1. Munir Gharaibeh, MD, PhD, MHPE
Diabetes Mellitus
Munir Gharaibeh, MD, PhD, MHPE
Faculty of Medicine
The Jordan University
August 2015
August 18
Munir Gharaibeh, MD, PhD, MHPE

2. Munir Gharaibeh, MD, PhD, MHPE
Diabetes Mellitus
Diabetes is a major cause of heart disease and stroke
Diabetes is a leading cause of renal failure, lower-limb amputations, and blindness.
Diabetes is the seventh leading cause of death in the United States
August 18
Munir Gharaibeh, MD, PhD, MHPE

3. Type I; Juvenile-onset; IDDM
10-20% of diabetics
Most commonly occurs in childhood or adolescence but may occur at any age
August 18
Munir Gharaibeh, MD, PhD, MHPE

4. Type I; Juvenile-onset; IDDM
Patients have little or no pancreatic function
Often present with ketoacidosis
Characterized by downhill course-severe type of DM with high mortality.
Easy to diagnose ( severe weight loss; easy fatigability; polyuria; polydipsia; polyphagia etc…)
August 18
Munir Gharaibeh, MD, PhD, MHPE

5. Type II; Maturity or Adult-onset; IIDM
Represents 80-90% of diabetics
Usually discovered accidentally after age
30-40 yrs
Most patients are obese .
More common in females as compared to males.
Patients have strong family history of DM (?genetic background).
August 18
Munir Gharaibeh, MD, PhD, MHPE

6. Type II; Maturity or Adult-onset; IIDM
Most cases have mild polyuria and fatigue.
Ketoacidosis is rare, unless in certain circumstances of unusual stress.
Insulin blood levels could be low, normal or high.
Insulin resistance is common (pre-receptor; receptor; post-receptor mechanisms)
August 18
Munir Gharaibeh, MD, PhD, MHPE

7. Munir Gharaibeh, MD, PhD, MHPE
Clinical Picture of DM
Early manifestations:
Polyurea, Polydipsia, Polyphagia, Ketoacidosis (type I).
Late manifestations or complications:
Atherosclerosis, IHD, Retinopathy, Nephropathy , Neuropathy
August 18
Munir Gharaibeh, MD, PhD, MHPE

8. Munir Gharaibeh, MD, PhD, MHPE
Management of DM
-Type I:
Diet
+ Insulin therapy
-Type II:
Diet + exercise
± Oral hypoglycemic agents
± Insulin
August 18
Munir Gharaibeh, MD, PhD, MHPE

9. Munir Gharaibeh, MD, PhD, MHPE
Secretion of Insulin
Ca++ dependent
Blood glucoselevel is the major regulator.
Factors/drugs ↑ release:
Glucose; AAs; FAs; GH; glucagon; ACTH; sulfonylureas; β-adrenergics, cholinergic drugs…
Factors/drugs ↓ release:
α-adrenergics; anticholinergics; phenytoin; alloxan; streptozocin.
August 18
Munir Gharaibeh, MD, PhD, MHPE

10. Munir Gharaibeh, MD, PhD, MHPE
Effects of Insulin
↑ Glucose uptake or transport into muscles and adipocytes.
↑ Glucose oxidation by muscles.
↓ Hepatic gluconeogenesis.
↑ Hepatic glycogen synthesis and storage.
↓ Glycogenolysis.
↑ AA uptake and protein synthesis by muscles and liver.
↓ Lipolysis.
↓ Ketogenesis.
August 18
Munir Gharaibeh, MD, PhD, MHPE

11. Munir Gharaibeh, MD, PhD, MHPE
Insulin Preparations
Natural:
Bovine
Porcine.
Old preparations, no longer available in Jordan.
Impure, cause allergy.
Biosynthetic: rHI
August 18
Munir Gharaibeh, MD, PhD, MHPE

