Insulin resistance is caused by decreased biological response to normal insulin levels and is often seen with conditions like diabetes, metabolic syndrome, obesity, and pregnancy. It can cause an inability to focus, increased hunger, weight gain, and high blood pressure. Insulin resistance is associated with increased insulin production by the pancreas and can lead to diabetes, cardiovascular disease, and other health issues. It involves defects in insulin signaling pathways involving proteins like PKB, IRS, and PI3 kinase. Treatment involves lifestyle changes and medications to lower blood sugar and insulin levels.

1. INSULIN RESISTANCE CAUSES AND
CONSEQUENCES
DR .KAPIL DEV

2. 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

3. INSULIN RESISTANCE IS OFTEN SEEN
WITH THE FOLLOWING CONDITIONS
DM,
 Metabolic syndrome,
 Obesity ,
 Pregnancy ,
 Infection or severe illness,
 Stress ,
 Inactivity and excess weight.


4. 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).


Increased blood pressure

Increased pro-inflammatory

.
Acanthosis nigricans.


Depression.
Increased blood triglyceride levels.

5. 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

8. 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


9. Protein Kinase B
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

10. 
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

11. Insulin receptor substrate 1
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.

12. 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

13. CAUSES OF SERINE PHOSPHORYLATION
OF IRS-1 PROTEINS ARE
Obesity
 Stress
 Hyperinsulinemia


PKC θ
• hyperglycemia
• Diacylglycerol
• inflammation

14. 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

16. PKC
Ca2+
cPKCs
(α, βⅠ, βⅡ,
γ)
DAG
+
+
nPKCs
(δ, ε, θ, η)
aPKCs
(ζ, λ)
+
No response
No response

17. FATTY ACID INDUCED IR
defective insulin-stimulated glucose transport activity
↑intramyocellular lipid metabolites (fatty acyl CoAs & diacylglycerol)
Activating PKC
activate a serine/threonine kinase cascade
Defect insulin signaling through the Ser/Thr phosphorylation IRS-1
Reduced IRS 1 associated PI3K activity
Defective regulation of GLUT4

18. 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.

19. PREGNANCY

Due to the combined effects of human placental lactogen,
progesterone, oestradiol and cortisol, which act as counterregulatory 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

20. PCOS

In 2003 Rotterdam- indicated PCOS


excess androgen activity


Oligoovulation &/or anovulation
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.

21. Hyperinsulinemia
abnormalities of hypothalamic-pituitary-ovarian axis
↑ GnR pulse frequency,
↑ovarian androgen production
↑ LH/FSH ratio,
↓follicular maturation,↓ SHBG binding.

PCOS

22. 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.

23. METABOLIC SYNDROME

24. 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.

25. 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.

26. 
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.

27. 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

28. MEASUREMENT OF INSULIN RESISTANCE
Research Methods

HOMA IR
= Fasting Glucose(mmol/L) x Fasting Insulin(mU/L)
22.5

Quantitative
Insulin Sensitivity
Check Index
(QUICKI )
= 1 / [log(fasting insulin µU/mL) + log(FBG mg/dL)]

29. 
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

30. TREATMENT

31. REFERENCES

Review Article -Insulin and Insulin Resistance-Gisela WilcoxMelbourne 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