Insulin resistance causes and consequences

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