Type 2 Diabetes Mellitus

Aetiology, Pathogenesis, History, and Treatment

The Diabetes Mellitus epidemic

• Estimated 180 million people in the world have DM. That’s roughly 6% of the world population.

• These numbers are estimated to double by 2030.

• Healthcare costs approaching 92 billion a year for the U.S.

What is Diabetes Mellitus?

• A metabolic disorder that results when the body is unable to maintain adequate insulin secretion to prevent hyperglycemia.

• Disease classification:

Type 1 or Type 2

• 90% of DM cases are Type 2

Type 2 DM

• Inception of disease begins with development of key metabolic abnormality, insulin resistance.

• Integral to understanding of type 2 DM is the role of insulin/glucose in the metabolic system.

Insulin

• A polypeptide hormone secreted by the islet of Langerhans in β-cells of the pancreas.

• First isolated in 1921 by Canadian researchers Banting & Best

• Essential in homeostatic regulation of blood glucose

Insulin’s function

• Standard metaphor (Lock & Key)Insulin (the key) must be bound to target cell (the lock) in order for glucose to enter the target cell from the bloodstream.

• Homeostatic functionSignals muscle/adipose tissues and liver to absorb glucose and utilize it. When energy requirements are met, insulin in the bloodstream triggers the liver to absorb glucose and convert it into energy saving form glycogen.

Insulin Resistance

• Metabolic abnormality that triggers the onset of type 2 DMNormal amount of insulin becomes inadequate for proper absorption of blood glucose

The body’s energy absorption system becomes inept

• Hypothesized triggers of IR1 in 10 people have genetic code for IR.

Obesity, Aging, Genetics, Diet high in sucrose/HFCS

Ensuing Hyperglycemia

• Complications

Vascular problems

(neuropathy, nephropathy, retinopathy)

Cardiovascular disease

Wound infection

• Symptoms

Frequent urination

(polyuria)

Frequent thirst

(polydipsia)

Excessive hunger

(polyphagia)

Type 2 DM Diagnosis

Fasting blood glucose level - diabetes is diagnosed if higher than 126 mg/dL on two occasions.

Random (non-fasting) blood glucose level - diabetes is suspected if higher than 200 mg/dL and accompanied by the classic symptoms of increased thirst, urination, and fatigue.

Oral glucose tolerance test - diabetes is diagnosed if glucose level is higher than 200 mg/dL after 2 hours.

Treatment of type 2 DM

• First goal is to eliminate symptoms and stabilize blood glucose levels.

• If diet/exercise fail, then oral medications are used

• Treatments include agents which increase the amount of insulin secreted by the pancreas agents which increase the sensitivity of target organs to insulinagents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.

Oral Medications Overview

• Sulfonylureas• Meglitinides• Biguanides• Thiazolidinediones• α-Glucosidase

inhibitors• Dipeptidyl peptidase-

4 inhibitors

Sulfonylureas• Stimulates insulin

secretion by β cells.

• Binds and closes K+ channels on β cells causing influx of Ca2+

which triggers the release of insulin.

• Not glucose dependent.Cause insulin release regardless of glucose level

• 1st generationAcetohexamideChlorpropamideTolbutamideTolazamide

• 2nd generationGlipizideGliclazideGlyburideGlimepiride

Meglitinides

• Also stimulates insulin secretion by β cells

• Similar mechanism of action to Sulfonylureas. Attaches to K+ channel at a different binding site

• Insulin efflux is glucose dependent. High glucose levels are needed for optimal action.

• Repaglinide

• Nateglinide

Biguanides

• Improves insulin’s ability to move glucose into cells (particulary in muscle tissue)

• Exact mechanism of action is not fully elucidated

• First-line medication used for treatment of type 2 DM

• Metformin

Thiazolidinediones

• Improves insulin sensitivity (adipose tissue)• Bind to steroid hormone nuclear receptor family-

peroxisome proliferator activated receptors [PPARs]- specifically PPARγ isoform.

• Activated PPARγ causes the transcription of specific genes that are intimately involved in cellular metabolism.

• Activated genes regulate glucose/fat metabolism and result in increased insulin sensitivity.

• rosiglitazone (Avandia) pioglitazone (Actos)

α-Glucosidase inhibitors

• Prevents digestion of carbohydrates

• Thus, they reduce their impact on blood glucose

• Competitively inhibits enzymes needed for carbohydrate digestion

• Acarbose

• Miglitol

Dipeptidyl peptidase 4 inhibitors

• Causes increased Incretin levels

• Vildagliptin

• Sitagliptin

Drug cocktails

• Combination therapy is sometimes used. Two drugs combined into one tablet.

• Examples include:

Sulfonylurea + Metformin = Glucovance

+

Metformin + Thiazolidinedione = Metaglip

Future of type 2 DM

• Complications can be prevented through proper diet and exercise

• Goal of future drug research is normalizing blood glucose and decreasing insulin resistance

• Proper education is necessary. Majority of complications are caused by negligence.