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…….

THANK YOU FOR YOUR ATTENTION!