The document discusses diabetes mellitus, its types, and treatment options, including insulin therapy and oral hypoglycemics. It categorizes diabetes into four types: Type 1 (insulin-dependent), Type 2 (non-insulin-dependent), secondary diabetes, and gestational diabetes, detailing their characteristics and complications. It also explains the mechanisms of various drug categories used to manage diabetes, such as insulin secretagogues, biguanides, thiazolidinediones, and α-glucosidase inhibitors.

1. DRUGS FOR DIABETES MELLITUS
(Insulin & Glucagon)
Dr. Amon Agaba
Semester II 2010/11

2. Diabetes Mellitus (DM)
• Chronic metabolic disorder characterized by hyperglycemia due to:
– absent or ↓ insulin secretion or
– impairment of insulin action.
• Insulin is a hormone secreted by the β-cells of the pancreatic islet of Langerhans.
• Etiology of DM: genetic and environmental factors
• Associated with Complications, if not well controlled:
– Microvascular disease (esp. heart, kidney, brain, eyes)
– Neuropathy
– Increased susceptibility to infection
– Complicated pregnancy

3. Impaired glucose tolerance in DM
Normal and abnormal glucose tolerance tests

4. Types of DM
Type Characteristics
1. Insulin-Dependent DM (IDDM),
[Type 1], [Juvenile onset],
[ketosis-prone]
↓ levels or no endogenous insulin; abnormal
immune response -cell destruction. Onset
mostly <30 yrs. Multi-factorial genetic linkage.
2. Non-Insulin-Dependent DM
(NIDDM), [Type 2]
[Adult-onset], [Maturity onset]
Resistance to insulin with relative ↓insulin;
Onset mostly >30yrs; 60% patients are obese;
strongly genetic (concordancy in 100%
monozygotic twins)
3. Secondary DM (“Other”) Identifiable cause e.g. hormonal or pancreatic
dx, drug/chemical toxicity, etc.
4. Gestational DM Onset in pregnancy (d/t placenta & placental
hormonesinsulin resistance)

5. Diabetogenic agents (Be aware in 2o
DM)
Affect insulin secretion or action
• Hormones
– Epinephrine
– Thyroid hormone
– Growth hormone
– Corticosteroids
• Drugs
– Phenytoin
– Diuretics
– Steroids
– Diazoxide
• Pesticides
– DDT
– Fluoride
• Psychopharmacologic
agents
– Ethanol
– Opiates

6. Insulin Therapy
• Cornerstone treatment for type I DM, also used in other types.
• Forms of insulin:
– Animal-derived (beef, pork)
– Biosynthetic human insulin
• Human insulin:
– Produced by recombinant DNA techniques (in E.coli or yeast)
– Differs in amino acid sequence from pork (by 1) and beef (by 3)
– Less immunogenic
– More rapidly absorbed
– Commonly used
• Animal insulin:
– Beef more antigenic than pork; no longer in use
– Pork still available, but requires special ordering

7. Chemistry of Insulin
• A small protein with MW (in humans) of 5808
• Contains 51 amino acids arranged in 2 chains (A & B),
linked by disulfide bonds.
• processed as pro-insulin within the Golgi apparatus
packaged into granules, where it is hydrolysed into
insulin and the C-peptide
• stored within granules in the β cell (in form of zinc
crystals)

8. Structure of Insulin

9. Characteristics of Insulin preparations
Formulations Constituents/properties Onset of
action (hr)
Duration
(hr)
RAPID-ACTING
-Lispro (humalog),
-Aspart
-recombinant human insulin 5-15min
10-20min
3-5
3-5
SHORT-ACTING
-Regular Humulin
(Soluble)
-crystalline zinc insulin (CZI)
(only type suitable for I.V admin)
0.5-1 5-8
INTERMEDIATE-ACTING
-NPH
-Lente
-Protamine zinc, phosphate buffer
-Amorphous, acetate buffer
1.5
2.5
10-14
10-14
LONG-ACTING
-Ultralente
-Glargine (soluble ‘peakless”)
-Amorphous & crystalline mix
-CZI (reproducible 24hr pattern)
8-14
1.5
18-24
11-24
PREMIXED
-%NPH/%Regular NPH 70%, regular 30% 1-2 4-14