12. Munir Gharaibeh, MD, PhD, MHPE
Insulin Preparations
- Potency:
Human > porcine > bovine
Allergy:
- Bovine > porcine > human(proinsulin is a major contaminant).
Insulins are classified according to duration of action (DOA)
August 18
Munir Gharaibeh, MD, PhD, MHPE

13. Factors Affecting Insulin Absorption
- Site of injection:
abdomen > arm > buttocks > thigh.
- Exercise increases blood flow at site.
- Depth of injection.
- Concentration and dose of insulin.
- Addition of protamine or isophane to insulin preparations delays absorption and hence duration of action.
August 18
Munir Gharaibeh, MD, PhD, MHPE

14. Munir Gharaibeh, MD, PhD, MHPE
Insulin Preparations
Ultra-rapid onset; very short acting:
O (hr) P (hr) DOA (hr)
Insulin Lispro
Insulin Aspart
Insulin Glulisine
Rapid onset and short acting:
Crystalline zinc
(Regular; Soluble)
Insulin zinc prompt
(Semilente)
August 18
Munir Gharaibeh, MD, PhD, MHPE

15. Munir Gharaibeh, MD, PhD, MHPE
Insulin Preparations
Intermediate onset and action:
Insulin zinc suspension
(Lente)
Isophane insulin suspension
(NPH; Humulin)
Slow onset and action:
Protamine zinc suspension
Extended insulin zinc suspension
(Ultralente)
August 18
Munir Gharaibeh, MD, PhD, MHPE

16. Munir Gharaibeh, MD, PhD, MHPE
Insulin Preparations
Peakless Insulins:
Insulin Glargine
Insulin Detemir
Mixed insulins:
Int. + short
Int. + long
August 18
Munir Gharaibeh, MD, PhD, MHPE

17. Munir Gharaibeh, MD, PhD, MHPE
Insulin Preparations
Advantages of peakless insulins over intermediate-acting insulins:
- Constant circulating insulin over 24hr with no pronounced peak.
- Reduced risk of hypoglycemia (especially nocturnal hypoglycemia).
- Clear solution that does not require
resuspension before administration.
August 18
Munir Gharaibeh, MD, PhD, MHPE

18. Munir Gharaibeh, MD, PhD, MHPE
August 18
Munir Gharaibeh, MD, PhD, MHPE

19. Munir Gharaibeh, MD, PhD, MHPE
August 18
Munir Gharaibeh, MD, PhD, MHPE

20. Munir Gharaibeh, MD, PhD, MHPE
All insulin preparations are mainly given S.C; except regular insulin, insulin Glulisine & insulin Aspart , which can also be given IV
August 18
Munir Gharaibeh, MD, PhD, MHPE

21. Methods of insulin administration
- Insulin Syringes
- Pre-filled insulin pens
- Insulin Jet injectors
- External insulin pump
Methods under clinical trials:
- Oral tablets
- Inhaled aerosol
Intranasal,
Transdermal
- Buccal spray
August 18
Munir Gharaibeh, MD, PhD, MHPE

22. Munir Gharaibeh, MD, PhD, MHPE
August 18
Munir Gharaibeh, MD, PhD, MHPE

23. Munir Gharaibeh, MD, PhD, MHPE
August 18
Munir Gharaibeh, MD, PhD, MHPE

24. Side Effects of Insulin Therapy
Hypoglycemia; manifested as symptoms of sympathetic ove ractivity.
Lipodystrophy
Allergy
Induration
August 18
Munir Gharaibeh, MD, PhD, MHPE

25. Oral Hypoglycemic Agents Biguanides
Metformin
Only effective in type II DM (effects require insulin).
↓ CHO absorption.
↓ Hepatic gluconeogenesis; ↑ glycolysis.
↓ Glucagon release.
↑ Peripheral utilization of glucose.
August 18
Munir Gharaibeh, MD, PhD, MHPE

26. Munir Gharaibeh, MD, PhD, MHPE
Biguanides
Side effects:
Nausea and vomiting, metallic taste.
Abdominal pain and diarrhea.
Hypoglycemia is rare.
Lactic acidosis.
↓ Vitamin B12 absorption.
August 18
Munir Gharaibeh, MD, PhD, MHPE

