INSULIN RESISTANCE CAUSES AND CONSEQUENCES

DR .KAPIL DEV

INSULIN RESISTANCE

Decreased biological response to normal

concentration of circulating insulin.

Insulin (endogenous) or administered (exogenous).

Beta cells in the pancreas subsequently increase their

production of insulin, further contributing to

hyperinsulinaemia

INSULIN RESISTANCE IS OFTEN SEEN WITH THE FOLLOWING CONDITIONS

DM, Metabolic syndrome, Obesity , Pregnancy , Infection or severe illness, Stress , Inactivity and excess weight.

SIGNS AND SYMPTOMS Inability to focus.

Increased hunger.

Intestinal bloating (cannot digest and absorb).

Sleepiness (after meals).

Weight gain, difficulty losing weight ( around abdominal organs

in both males and females).

Depression.

Acanthosis nigricans.

Increased blood pressure

Increased pro-inflammatory

Increased blood triglyceride levels. .

ACANTHOSIS NIGRICANS

brown to black, poorly defined, velvety

hyperpigmentation of the skin.

found in body folds

↑insulin activates keratinocyte insulin-like growth

factor receptors, particularly IGF-1.

At high concentrations, insulin may also displace

IGF-1 from IGFBP.

Increased circulating IGF may lead to

keratinocyte and dermal fibroblast proliferation

CAUSES AND CONSEQUENCES

PKB mutation Mutation in IRS Increased in serine phosporylation of IRS protein PI3 Kinase Activity Metabolic syndrome. Type 2 Diabetes mellites. Obesity/ Inactivity and excess weight

PKB MUTATION The serine/threonine kinase Akt (also called PKB), triggers

insulin effects on the liver

Akt1 --inhibiting apoptotic processes, induce protein

synthesis pathways, key signaling protein in cellular that

lead to skeletal muscle hypertrophy, general tissue growth

Akt2 is required for the insulin-induced translocation of

glucose transporter 4 (GLUT4) to the plasma membrane

Protein Kinase B

Phosphorylation of the serine stimulates Akt phosphorylation

at a T308 residue.

Glycogen synthase kinase 3 (GSK-3) inhibited upon

phosphorylation by Akt, which results in increase of glycogen

synthesis

Suppression of hepatic glucose , PEPCK inhibition.

Glycogen synthase kinase

MUTATION IN IRS

Most of the metabolic and antiapoptotic effects of

insulin are mediated by the signaling pathway

involving the phosphorylation of the insulin receptor

substrate (IRS) proteins, IRS-1, IRS- 2

Mutation of IRS 1 results in IR in muscles and adipose

tissue.

Mutation of IRS 2 results in IR in liver.

Insulin receptor substrate 1

INCREASED IN SERINE PHOSPORYLATION OF IRS PROTEINS

Serine phosphorylation of IRS proteins can reduce the ability of

IRS proteins to attract PI3-kinase, minimizing its activation.

Serine phosphorylation in turn ↓ IRS-1 tyrosine

phosphorylation, impairing downstream effectors.

serine phosphorylation may lead to dissociation between

insulin receptor/IRS-1 &/or IRS-1/PI3-kinase, preventing PI3-

kinase activation or increased degradation of IRS-1

circulating FFA & adipokine tumour necrosis factor (TNF) may

↑ serine phosphorylation of IRS proteins, causing impaired

insulin signal transduction

CAUSES OF SERINE PHOSPHORYLATION OF IRS-1 PROTEINS ARE

Obesity Stress Hyperinsulinemia PKC θ

• hyperglycemia• Diacylglycerol• inflammation

PI3 KINASE ACTIVITY class 1a

Consisting of a regulatory subunit p85, tightly associated with a

catalytic subunit, p110.

p85 monomer & p85-p110 heterodimer compete for same binding

sites on tyrosine-phosphorylated IRS proteins, Imbalance could

cause either ↑ or ↓PI3kinase activity

Human placental growth hormone causes severe insulin resistance

by specifically ↑ expression of p85α subunit

Subsequently affecting the ability of insulin to stimulate the

association of the p85-p110 heterodimer with IRS-1

Reducing the PI3-kinase insulin signaling resistant states induced

by obesity, type 2 diabetes

PKC

Ca2+ DAG

cPKCs(α, βⅠ, βⅡ, γ)

+ +

nPKCs(δ, ε, θ, η)

+

aPKCs(ζ, λ)

No response

No response

FATTY ACID INDUCED IRdefective insulin-stimulated glucose transport activity

activate a serine/threonine kinase cascade

Reduced IRS 1 associated PI3K activity

Defective regulation of GLUT4

↑intramyocellular lipid metabolites (fatty acyl CoAs &

diacylglycerol)

Defect insulin signaling through the Ser/Thr phosphorylation

IRS-1

Activating PKC

DIABETES

The primary defects in insulin action appear to be in muscle

cells and adipocytes, with impaired GLUT 4 translocation

resulting in impaired insulin-mediated glucose transport.

