Type 2 Diabetes Mellitus

Aetiology, Pathogenesis,
History, and Treatment

The Diabetes Mellitus epidemic

Estimated 180 million people in the
world have DM. Thats 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 -cells of
the pancreas.
First isolated in 1921 by
Canadian researchers
Banting & Best
Essential in homeostatic
regulation of blood
glucose

Insulins 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 function
Signals 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 DM
Normal amount of insulin becomes inadequate for proper
absorption of blood glucose
The bodys energy absorption system becomes inept

Hypothesized triggers of IR
1 in 10 people have genetic code for IR.
Obesity, Aging, Genetics, Diet high in sucrose/HFCS

Ensuing Hyperglycemia
Complications

Symptoms

Vascular problems
(neuropathy, nephropathy,
retinopathy)

Frequent urination
(polyuria)
Frequent thirst
(polydipsia)
Excessive hunger
(polyphagia)

Cardiovascular disease
Wound infection

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 insulin
agents which decrease the rate at which glucose is
absorbed from the gastrointestinal tract.

Oral Medications Overview

Sulfonylureas
Meglitinides
Biguanides
Thiazolidinediones
-Glucosidase
inhibitors
Dipeptidyl peptidase4 inhibitors

Sulfonylureas
Stimulates insulin
secretion by cells.
Binds and closes K+
channels on cells
causing influx of Ca2+
which triggers the release
of insulin.
Not glucose dependent.
Cause insulin release
regardless of glucose
level

1st generation
Acetohexamide
Chlorpropamide
Tolbutamide
Tolazamide

2nd generation
Glipizide
Gliclazide
Glyburide
Glimepiride

Meglitinides
Also stimulates insulin
secretion by cells

Repaglinide

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.

Nateglinide

Biguanides
Improves insulins 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 familyperoxisome proliferator activated receptors
[PPARs]- specifically PPAR isoform.
Activated PPAR 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)

-Glucosidase inhibitors
Prevents digestion of
carbohydrates

Acarbose

Thus, they reduce their

impact on blood glucose
Competitively inhibits
enzymes needed for
carbohydrate digestion

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.