1. DIABETES TYPE 2 Humaira Fareed Hassan April 21 st, 2009

2. TODAY, I WILL DISCUSS … Definition What is insulin? Types of Diabetes What sets Type 1 & Type 2 apart? Testing for Diabetes Statistics Medications Sulfonylureas Biguanides α-glucosidase inhibitors Thiazolidinediones

3. WHAT IS DIABETES? Refers to the group of diseases that lead to high blood glucose levels due to defects in either: insulin secretion insulin action Computer-generated image of insulin hexamers. Structure of insulin: Carbon, Hydrogen, Oxygen, Nitrogen. May be considered an autoimmune disease Commonly linked with obesity, environment, & genetics Actual etiology is unknown

4. WHAT’S THE DIFFERENCE?! Juvenile diabetes mellitus Don’t be fooled by its name!!! β-cells that produce insulin are destroyed. Results in insulin dependence: Injection (most common), jet injection, indwelling catheters, & inhaled insulin. Adult onset diabetes mellitus 90% of cases are Type 2 Ineffective insulin activity Insulin resistance Eventually leads to insulin dependence: Similar administrative techniques as Type 1. Type 1Type 2 Now classified according to etiology rather than the type of pharma- cologic treatment.

5. TESTING TESTING … Diagnosed according to the following standards: Casual (not fasting) PG concentration: ≥200mg/dL 2 hour (fasting) PG concentration: ≥200mg/dL 8-hour (fasting) PG concentration: ≥126mg/dL Normal resting PG concentration ranges between: 80mg/dL – 100mg/dL Fasting PG Test: Detects PG concentrations between 100mg/dL – 125mg/dL Inexpensive and fast Oral Glucose Tolerance Test: Detects PG levels between 140mg/dL - ≥200mg/dL Takes longer since PG level is monitored for approximately two hours.

6. WHY IS THIS BAD? You can’t see or feel the symptoms – until something really bad happens!  People with undiagnosed diabetes have a high risk of coronary artery disease, stroke, peripheral vascular disease, renal failure, and blindness. Retinopathy can develop 7 years or more prior to the diagnosis of Type 2 diabetes.

7. STATISTICS Type 2 Diabetes affects an estimated 8 million Americans ~ ⅓ undiagnosed Accounts for 9 – 15% of total costs for healthcare systems in the United States ~$132 billion spent in 2002! An estimated 200 million suffer from it worldwide Diabetics are: 2 – 6 fold more likely to have heart disease 2 – 4 fold more likely to have a stroke Diabetes is the most common cause of blindness in the working population

10. MAJOR TARGETED SITES OF DRUG CLASSES Pancreas ↓ Glucose level Gut α -glucosidase inhibitors Muscle & fat Liver Thiazolidinediones DPP-4 inhibitors GLP1 analogue Insulin Biguanides Insulin Sulfonylureas Meglitinides DPP-4 inhibitor Beta-cell dysfunction Reduced glucose absorption Hepatic glucose overproduction Insulin resistance Thiazolidinediones

11. SULPHONYLUREAS First Generation: Acetohexamide Chlorpropamide Tolbutamide Tolazamide Gliclazide Glimepiride Second Generation Glipizide Gliclazide Glibenclamide Gliquidone Glyclopyramide Third Generation Glimepiride

12. SULPHONYLUREAS Bind to ATP-dependent K + channels on the cell membranes of pancreatic β -cells Potential over cell becomes positive Open up Ca 2+ voltage gated channels  [Ca 2+ ]  more insulin needed!! Main precaution: hypoglycaemia Excess dose Excreted mainly by the kidney Thus, main side effects are mild & include nausea & diarrhea

13. Chlorpropamide rarely used long half-life, not well tolerated Glipizide & Glibencla- mide should be avoided in older patients Tolbutamide has a great pharmacokinetic profile, but poor clinical effect Most common prescribed: Gliclazide Reasonable half-life Great clinical effect Glipizide Glibenclamide Chlorpropamide Tolbutamide Gliclazide

14. BIGUANIDES Metformin Trade Names: Glucophage, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, Diaformin, & more Phenformin Buformin Metformin Phenformin Buformin Biguanides

15. BIGUANIDES From French Lilac Galega officinalis Complete mode of action not fully understood Do not affect the output of insulin NOT like sulfonyl- ureas May be used for both Type 1 & 2 diabetes! Suppresses hepatic gluconeogenesis Type 2 diabetic has three times normal rate of gluconeogen- esis Cuts back ⅓ ! MetforminBiguanides  insulin sensitivity  fatty acid oxidation  absorption of glucose in gastroin- testinal tract