β cells fail to compensate for the prevailing insulin resistance

leading impaired glucose tolerance.

As glucose levels rise, β cell function deteriorates further,

with diminishing sensitivity to glucose and worsening

hyperglycemia and diabetes develops.

PREGNANCY

Due to the combined effects of human placental lactogen,

progesterone, oestradiol and cortisol, which act as counter-

regulatory hormones to insulin mainly in 3rd trimester of

pregnancy.

Exaggeration of the insulin resistance normally seen in

pregnancy is associated with gestational diabetes mellitus

and gestational hypertension

PCOS In 2003 Rotterdam- indicated PCOS

Oligoovulation &/or anovulation

excess androgen activity

polycystic ovaries (ultrasound)

The ovarian dysfunction relates to the effects of compensatory

hyperinsulinaemia increasing pituitary LH secretion & androgen

production by the theca cells of the ovary.

Aromatization of androgens in setting of obesity ↑production of

oestrogens, further impairing function of the HPA axis.

Hyperinsulinaemia also suppresses SHBG production by liver, ↑ free

androgens. Elevated androgens in turn further aggravate insulin

resistance.

Hyperinsulinemia abnormalities of hypothalamic-pituitary-ovarian axis

↑ GnR pulse frequency, ↑ovarian androgen production ↑ LH/FSH ratio, ↓follicular maturation,↓ SHBG binding.

PCOS

INSULIN RESISTANCE SYNDROME

Constellation of associated clinical and laboratory

findings consisting of Insulin resistance,

Hyperinsulinemia dyslipidemia (↓HDL,↑ TG),

Hypertension

Clinical syndromes associated with insulin resistance

include type 2 diabetes, cardiovascular disease,

essential hypertension, polycystic ovary syndrome, non-

alcoholic fatty liver disease, certain forms of cancer and

sleep apnoea.

METABOLIC SYNDROME

HYPERTENSION

Insulin is a vasodilator with secondary effects on Na+2

reabsorption.

Hyperinsulinemia may result in enhanced sodium

reabsorption and increased sympathetic nervous

system (SNS) activity and contribute to the

hypertension.

INSULIN RESISTANCE ROLE IN DEVELOPMENT OF ATHEROSCLEROSIS AND HYPERTENSION

Compensatory hyperinsulinaemia is associated higher levels

of plasminogen activator inhibitor-1 (PAI-1) and ↑ fibrinogen

levels

Dyslipidaemia with ↑ LDL, ↓ HDL are also found in insulin

resistant states.

Again, lower levels of testosterone in men have been

associated with a proatherogenic lipid profile (high total and

LDL cholesterol)

Testosterone is an L-channel calcium blocker acting directly at

the level of the ion pore serve as systemic vasodilator

improve cardiac index and functional capacity.

Endothelin 1, a potent vasoconstrictor also inhibits insulin

signalling via PIP-3 kinase & competes with NO resulting in

endothelial dysfunction.

Mitogenic properties, mediated via MAP (mitogen activated

protein) kinase pathway, remain intact.

These mitogenic effects of insulin on endothelial smooth

muscle cell proliferation probably contribute to

atherosclerosis.

UNCOMMON GENETIC DISORDERS ASSOCIATED WITH INSULIN RESISTANCE

Down’s Syndrome Turner’s Syndrome Klinefelter’s Syndrome Thalassaemia Haemochromatosis Lipodystrophy Progeria Huntington’s Chorea Myotonic dystrophy Friedrich’s ataxia Laurence-Moon-Biedel syndrome Glycogen storage diseases type I & III Mitochondrial disorders

MEASUREMENT OF INSULIN RESISTANCE

HOMA IR = Fasting Glucose(mmol/L) x Fasting Insulin(mU/L)

22.5

Research Methods

= 1 / [log(fasting insulin µU/mL) + log(FBG mg/dL)]

Quantitative Insulin Sensitivity Check Index (QUICKI )

Functional Measures of Insulin Resistance McLoughlin et al were able to identify insulin resistant individuals

from an overweight-obese cohort plasma triglyceride concentration, ratio of triglyceride to high-density lipoprotein cholesterol concentrations insulin concentration.

Using cut points of 1.47 mmol/L for TG, 1.8 mmol/L for the TG-HDL - cholesterol ratio 109 pmol/L (16 mIU/L) for insulin

TREATMENT

REFERENCES

Review Article -Insulin and Insulin Resistance-Gisela Wilcox-

Melbourne Pathology, Collingwood, VIC 3066, Monash

University Department of MUnit, C/- Body Composition

Laboratory, Monash Medical Centre, Clayton, VIC 316

Willams Endocrinology12TH EDN

Teitz Clinical Chemistry 5TH EDN

Text book of biochemistry 3rd EDN lby dr.dinesh puri

thanks