Diabetes Mellitus

American Diabetes Association Definition Diabetes Mellitus is a group of Metabolic Diseases characterized by Hyperglycemia resulting from defects in insulin secretion, insulin action, or both. American Diabetes Association

Diabetes: Clinical Features Symptoms: Polyuria Polydipsia = thirst Polyphagia= appetite Asthenia & Loss of weight Signs: No specific signs may be signs of complications

“Leonard Thompson (14 year old boy) & Elizabeth Hughes (aged 14 years), were the first patients to be treated with insulin in 1922.

“Fredrick Banting (1921), successfully, extracted insulin, gaining the Nobel prize for this great discovery”.

“Claude Bernard and Von Mering (1889), discovered in the same year that pancreatectomy causes diabetes”

“Mathew Dobson (1776), identified glycosuria.

“ Thomas Willis (1621 - 1679), discovered the sweetness of urine, hence, the name Diabetes Mellitus arised”

“ Diabetes was long thought to be a kidney disease (Greek & Arabic Methodology).

Predisposing Factors IDDM Heredity. Histocomptability. Virus infection. Seasonality. Cell-mediated immunity.

Insulin Synthesis PrePro Insulin Split at position 61/62 Pro Insulin C peptide

Insulin Secretion Curve Biphasic insulin response to a constant glucose stimulation (IVGTT - hyperglycemic Clamp) Insulin rate Basal Time (min) 4 60

Fate of Absorbed Glucose Glycogenesis G Muscle Cells 50 % Glycolysis Glycogenesis Liver Cells 30 % G Glycolysis Lipogenesis G Fat Cells 5 % Glycolysis

Hypoglycaemic Hormone Counter regulatory Hormones Hormonal Regulation Blood Glucose Level < 110 mg/L Glucagons Growth Hormone Adrenaline Cortisol Insulin Hypoglycaemic Hormone Counter regulatory Hormones

Diabetes Estimates and Projection

Classification of Diabetes Mellitus Primary Diabetes Type 1 insulin dependent diabetes Type 2 non insulin dependent diabetes

Classification of Diabetes Mellitus Secondary Diabetes Gestational diabetes Malnutrition related diabetes Diabetes resulting from: Pancreatic disease Hormonal diseases Drug/chemical induced Genetic syndromes

METABOLIC ASPECTS

insulin secretion disorder in hepatic glucose production Key Organs of Diabetes Pancreas insulin secretion disorder Muscle Liver in hepatic glucose production in glucose storage Hyperglycemia

Peripheral Abnormalities Muscles Liver Fat tissues Glycogenogenosis Gluconeogenesis Glycolysis Glycolysis Gluconeogenesis Lipogenesis Lipolysis Glycogenogenesis FFA Glucose production Glucose Storage Hyperglycaemia

Pathogenesis of diabetes: metabolic features Genetic predisposition Insulin resistance Defective insulin secretion Hyperglycemia 7

Impaired Insulin Secretion

Causes of Impaired Insulin Secretion Decrease in number of Beta cells by 40-50 % {In Insulin resistance states, the number is either normal or increased}

Causes of Impaired Insulin Secretion Amyloid deposits Amylin : amyloid material secreted by B cells Interferes with the recognition of the glucose signal

Causes of Impaired Insulin Secretion Reduced activity of the glucokinase ATP production reduced inside B cells Closure of K channel decreases Entry of Calcium reduced release of Insulin reduced

Insulin Resistance

Types of Insulin Resistance Receptor defect Post Receptor defect

Types of Insulin Resistance Receptor defect Decrease in the affinity Decrease in number (rare)

Types of Insulin Resistance Post receptor defect Glucose Transporters Intra cellular utilization Enzymatic activity

Gluco-toxicity Insulin secretion disorder Chronic Hyperglycemia resistance

Vascular Complications

Vascular complications Micro-vascular complications Macro-vascular complications

Micro-vascular complications Retinopathy Nephropathy Neuropathy

Macro-vascular complications CHD CVD PAD 10 years accelerated

Treatment Of Diabetes

Treatment of diabetes: Life style modification Insulin Oral hypoglycemic agents

Life style modification Diet control Exercise Smoking cessation

Diet Control

DIET CONTROL All diabetic patients should be on diet control. Diet control is a must either the patient is taking insulin or oral therapy. Over weight should be reduced .

DIET CONTROL Diet control should be tried at first before the next step [insulin or tablets] especially in obese patients, When diet fails drugs are indicated.

DIET CONTROL The diet for a diabetic patient is not so different from the healthy diets for the whole population. Simple sugars Carbohydrate [as sucrose], should be limited for the diet of diabetic patients.

DIET CONTROL Carbohydrate content should be in a fiber-rich diet [for example fruits containing fibers as apples]. ….. because the fiber content of diet delays absorption of carbohydrates avoiding the rapid elevation of blood glucose levels.

DIET CONTROL Calories : Calories should be tailored to the need of the patient. Diet should contain: Carbohydrates → 50 - 55% Fat→ 30-35% Protein →10 - 15%

INSULIN

Indication of Insulin Type 1 diabetes Unstable diabetes Type 2 diabetes failed on SUs. Pregnant diabetic patients Surgery (all diabetic patients) Diabetic coma

Oral Hypoglycemic agents

Oral hypoglycemic agents Biguanides Sulfonylureas α- glucosidase inhibitors Thiazolidinediones Prandial glucose regulator

Biguanides Biguanides are derivatives of the antimalarial agent Chloroguanide. Which is found to have hypoglycemic action. The most commonly used member of biguanides is Metformin [Cidophage].

