DIABETES TYPE 2Humaira Fareed Hassan

April 21st, 2009

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

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

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 1 Type 2

Now classified according to etiology rather than the type of pharma-cologic treatment.

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.

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.

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

MAJOR TARGETED SITES OF DRUG CLASSES

Pancreas

↓Glucose level

Gut

α-glucosidase inhibitors

Muscle & fatLiver

Thiazolidinediones

DPP-4 inhibitors

GLP1 analogue

Insulin

Biguanides

Biguanides

Insulin

Sulfonylureas

Meglitinides

DPP-4 inhibitor

Beta-cell dysfunction

Beta-cell dysfunction

Reduced glucose

absorption

Reduced glucose

absorption

Hepatic glucose

overproduction

Hepatic glucose

overproductionInsulin

resistanceInsulin

resistance

Thiazolidinediones

SULPHONYLUREAS

First Generation: Acetohexamide Chlorpropamide Tolbutamide Tolazamide

Tolazamide

Gliclazide

Glimepiride

Second Generation Glipizide Gliclazide Glibenclamide Gliquidone Glyclopyramide

Third Generation Glimepiride

SULPHONYLUREAS Bind to ATP-dependent K+

channels on the cell membranes of pancreatic β-cells

Potential over cell becomes positive

Open up Ca2+ voltage gated channels

[Ca2+] more insulin needed!!

Main precaution: hypoglycaemia Excess dose

Excreted mainly by the kidney Thus, main side effects are

mild & include nausea & diarrhea

SULPHONYLUREAS 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

BIGUANIDES

Metformin Trade Names:

Glucophage, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, Diaformin, & more

Phenformin Buformin

Metformin

Phenformin

Buformin

Biguanides

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

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

ALPHA-GLUCOSIDASE INHIBITORS Acarbose

Trade Names: Glucobay, Precose, Prandase

Miglitol Trade Name: Glyset Acarbose

Miglitol

Voglibose

Voglibose

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 hemoglobinA1c levels

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

Acarbose Miglitol & Voglibose

Acarbose

Miglitol Voglibose

THIAZOLIDINEDIONES

Rosiglitazone Trade Name:

Avandia

Pioglitazone Trade Names: Actos,

Glustin, Zactos

Troglitazone Trade Names: Rezulin,

Resulin, Romozin

Troglitazone

Pioglitazone

Rosiglitazone

Thiazolidinedione

THIAZOLIDINONES

Work by activating PPARϒ (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

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

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

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 PPARϒ Increased release of insulin from fat and skeletal

muscle tissue

Chlorpropamide Biguanides Miglitol Thiazolidinedione

REFERENCES"Alpha-glucosidase inhibitor."

Wikipedia, the free encyclopedia. 19 Apr. 2009 <http://en.wikipedia.org/wiki/Alpha-glucosidase_inhibitor>.

"Biguanide." Wikipedia, the free encyclopedia. 19 Apr. 2009 <http://en.wikipedia.org/wiki/Biguanide>.

"Clinical Pharmacy Corner: How Do Sulfonylureas Work? |." Clinical Correlations. 18 Apr. 2009 <http://www.clinicalcorrelations.org/?p=500>.

"Diabetes mellitus." Wikipedia, the free encyclopedia. 18 Apr. 2009 <http://en.wikipedia.org/wiki/Diabetes>.

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 <http://en.wikipedia.org/wiki/Sulfonylurea>.

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