Post on 12-Apr-2017
INSULIN RESISTANCE
Mr.Tapeshwar Yadav.P.G Final Year
Dept. of BiochemistryMamata Medical College
6th April 2012
Insulinpolypeptide hormoneLangerhans—clusters of cells
Normal blood insulin level:5-15µU/ml
Pancreas:• Only 2% of the pancreas weight is beta cell.
• 1 unit/kg of body weight.
• Over 80% of beta cells should be lost before diabetes develops.
GLUCAGON
INSULIN
Glu
ThrLys
ThrTyr Phe Phe Gly Arg
Glu Gly
Cys
ValLe
TyrLeuAla
Val
Leu
HisSer
GlyCysLeuHisGlnAsnValPhe
Asn CysTyr
Asn
Glu
Leu
Gln
TyrLeu
SerCysIleSerThrCysCys
Gln
Glu
Val
Ile
Gly
Pro
Insulin Structure
Alpha chain
Beta chain
Disulfide bridges
• The hormone is protein with high molecular weight.
• Unstable if taken orally.• Metabolized by the kidney.
Structure of insulin
Synthesis of insulin
Proinsulin
Centr-omereCATCALPTH
c-Ha-ras
INS IGF-2 -globin
Short arm of chromosome 11
C peptide
Insulin A chain
Insulin B chain
Proinsulin
Insulin A chain
Insulin B chain
C peptide
Insulin Production
Insulin Resistance Definition
The condition in which normal amounts
of insulin are inadequate to produce a
normal insulin response from fat, muscle and liver cells.
Etiology of IR• Genetic factor• Medication : steroid, glucosamine
etc• Conditions : Obesity, Metabolic
syndrome, pregnancy, infection or severe illness, stress etc
Insulin resistance and obesity
Insulin resistance and Type 2 diabetes:
Dysfunctional β cells
Fig:-Typical progression of Type 2 diabetes
MEASUREMENT OF INSULIN RESISTANCE
Hyperinsulinemic euglycemic clamp
INSULIN TOLERANCE TEST
MINIMAL MODEL TEST HOMEOSTATIC MODEL
TEST Quantitative insulin
sensitivity check index (QUICKI)
Hyperinsulinemic Euglycemic Clamp
– A measure of peripheral insulin
sensitivity– High insulin infusion rate: 80 mU/m2 body
surface area– Variable infusion rate of dextrose to keep
blood glucose levels in the range of 90-100 mg/dl.
– A higher glucose infusion rate (GIR) indicates better insulin sensitivity
Insulin Tolerance test
• First method developed to measure in vivo insulin sensitivity
• GTT with Insulin tolerance test• BMI is to be considered
Plasma Glucose
0
50
100
150
200
250
300
350
400
0 0.5 1 1.5 2 2.5 3
Hours
Plas
ma
Glu
cose
(Mg/
dl)
NormalMildSevere
Plasma Insulin
0
200
400
600
800
1000
1200
0 0.5 1 1.5 2 2.5 3
Hours
Plas
ma
Insu
lin (μ
U/d
l)
NormalMildSevere
Homeostatic Model test
• Fasting plasma glucose and fasting plasma insulin concentrations are used to estimate IR– Used to assess hepatic insulin sensitivity– a lower score indicates better insulin sensitivity
Who is a risk for IR• Overweight (BMI > 25)• A man with a waist > 40 inches or a woman
with a waist > 35 inches• > 40 years of age• Latino, African American, Native American or
Asian American• have family history with type 2 diabetes,
Hypertension or arteriosclerosis• have had gestational diabetes• Have high BP, high blood TG, low HDL-C
OBESITY50-80% of PCOS are obese
Obesity induced hyperinsulinemia contributes to obesity specific insulin resistance
Insulin resistance in PCOS is genetic and obesity worsens it.
Some Medical Condition are associated with IR
• Metabolic syndrome• Abnormally sedentary lifestyle (aging and
obesity)• Type 2 diabetes• Fatty liver• Arteriosclerosis• Skin lesions or skin tags : Achanthosis
nigricans• Reproductive abnormalities in woman (PCOS)• Hyperandrogens• Growth abnormalities
INSULIN RESISTANCE The vicious cycle of insulin resistance
Insulin Resistance
Overeating Truncal obesity
High blood sugar
Hunger Craving carbohydrates
Excessiveinsulin productionby reduced number of beta cells
Beta cell burnout
OBESITY
DIABETES MELLITUS
INSULIN RESISTANCE
INSULIN SECRETIONDEFECT
GENETICPREDISPOSITION
ENVIRONMENTALFACTORS
GLUCO-ANDLIPO-
TOXICITY
Low physical activityHigh energy intake
Genes
Vicious
circle
IGT
FFATNF-a, resistin, leptin, adiponectin …
Liver Muscles
Treatment of IRWeight reduction,Exercise and Dietary modifications
IR & OBESITY
Weight Loss•Reduces insulin levels•Improves status – Clinical - Metabolic - Endocrinal•Androgen level falls by 44%Weight loss is first line therapeutic option
Dietary Components Which May Affect Insulin Resistance
↓ IR Whole grains Fruits and vegetables Low fat dairy products Magnesium Calcium Dietary fiber Omega-3 fatty acids Low GI foods
↑ IR• Saturated fat• Salt (deficiency or
excess)• Alcohol
(>30g/day)
Increased intake of fruits, vegetables, and low fat dairy products is associated with:
↑ed insulin sensitivity↓ed risk of metabolic syndrome ↓ed risk of Type 2 diabetes↓ed risk of hypertension
High intakes of calcium and magnesium are associated with: ↑ed insulin sensitivity
↓ed risk of metabolic syndrome ↓ed risk of Type 2 diabetes
The Diet: Epidemiologic Studies
Insulin Resistance At A Glance:-Insulin resistance is a condition in which the cells of the body become resistant to the hormone, insulin. Insulin resistance may be part of the metabolic syndrome, and associated with the development of heart disease.
Insulin resistance precedes the development of type 2 diabetes.
Insulin resistance is associated with other medical conditions including fatty liver, arteriosclerosis, acanthosis nigricans, skin tags, and reproductive abnormalities in women.
Individuals are more likely to have insulin resistance if they have any of the associated medical conditions listed above.
They also are more likely to be insulin resistant if they are obese or are Latino, African-American, Native American, and Asian-American.
While there is a genetic component, insulin resistance can be managed with diet, exercise, and medication.
Contd…….
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