Biguanides Indication: Type 2 diabetes failed on diet Metformin can be given alone or in combination with sulfonylureas or Insulin

Biguanides Mode of action Biguanides [Metformin] is an Antihyperglycemic and not Hypoglycemic agent. It does not stimulate pancreas to secrete insulin and does not cause hypoglycemia (as a side effect) even in large doses. Also it has no effect on secretion of Glucagon or Somatostatin.

Biguanides Mode of action: Decreases the intestinal absorption of CHO Increases glucose uptake (GLUT 4) Increases glucose utilization (glycogensynthase) Increases glycolysis via anaerobic pathway (lactic acidosis)

Biguanides Pharmacokinetics: Metformin is well absorbed from small intestine, stable, does not bind to plasma proteins, excreted unchanged in urine. Half life of Metformin is 1.5 - 4.5 hours, taken in three doses with meals

Biguanides Side effects: occur in 20-25 % of patients. include.. Diarrhea, abdominal discomfort, nausea, metallic taste and decreased absorption of vitamin B12.

Biguanides Contraindications Patients with renal or hepatic impairment. Past history of lactic acidosis. Heart failure, Chronic lung disease. .. These conditions predispose to increased lactate production which causes lactic acidosis which is fatal.

SULFONYLUREAS SUs., have been discovered during the 2nd. World war (sulfonamide). SUs are drugs that used orally to control blood glucose levels of type 2 diabetes.

SULFONYLUREAS Types: First generation, Chlorpropamide (Pamidin) Tolbutamide (Diamol) Second generation, Gliclazide (Diamicron) Glibenclamide (Daonil) Glipizide (Minidiab) Third generation, Glimepiride (Diabride) (Amaryl)

SULFONYLUREAS Mechanism of action: Pancreatic effect Extra-pancreatic effect

SULFONYLUREAS Pancreatic effect: Increase insulin release from pancreas Suppress secretions of Glucagons

SULFONYLUREAS Extra pancreatic effect: Increases the number of insulin receptors Increases post-receptor insulin sensitivity Increases glucolysis Increases glycogen storage in muscle and liver Decreases the hepatic output of glucose

SULFONYLUREAS Pharmacokinetics: They are effectively absorbed from gastrointestinal tract. Food can reduce the absorption of sulfonylurea. Sulfonylureas are more effective when given 30 minutes before eating. Plasma protein binding is high 90 – 99 % .. mainly bind to albumen.

SULFONYLUREAS Pharmacokinetics: 1st generation members have short half lives. 2nd generation is administered once, twice or several times daily. 3rd generation is administered once daily.

SULFONYLUREAS Pharmacokinetics: All sulfonylurea are metabolized by liver and their metabolites are excreted in urine with about 20 % excreted unchanged. Sulfonylurea should be administered with caution to patients with either renal or hepatic insufficiency.

SULFONYLUREAS Adverse Reactions : Very few adverse reactions [4 %] in the first generation and rare in the 2nd and 3rd generation. SUs may induce hypoglycemia especially in elderly patients with impaired hepatic or renal functions-These cases of hypoglycemia are treated by I/V glucose infusion.

SULFONYLUREAS Adverse Reactions : First generation may induce other side effects as …nausea and vomiting & dermatological reactions …These side effects are fewer in the 2nd generation and rare in the 3rd generation.

SULFONYLUREAS Drug interactions: Some drugs may enhance or suppress the actions of sulfonylureas Either by affecting: Their metabolism and excretion The concentration of free sulfonylureas in plasma through competing them on plasma proteins.

SULFONYLUREAS Contraindications : Type 1 DM Pregnancy and Lactation. Significant hepatic or renal failure.

Drug – Drug interaction NSAIDs Salicylates Sulfonamide ß-blockers Chloramphenicol Diazepam MAOI Barbiturates Thiazide and loop diuretics Sympathomimetics Corticosteroids Oestrogen / Progesterone combinations

α Glycosidase Inhibititor Acarbose (Glucobay) Indicated for type 2 diabetes In addition with diet In addition with other anti-diabetic therapies

Acarbose (Glucobay) Mode of action: Dose: Poorly absorbed 1% (act locally in G.I.T.) Inhibits α glucosidase, so inhibits CHO degradation Dose: 50mg to 100mg 3 times daily before meals

Acarbose (Glucobay) Side effects: Flatulence (77%) Diarrhea Abdominal pain (21%) Decreased iron absorption

Rosiglitazone (Avandia) Thiazolidenedione Rosiglitazone (Avandia) Pioglitazone (Actos)

Thiazolidenedione Mode of action: Insulin sensitizer (increase insulin sensitivity in muscle, adipose tissue & liver) They are not insulin secretagogues (Not insulin releasers)

Thiazolidenedione Drawbacks: Side effects: They are not effective alone in case of severe insulin deficiency and should be combined with sulfonylurea or metformin or both Side effects: Hepatotoxicity weight gain Dyslipidaemia (increases LDL)

Prandial glucose regulators (Meglitinide) Example: Repaglinide, Novonorm (NovoNordisk) Rational: Fast acting, short duration non-sulfonylurea Designed to minimize mealtime blood glucose peaks

Repaglinide, Novonorm Mechanism of action: Stimulation of pancreatic insulin release by closing ß-cells KATP channels Very rapid onset of action and short duration (TMAX = 1 hour, metabolized by liver T1/2 = 70 minutes) No hypoglycemic metabolites

Repaglinide, Novonorm Clinical efficacy: drawbacks: Improves postprandial glycemia Less effective in decreasing fasting blood glucose levels and HbA1C drawbacks: Fails to provides a stable 24 hours blood glucose control Complicated dosage style (3-8 tablets/daily) How to adapt the dosage to the meal volume?

SEDICO Pharmaceuticals The End