4–6 14–20 24–36

Glargine Clear 2–5 5–24 18–24

Detemir Clear 1–2 4–14 6–24

Adverse Effects of Insulin: Hypoglycemia

• Results from:– Delay in taking a meal

– Inadequate carbohydrate intake

– Unusual physical exertion

– Too large insulin doses

Symptoms

• Autonomic hyperactivity– Sympathetic

• Tachycardia, palpitations, sweating, tremulousness

– Parasympathetic:• Nausea, hunger

– Convulsions / Coma

• Hypoglycemia unawareness

• Treatment:– Glucose administration:

• Fruit juice / Glucose gel / Sugar containing beverage/food to eat at first sign

• If severe: 50% dextrose i.v.

Carry identity card

Adverse Effects of Insulin: Hypoglycemia

Adverse Effects of Insulin

Insulin Allergy:• Noninsulin protein contaminants

• Less with purified insulin preparations

• ? Anaphylaxis

Insulin Resistance [Requirement of > 200U/day]

• Acute:– Causes: Infections, trauma, surgery, stress (in stress

↑corticosteroids oppose insulin action)

– Treated by regular insulin

• Chronic:– Common in type II

– Cause: Antibodies to contaminating proteins which also bind insulin

– Treatment- change to human insulin

• Reversible– Pregnancy

Adverse Effects of Insulin

Insulin Lipodystrophy• Older insulin preparations → Repeated injections at the

same site → Atrophy / Hypertrophy of subcutaneous fat

• Atrophy not seen with newer human insulin preparations, hypertrophy still a problem

• ? Injection of newer insulin into atrophic area → Restoration of normal contours

• Sites of injection: Abdomen best, Keep changing

Insulin Edema• Na+ retention, Weight gain

Unitage of Insulin

• 1 U = Amount required to reduce blood glucose by 45 mg% in a fasting rabbit

• 1mg=28units

Insulin Delivery Systems

• Disposable needles and syringes: 27 G

• Portable Pen Injectors

• Jet injectors

• Continuous Subcutaneous Insulin Infusion: CSII– Most physiologic insulin replacement

– Insulin reservoir/ Program chip/ Keypad/ Display screen

– Excellent glycemic control eg, pregnancy

• Inhaled Insulin– Absorbed through alveolar walls

– Rapid onset of action / Short duration

– ? Pulmonary fibrosis/Pulmonary hypertension

• Oral insulin: Liposome encapsulated

Clinical Uses of Insulin

• Type 1 diabetes mellitus• Type 2 diabetes mellitus-Not controlled by oral agentsComplications: Diabetic ketoacidosis, Gangrene, To tide over: Infection, TraumaPregnancy [Gestational diabetes not controlled by

diet alone]

• Emergency treatment of hyperkalemia: Insulin + glucose

Indications of Human Insulin

1. Insulin resistance

2. Allergy to conventional preparations

3. Injection site lipodystrophy

4. Short term use- surgery, trauma

5. During pregnancy

Insulin regimens

• Intensive Insulin therapy-Based on formulae-CSII

• Conventional- For type 2

• Spl circumstances

• Principle:

• Supply postprandial needs

• Provide basal control

Glargine + 3 Analogs

2Long acting+2 Rapid or Short acting

CSII

Diabetic Ketoacidocis [Diabetic coma]

• Precipitated by infection, trauma, stress in insulin dependent patients

• Serious • Hypotension, shock,

tachycardia, dehydration, hyperventilation, vomiting, coma

Treatment:1.Regular insulin-I.V.2.Bolus followed by infusion3.i.v fluids.4.Kcl ???5.NaHco36.Phosphate7.Antibiotics

Drug interactions

• Beta blockers-

• Inhibit comp mechanisms

• Warning signs of hypoglycemia are masked

• Thiazides, Furosemide, Corticosteroids, OCPs, reduce the effect of insulin

• Salicylates, Li, increase insulin secretion

Disposable needles and syringes: 27 G

Insulin Delivery Systems

Portable Pen Injectors

Insulin Delivery Systems

 A device that uses high pressure instead of a needle to propel insulin through the skin and into the body. 

Inhaled Insulin

Insulin Delivery Systems

Continuous Subcutaneous Insulin Infusion: CSII

1 - Continuous glucose sensor monitors blood sugar level2 - Data transmitted for the computer program to work out insulin dose3 - Insulin pump delivers the dose

Insulin Delivery Systems

‘Artificial pancreas’Sensor activated pump