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Insulin resistance causes and consequences
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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