Insulin Resistance And Its Implications In The Management of Type II Diabetes

Insulin Resistance And Its Implications In The Management

of Type II Diabetes

Insulin Resistance

• The possibility that there can be defect in the insulin sensitivity in people with diabetes was first reported 50 years ago (1- Himsworth et.al., 1936)

• Now ‘Insulin Resistance’ has clearly emerged as an important cause of glucose intolerance leading to type II diabetes

• ‘Insulin Resistance’ may even play role in other pathological conditions.

• Reducing insulin resistance improves glucose homeostasis(Consensus Development conference on Insulin Resistance, American

Diabetes Association, 5-6 November 1997)

What is Insulin resistance?

Definition: Impaired biological response to either exogenous

or endogenous insulin

• Insulin resistance does not have to be confined just to glucose metabolism parameters.

• Insulin resistance should also apply to the biological action of insulin which includes lipid and protein metabolism, vascular endothelial function & gene expression

(Consensus Development conference on Insulin Resistance, American Diabetes Association, 5-6 November 1997)

Conditions Frequently associated with insulin resistance

• Insulin resistance syndrome OR Syndrome X (group of clinical and laboratory findings associated with insulin resistance)

• Obesity

• NIDDM

• IDDM

• Physiological states (Puberty, Pregnancy)

• Polycystic ovarian syndrome

• Glucocorticoid therapy

• Severe illness (Sepsis)

• Metabolic derangement (Acidosis, uremia)

• Endocrinopathies (Cushing syndrome, Acromegaly)(Josllin’s Diabetes Mellitus, 13th ed., 1994)

Mechanism(s) of insulin resistance

• Primary mechanism appears to be block in glucose transport.

• This defect has two components

1. Primary genetic component

2. Secondary environmental component


Primary genetic component

Characterized by• Reduced efficiency of translocation of GLUT4 in muscle cells

(GLUT- Glucose transporters, present inside the cells.

Insulin stimulates translocation of these transporters to the

plasma membrane, which subsequently transport glucose

inside the cells) • Defect in glycogen synthesis


Secondary environmental componentIt involves the effects of increased levels of glucose and free fatty acids

Chronic hyperglycemia (Glucotoxicity)

Decreased GLUT4 translocation in muscle

Reduction in insulin-stimulated glucose uptake

Elevated plasma free fatty acid levels (Lipotoxicity)

Decrease glucose transport and inhibits glycolysis

Insulin resistance(Consensus Development conference on Insulin Resistance, American Diabetes Association, 5-6 November 1997

Insulin resistance and relationship with Glucose toleranceType II diabetes is a metabolic disorder much beyond just abnormal glycemic parameters.

Natural history of type II diabetes

Age

Obesity

Ethnicity

Physical inactivity

Normal glucose tolerance

Insulin resistance Weight reduction

Physical activity

Impaired glucose tolerance Pharmacological agents

Beta cell dysfunction

Type II diabetes

• Studies have shown that subjects with IGT are more insulin resistant.

(Difficult Diabetes,Geoff Gill et. al. 2001)

Does insulin resistance predict diabetes?

• Plasma insulin levels are powerful predictor for type II diabetes (Independent of obesity and waist circumference)

• The risk is particularly strong for individuals with a family history of diabetes.

• Thus identification of insulin resistance at an early age may be especially beneficial for the offspring of type II diabetic patients.


In whom to suspect insulin resistance?

• Overweight (particularly with central obesity)

• With strong family history of diabetes

• History of gestational diabetes

• Impaired fasting plasma glucose ( between 110-125mg/dl)

• People with dyslipidemia or hypertension


Should insulin resistance be treated for the primary prevention of diabetes or other disease?

• Insulin resistance is associated with morbidity and mortality BUT it does not prove that it is the cause of these outcomes

• It is unclear whether insulin resistance causes or is simply associated with many other high-risk conditions such as hypertension, dyslipidemia and accelerated atherosclerosis.

• Since the pathophysiology of type II diabetes virtually always includes significant insulin resistance, treatment of insulin resistance could prevent or delay the onset of type II diabetes


Should insulin resistance be treated for the secondary prevention of the complications of

diabetes or other diseases?

Secondary complications of diabetes:

A) Macrovascular: Cardiovascular, cerebrovascular and peripheral vascular disease

B) Microvascular: Retinopathy, nephropathy and neuropathy

• Role of insulin resistance is more established in macrovascular complications


Insulin resistance &Complications of Diabetes• Insulin resistance itself, independent of other risk factors increases the

risk of atherosclerosis.• Insulin stimulates generation of local vasodilator- nitric oxide from

endothelial cells• This potentially beneficial effect is blunted in insulin resistant subjects

with obesity and/or type II diabetes.• Subnormal generation of nitric oxide could promote cardiovascular

events by diminishing the normal inhibitory actions of nitric oxide on vascular smooth muscle proliferation, platelet adhesiveness, vasoconstriction or development of hypertension


Complications of Diabetes: Macrovascular (Contd.)