27. Munir Gharaibeh, MD, PhD, MHPE
Sulfonylureas
First Generation t1/ DOA
Tolbutamide
Chlorpropamide
Tolazamide
Acetohexamide
August 18
Munir Gharaibeh, MD, PhD, MHPE

28. Munir Gharaibeh, MD, PhD, MHPE
Sulfonylureas
Second Generation t1/ DOA
Glyburide (Glibenclamide)
Glipizide
Gliclazide
Glimeperide
August 18
Munir Gharaibeh, MD, PhD, MHPE

29. Actions of Sulfonylureas
↑ Insulin release (major MOA) (Receptor-mediated effect)
↑ Number of β-cells and insulin receptors.
↑ Peripheral cells sensitivity to insulin effect.
↑ Insulin binding to its receptors.
↑ Insulin affinity to its receptors.
↓ Hepatic gluconeogenesis.
↓ Glucagon release.
↑ Somatostatin release.
August 18

30. Munir Gharaibeh, MD, PhD, MHPE
Sulfonylureas
Sulfonylureas differ in potency, bioavailability, duration, tolerance, extent of protein binding, and metabolic fate.
Sulfonylureas have many interactions:
Propranolol, sulfa drugs, oral anticoagulants, aspirin, ↑ effects of sulfonylureas
Clinical uses: DM
Nocturnal enuresis (Glyburide → ↑ ADH release)
August 18
Munir Gharaibeh, MD, PhD, MHPE

31. Side Effects of Sulfonylureas
Hypoglycemia, like insulin.
Nausea, vomiting, dizziness.
Allergy, due to sulfa moiety.
Agranulocytosis.
Hepatic dysfunction.
August 18
Munir Gharaibeh, MD, PhD, MHPE

32. α-Glucosidase Inhibitors
Acarbose
Miglitol (more potent)
Effective in type II DM
↓ CHO absorption
Inhibit α-glucosidase , an enzyme in the brush border of intestine responsible for breakdown of CHO, and hence ↓ glucose absorption.
↓ Fasting and postprandial hyperglycemia.
August 18
Munir Gharaibeh, MD, PhD, MHPE

33. Prandial Glucose Regulators
Repaglinide
Nateglinide
Mitiglinide…
↑ Insulin release (similar action to sulfonylureas).
Taken before meals.
Could be taken with metformin or insulin.
Hypoglycemia is infrequent.
August 18
Munir Gharaibeh, MD, PhD, MHPE

34. Thiazolidinediones (TZD’s)
Rosiglitazone
Pioglitazone
Troglitazone
Peroxisome Proliferator-Activated Receptors (PPAR) agonists.
↑ Sensitivity of peripheral tissues to insulin effect.
↓ Glucose exit or output from the liver.
↓insulin resistance.
August 18
Munir Gharaibeh, MD, PhD, MHPE

35. Incretin Hormones Inhibitors
Sitagliptin
Gemigliptin
Linagliptin
Orally effective selective DPP-4 inhibitors
↑ blood levels of GLP-1, GIP, insulin, and C-peptide and ↓ glucagon blood levels.
August 18
Munir Gharaibeh, MD, PhD, MHPE

36. Aldose Reductase (AR) Inhibitors
Epalrestat
Ranirestat
Fidarestat
AR AR
Glucose Fructose Sorbitol
Sorbitol has been implicated in the pathogenesis of retinopathy, neuropathy and nephropathy
AR inhibitors proved to improve diabetic polyneuropathy.
Orally effective.
August 18
Munir Gharaibeh, MD, PhD, MHPE

37. Munir Gharaibeh, MD, PhD, MHPE
Other Drugs
Somatostatin
In low doses → ↓ glucagon release
Drugs Under Evaluation:
ACEI’s; ARB’s; Statins.
Pancreatic transplantation and gene therapy
August 18
Munir Gharaibeh, MD, PhD, MHPE