1. Diabetes mellitus

2. Introduction
It is a clinical syndrome characterized by disturbance in carbohydrates, fat, & proteins metabolism due to either insulin deficiency or insulin resistance.
Clinical presentation:
Polyuria, polydipsia, polyphagia, and weight changes.
Complications of diabetes: recurrent infections, neuropathy, retinopathy, nephropathy, DKA.

3. Types of diabetes
Type 1 DM: Autoimmune destruction of pancreatic beta cells. There is absolute insulin deficiency
Type 2 DM: Pancreas produces some insulin but either the amount is not sufficient, or there is insulin resistance

4. Preparation of insulins
Onset of effect
Peak
Activity duration
(hours)
Rapid-acting insulins
Insulin Lispro
Insulin Aspart
10 – 20 minutes
30 – 60 minutes
3 – 5
Short-acting insulins
Regular insulin
1 – 2 hours
5 – 7
Intermediate-acting
NPH (Neutral protamine Hagedorn)
Insulin Lente
6 – 12 hours
18 – 24
Long-acting insulins
Insulin Ultralente
Insulin glargine
4 – 6 hours
16 – 18 hours
No peak
24 – 36 24
Note: All are administered subcutaneously; Regular insulin can be administered I.V., especially in the management of diabetic ketoacidosis; surgery and during acute infections.

5. Mechanism of Action of Insulin
Insulin binds to a specific transmembrane tyrosine- kinase linked receptor located in cell membranes of most tissues. The receptor consists of two alpha subunits linked to two beta subunits.
Insulin binding to the alpha subunits causes the activation of the beta receptor subunit, which contain the tyrosine kinase. The enzyme is phosphorylated and this turn leads to the following two cascade pathways:
IRS-1 Pathway
IRS-2 Pathway

6. Mechanism of Action of Insulin
Insulin receptor substrate-1 (IRS-1) pathway: Leading to
Regulation of proliferation and differentiation of several cell types
Regulation of DNA synthesis
Insulin receptor substrate-2 (IRS-2) pathway: Leading to
Increased glucose uptake by the lipid and muscle cells
Increased glycogen formation
Regulation of gene transcription

8. Pharmcodynamics of Insulin
The general physiological function of insulin is to conserve fuel by facilitating the uptake, utilization and storage of glucose, amino acids and fats after meals.
Effects on carbohydrate metabolism
Increased glucose transport into the cells
Increased glycogen synthesis
Increased glycolysis
Decreased glycogenolysis
Decreased gluconeogenesis
Effects on protein metabolism
Increased amino acid transport into the cells.
Increased protein synthesis.

9. Pharmcodynamics of Insulin
Effects on lipid metabolism
Increased triglyceride formation and storage
Decreased lipolysis
Increased lipogenesis (glucose is converted to fat)
Other metabolic effects
Increased transport into cells of K+, Ca++, nucleosides and phosphate.
Long-term actions
Stimulation of cell proliferation

10. Methods of administration:
S.C. injection.
Portable pen injector.
Pump.
Follow up of insulin therapy:
By estimation of glucose in urine using urine dipsticks
From capillary blood glucose level using portable glucometers.

11. Indications of insulin
Type 1 DM.
Type 2 DM in some conditions:
After failure of oral drugs.
If the patient of type 2 got “stress conditions” e.g. infections, surgery, or pregnancy.
Diabetic ketoacidosis: regular insulin is the only type used I.V.
Hyperkalemia (insulin + glucose): insulin ↑ shift of K+ from blood to tissues.

12. Side effects of insulin
Hypoglycemia: the most common and dangerous side effect. If unconscious treated with IV glucose
Hypokalemia: insulin causes shift of K+ from extra- to intracellular fluid.
Hypersensitivity reactions; with animal insulin
Insulin resistance.
Local side effects
Lipodystrophy: (atrophy or hypertrophy) of s.c. tissue after repeated injections.
Local infection (rare now).

