Transcript Type 2 Diabetes Mellitus

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 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 body’s 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
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Sulfonylureas
Meglitinides
Biguanides
Thiazolidinediones
α-Glucosidase
inhibitors
• Dipeptidyl peptidase4 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 generation
Acetohexamide
Chlorpropamide
Tolbutamide
Tolazamide
• 2nd generation
Glipizide
Gliclazide
Glyburide
Glimepiride
Meglitinides
• Also stimulates insulin
secretion by β 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 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 familyperoxisome 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
• 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.