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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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