14. Interaction of Insulin with Other Drugs
Clinical Relevance
Alcohol
Hypoglycemia (ethanol inhibits gluconeogenesis)
High
Beta-blockers
Prolonged hypoglycemia and masking of certain symptoms of hypoglycemia
Salicylates
Hypoglycemia, with large doses (mechanism unknown)
Medium
Fenfluramine
Hypoglycemia (the drug increases the uptake of glucose into striated muscle)
MAO inhibitors
Hypoglycemia (MAO inhibit gluconeogenesis)

15. Events Requiring an Increase in Dosage of Insulin in Diabetic Patients
Infections
High fever
Trauma, surgical operations
Myocardial infarction
Pregnancy
Hyperthyroidism
Diabetic ketoacidosis

16. Oral antidiabetic drugs
Sulfonylureas
Meglitinides.
Biguanides
Thiazolidinediones
α- glucosidase inhibitors

17. 1. Sulfonylureas Classification:
First-generation compounds: chlorpropamide, tolbutamide
Second-generation compounds: glibenclamide, glyclazide and glipizide.
Third-generation compounds: glimepiride

18. Pharmacokinetics
Given 30 minutes before breakfast.
Plasma protein binding is high 90 – 99 %.
Metabolized by liver and their metabolites are excreted in urine with about 20 % excreted unchanged.
Mechanism of action:
1. Pancreatic action:
↑ insulin secretion by pancreatic β cells.
↓ serum glucagon.
2. Extrapancreatic action:
↑ insulin receptor sensitivity,
↓ hepatic output of glucose.

19. Therapeutic uses
Type 2 DM (they are not effective in type 1 DM).
Chloropropamide may be used in treatment of nephrogenic diabetes insipidus (it ↑ sensitivity of renal tubules to ADH).
Contraindications and Precautions
Type I diabetes (as sole therapy)
Pregnancy (risk of hypoglycemia in the newborn).
Severe liver or kidney disease.
Sulfa drug hypersensitivity.

20. Adverse effects:
Hypoglycemia .
Increased appetite and weight gain.
Pharmacologic failure is common due to progressive decline in β cell function.
Hepatotoxicity .
Teratogenicity .
Allergic reactions.
Disulfiram-like reaction in patients ingesting alcohol (chlorpropamide)
Dilutional hyponatremia, SIADH (mainly with chlorpropamide)

21. 2. Meglitinides Repaglinide & nateglinide
They increase insulin secretion .
Fast onset and short duration so; they are taken orally just before meals to control postprandial hyperglycemia.
Hypoglycemia is the major side effect .
They should be used with caution in patients with hepatic or renal impairment .

22. 3. Biguanides Metformin Mechanism of action:
↑ insulin receptors sensitivity.
↓ intestinal glucose absorption
↓ hepatic gluconeogenesis.
It does not increase insulin secretion (so it doesn’t cause hypoglycemia).

23. Pharmacokinetics
Metformin is well absorbed from small intestine.
Does not bind to plasma proteins
Excreted unchanged in urine.
Half life is hours, taken in three doses with meals.
Therapeutic uses:
Type 2 DM either alone (in mild cases) or in combination with other drugs.
To enhance weight loss in obese patients.
Polycystic ovary syndrome; it lowers serum androgens and restores normal menstrual cycles and ovulation.

24. Adverse effects:
GIT upset (the most common): anorexia, vomiting, and diarrhea.
↓ absorption of vitamin B12: rarely a clinical problem.
Lactic acidosis.
Contraindications
Patients with renal impairment.
Patients with hepatic impairment.
Past history of lactic acidosis.
Chronic lung disease.

25. 4. Thiazolidinediones
Pioglitazone , Rosiglitazone (Insulin sensitizers)
Mechanism of action
They bind to a nuclear receptor (peroxisome proliferator activated receptor, PPAR), located mainly in adipose tissue, skeletal muscle and liver, which regulates the transcription of several insulin responsive genes leading the following effects:
↑ Insulin receptor sensitivity (by about 60%).
↑ number of glucose transporters →↑ glucose uptake.
Have beneficial effect on serum lipoprotein levels (↓TGs).

26. Therapeutic uses:
To improve insulin resistance in type 2 DM.
Adverse effects:
Does not cause hypoglycemia
Hepatotoxicity
Fluid retention leading to peripheral edema & weight gain. (avoid in patients with CHF).

27. 5. αAlpha-Glucosidase inhibitors
Miglitol and acarbose
They act by competitive inhibition of intestinal α-glucosidase enzyme involved in the breakdown of starches into simple sugars → ↓ digestion & absorption of carbohydrates.
Does not cause hypoglycemia
GIT side effects are common: flatulence, diarrhea, abdominal pain.
Elimination: miglitol > 90% by the kidney (avoid in renal failure)
They should be avoided in patients with inflammatory bowel disease.

28. Drug interactions with oral hypoglycemic drugs
Drugs potentiate the hypoglycemic effect:
Microsomal enzyme inhibitors.
β-blockers.
Salicylates.
Drugs antagonize the hypoglycemic effect:
Microsomal enzyme inducers.
β-agonists.
Thiazides and diazoxide.
Anti-insulin hormones: e.g. steroids and glucagon.