16. BIGUANIDES Most popular of anti- diabetics (in US) 35 million prescriptions filled in 2006! Mostly prescribed for patients who are: Overweight Heart problems DO have normal kidney function Not metabolized Primarily excreted in the urine Elimination half-life ~6.2 hours MetforminBiguanides Lactic acidosis Build-up of lactic acid in body Decreases pH in body Why phenformin & buformin were taken off market Most commonly associated with gastrointestinal side effects Diarrhea, cramps, nausea, etc Toxic effects are rare Higher in older patients

17. ALPHA-GLUCOSIDASE INHIBITORS Acarbose Trade Names: Glucobay, Precose, Prandase Miglitol Trade Name: Glyset Acarbose Miglitol Voglibose

18. ALPHA-GLUCOSIDASE INHIBITORS Work by preventing the digestion of carbohydrates Startch, table sugar Carbohydrates normally digest to create simple saccharides Absorbed in the intestines (small) Mechanism of action includes competitive inhibition of enzymes needed to digest carbohydrates Reduces rate of digestion of carbohydrates! Long-term effects include a small decrease in hemoglobin A1c levels

19. ALPHA-GLUCOSIDASE INHIBITORS  postprandial hyperglycemia Inhibits glycoside hydrolases glucosidase Taken at beginning of a meal Gastrointestinal side effects Common Higher efficacy than Voglibose  postprandial hyperglycemia Inhibit glycoside hydrolases Taken at beginning of a meal Miglitol is systemically absorbed Excreted by the kidneys Voglibose is newest: less side effects economical AcarboseMiglitol & Voglibose Acarbose Miglitol Voglibose

20. THIAZOLIDINEDIONES Rosiglitazone Trade Name: Avandia Pioglitazone Trade Names: Actos, Glustin, Zactos Troglitazone Trade Names: Rezulin, Resulin, Romozin Troglitazone Pioglitazone Rosiglitazone Thiazolidinedione

21. THIAZOLIDINONES Work by activating PPAR ϒ (peroxisome proliferator-activated receptor-gamma)  insulin in fat tissue/skeletal muscle  insulin resistance  leptin count   appetite (weight gain) May be used alone or with Metformin (biguanide) or a sulfonylurea (Glitazone) Particularly prescribed for overweight patients

22. THIAZOLIDINONES Slow to act A lot more side effects than other anti-diabetic medications: Water retention Unrecognized heart failure Troglitazone Troglitazone banned: Linked to liver failure including hepatitis! Rosiglitazone & Pioglitazone approved: Less serious side effects Pioglitazone Rosiglitazone

23. IN SUMMARY … Two main types of diabetes: Type 1 – “insulin-dependent” Type 2 – adult onset diabetes (>90% of cases) Insulin is a hexamer: Very important to help find new treatments and medications Symptoms of diabetes can rarely be seen or felt: Take charge by maintaining a healthy lifestyle Diabetes is one of the most treated diseases in the US: Costs billions of dollars

24. IN SUMMARY … Sulfonylureas ATP-dependent K + channels, which results in an increased positive potential  More insulin needed! Biguanides are from a natural source, but only metformin is actively prescribed these days. Suppress hepatic gluconeogenesis. Alpha-glucosidase inhibitors competitively inhibit those enzymes that digest carbohydrates Decrease postprandial hyperglycemia Thiazolidinones work by activating PPAR ϒ  Increased release of insulin from fat and skeletal muscle tissue ChlorpropamideBiguanidesMiglitolThiazolidinedione

25. REFERENCES "Alpha-glucosidase inhibitor." Wikipedia, the free encyclopedia. 19 Apr. 2009. "Biguanide." Wikipedia, the free encyclopedia. 19 Apr. 2009. "Clinical Pharmacy Corner: How Do Sulfonylureas Work? |." Clinical Correlations. 18 Apr. 2009. "Diabetes mellitus." Wikipedia, the free encyclopedia. 18 Apr. 2009. Jackson, Timothy. "Endocrinology." West Virginia, Morgantown. West Virginia University School of Medicine. 18 Apr. 2009. Lowey, A. "Drug Treatment of Type 2 Diabetes in Adults." Nursing Standard 20 (2005): 55-64. SciFinder Scholar. 18 Mar. 2009. Keyword: Diabetes Type 2. McConnell, Edwina A. "Myth & Facts... About Diabetes Mellitus." Nursing (1999): 21-21. SciFinder Scholar. 18 Mar. 2009. Keyword: Diabetes Type 2. Muzuno, Cassia S. "Type 2 Diabetes & Oral Antihyperglycemic Drugs." Current Medicinal Chemistry 15 (2008): 61-74. SciFinder Scholar. 18 Mar. 2009. Keyword: Diabetes Type 2. "Sulfonylurea." Wikipedia, the free encyclopedia. 19 Apr. 2009.

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