10. Peak effect and duration of action of Insulins

11. Insulin Regimens

12. Effects of Insulin
• Major target organs: liver, muscle, and adipose tissue
• Receptor Mechanism: Activation of cell membrane tyrosine kinase
series of IC phosphorylations of IRS activation of 2o messenger
pathways e.g. translocation of glucose transporters (esp. GLUT-4) to
the cell membrane
– ↑ glucose uptake;
– ↑glycogen synthase activity ↑glycogen formation
– ↓plasma glucose
• Other effects:
– Enhanced DNA synthesis & ↑cell growth & division
– Altered lipid metabolism
– Altered protein metabolism

13. Cellular mechanism of Insulin

14. Insulin: Effects and Control Reflex Loop
Fed-state metabolism

15. Pharmacokinetics
• Factors that ↑ insulin absorption
– ↑ S.C. blood flow (exercise, massage, heat),
– IM injection
– abdominal wall injection
• Factors that ↓ insulin absorption
– ↓ SC blood flow (shock, cold),
– intradermal injection,
– lipohypertrophy,
• Insulin Clearence
– Hepatic & renal

16. Side Effects
• Hypoglycemia
– (know the mechanisms, the signs, and how it is treated?)
• Lipodystrophy at injection sites
– Atrophy of SC fatty tissue [older insulins]
– Hypetrophy “ “ “ [newer insulins]
• Orthostatic hypotension
– Direct vasodilation  ↓cerebral perfusion
• Immune reactions
– Insulin Allergy [immediate type, IgE-mediated]
– Immune insulin resistance [IgG anti-insulin antibodies]

17. Insulin Delivery Systems
• Intensive conventional therapy
– Multiple daily injections [MDI]; (SC, IV, IM)
– Portable pen injectors
• Continuous subcutaneous insulin infusion (CSII) devices
– Insulin pumps [most physiologic method of insulin replacement]
• Experimental
– “closed-loop” artificial endocrine pancreas
– Islet transplantation
– i.p. (portal insulin delivery)
– Inhaled
– liposomal

18. GLUCAGON
• A 29 amino acid peptide (MW 3485)
• Synthesized in the A () cells of the pancreatic islets
of Langerhans
• Effects:
– Dominate in Fasting State Metabolism
– Prevents hypoglycemia by  cell production of glucose
– Liver is primary target organ
• Causes Gs protein-linked ↑ adenylyl cyclase - ↑cAMP
• ↑gluconeogenesis and ketogenesis

19. Glucagon Action on Cells
Endocrine response to hypoglycemia

20. Clinical Uses of Glucagon
• Severe hypoglycemia
• beta-blocker overdose
• Aid in bowel radiology
• Diagnosis of endocrine disorders

21. DRUGS FOR DIABETES MELLITUS (ORAL
HYPOGLYCEMICS)
Semester II 2008/09
Dr. Amon Agaba

22. Categories
Category Mechanism of action
1. Insulin Secretagogues
-Sulfonylureas
-Meglitinides
-D-phenylalanines
 the release of insulin from the
pancreas
2. Biguanides Several: ↓hepatic gluconeogenesis,
↑glycolysis, ↓glucose absorption,
↓plasma glucagon
3. Thiazolidinediones ↑target tissue sensitivity to insulin
4. -Glucosidase Inhibitors ↓glucose absorption from the gut

23. Sulfonylureas
• Mechanism:
– close K+ channels in the pancreatic B cell membrane depolarization
↑insulin release.
– ↓serum glucagon levels (d/t insulin & somatostatin that inhibit A cells)
• Classification: according to generations
Generation: Examples Duration of
action (hr)
Remarks
1st
Chlorpropamide
Tolbutamide
Tolazamide
60
6-12
10-14
-Prolonged hypoglycemia
-safest in elderly
-
2nd
Glyburide
Glipizide
Glimepiride
10-24
10-24
12-24
-All more potent than 1st
generation; in overdose
cause hypoglycemia

24. Mechanism of action of Sulfonylureas

25. 1st
Generation Sulfonylureas
• Tolbutamide
– Short duration of action with t1/2 of 4-5 hrs
– Administered in divided doses
– Safest sulfonylurea in elderly diabetics
• Chlorpropamide
– Long duration of action with t1/2 of 32 hrs
– Average maintenance dose 250mg, given o.d. in the morning
– other S/E: disulfiram-like effect, hepatotoxicity
– C/I in renal or hepatic insufficiency

26. 2nd
Generation Sulfonylureas
• More frequently prescribed than 1st
generation coz of fewer adverse effects
• Glyburide
– Causes disulfiram-like effect
– C/I in renal insufficiency & hepatic impairment
• Glipizide
– Has the shortest t1/2 of 2-4 hrs
– Less likely to serious hypoglycemia
– C/I in renal insufficiency & hepatic impairment
• Glimeperide
– Long duration of action (12-24 hr) and t1/2 (5hrs) that permits o.d dosing
– Very potent agent (doses as low as 1mg daily effective in some patients)
– Can be combined with insulin

27. Example Duration of
action (hr)
Remarks
1. Meglitinides
(Repaglinide) 4-5
-Approved for use in 1998
2. D-phenylalanines
(Nateglinide )
4 -latest insulin secretagogue
approved
•Relatively new class of insulin secretagogues
•Mechanism:
-close K+ channels in the pancreatic B cell membrane
depolarization ↑insulin release.
•Have rapid onset of action: good for control of postprandial glucose
excursions
•Metabolised by CYP3A4
Meglitinides & D-phenylalanines

28. Biguanides
• Mechanism: Specific mechanism not clear, but has several effects:
– ↓hepatic gluconeogenesis, ↑glycolysis, ↓glucose absorption, ↓plasma glucagon.
• Phenformin (an older biguanide), was discontinued because of risk of lactic
acidosis:
Example Duration of
action (hr)
Remarks
1. Metfomin 10-12 Side effects:
-GI distress (nausea, diarrhea)
-lactic acidosis in renal insufficiency
-inhibition of Vit B12 absorption
*Unlikely to cause Hypoglycemia

29. Metformin
• Clinical Use
– Considered a “euglycemic” agent
– Is an insulin sparing drug
– Very useful in patients with insulin resistance
– ↓risk of macro- & micro-vascular diseases
– Prevention of type 2 DM in high risk patients (obese, impaired
GTT)
• Contraindications
– Renal or hepatic disease, alcholism -  risk of lactic acidosis

30. Thiazolidinediones
• Mechanism:
– Stimulate the peroxisome proliferator-activated receptor-gamma (PPAR- receptor); a nuclear receptor
which regulates the transcription of genes encoding proteins involved carbohydrate and lipid metabolism.
– ↑glucose uptake in the liver, muscle & adipose tissue, ↓hepatic gluconeogenesis, affect body fat
distribution.
Examples Duration Remarks
Troglitazone Withdrawn from market coz of hepatotoxicity
Pioglitazone
Rosiglitazone
15-24
>24
-”euglycemic”
*Unlikely to cause Hypoglycemia
-↓LDL, HDL cholesterol
-can be combined with insulin, biguanides, or
sulfonyureas
-Side effects: edema, mild anemia

31. Example Duration of action
(hr)
Remarks
1. Acarbose 3-4 Adverse effects: flatulence, diarrhea,
& abdominal pain.
2. Miglitol 3-4
Mechanism:
-carbohydrate analogs; act within the intestine to inhibit -glucosidase, an
enzyme necessary for conversion of complex sugars to monosaccarides (form
that is readily absorbed).
-Glucosidase Inhibitors