• Hyperinsulinemia is a compensatory accompaniment to insulin resistance

• Hyperinsulinemia sensitize cell, such as vascular smooth muscle cells or endothelial cells to the mitogenic effects of various growth factors.

• Hyperinsulinemia or insulin resistance aggravate the dyslipidemia which increases the risk of atherosclerotic disease.


Complications of Diabetes: Microvascular

• Evidence strongly suggests hyperglycemia in the pathogenesis of these complications

• No evidence that suggests that insulin resistance independent of hyperglycemia, has a role in these complications

• Therefore only to the extent to which reduction in insulin resistance reduces hyperglycemia will have role in prevention of retinopathy, nephropathy and neuropathy(Consensus Development conference on Insulin Resistance, American

Diabetes Association, 5-6 November 1997)

Insulin resistance and dyslipidemia: Implications in management

• Insulin resistance affects virtually all lipids and lipoproteins leading to high Triglycerides, Low HDL, High small dense LDL

• Statins (Atorvastatin and simvastatin) lowers plasma total, LDL & VLDL cholesterol, increases HDL concentrations and improves insulin resistance

(Paolisso G. et.al,Atherosclerosis, 2000)

• Gemfibrozil &Fenofibrate has been reported to improve insulin sensitivity(Mussoni L. Et.al.,Atherosclerosis, 2000,

Idzior-Walus B. et.al.,Eur. J. Clin. Invest.2000) • Nicotinic acid can correct or improve all lipid or lipoprotein abnormalities in type

II diabetes but it causes insulin resistance and may precipitate hyperglycemia therefore contraindicated.

(Kreisberg RA,Am. J. Cardiol, 1998)

Insulin resistance and hypertension

• Insulin resistance is associated with an increased risk for development of hypertension

(Mangrum A.,Jour. Diab. Compli., 1997)

• Studies have shown that plasma insulin levels are increased in both treated and untreated patients with essential hypertension

(Bhanot S., Cardiovasc Res.,1996, Supiano MA et.al,Am.J. Physiol. 1992)

Proposed mechanisms of hypertension with insulin resistance

• A) Insulin-resistant patients may have increased responsiveness to angiotensin

(Gaboury et.al,Jour. Clin. Invest. 1994)

• B) Increased sympathetic activity may be present & increased levels of norepinephrine have been reported.

(Supiano MA et.al, Am.J. Physiol 1992)

• C) Endothelial dysfunction and impaired smooth muscle relaxation may also play a role.

(Steinberg HO,Jour. Clini. Invest., 1994)

• D) Insulin-mediated retention of sodium and fluid has also been implicated.

(Bhanot S.et.al., Cardiovasc.Res., 1996)

Insulin resistance & antihypertensives: Implications in management

• Thiazide diuretics, spironolactone, beta blockers impair insulin sensitivity.

• Angiotensin Converting Enzyme inhibitors, Angiotensin receptor blockers, Alpha-adrenergic blockers and Dihydropyridine Calcium channel blockers improve insulin sensitivity.

• Other CCBs and furosemide appear to be neutral

(Skyler JS et.al,Am. Jour.Hypertension, 1995.

Higashiura K et.al,Immunopharmacology, 1999)

Insulin resistance and coagulation abnormalities

• Plasminogen activator inhibitor (PAI-1) is the primary inhibitor of endogenous fibrinolysis.

• Elevated levels of PAI-1 have been associated with an increased risk of MI

(Juhan-Vague I et.al.,Diabetologia, 1991,

Vague P et.al.,Metabolism, 1986)

• Both insulin and proinsulin are known to increase synthesis of PAI-1

(Nordt TK et.al., Circulation, 1994)

Interventions to reduce insulin resistance

Dietary Implications

• Insulin resistance is reduced within a few days of instituting a hypocaloric diet.( Even before much weight loss has occurred)

• Distribution of dietary calories among carbohydrates and various fat sources does not appear to be so critical in influencing insulin resistance as is total caloric intake.

• Reduction of saturated fat intake is important in improving a high-risk lipid profile


Interventions to reduce insulin resistance(Contd.)

Weight Reduction• Weight reduction attained over longer time frame improves insulin

sensitivity• Avoiding excess weight gain may be the most effective means to prevent

insulin resistance.

Exercise• Regular vigorous exercise reduces insulin resistance, even in elderly.• But this effect drops quickly, within 5 days after cessation of the exercise


Interventions to reduce insulin resistance(Contd)

Pharmacological Approach

2 relatively specific pharmacological approaches

A) Biguanides- Metformin:

• Suppression of endogenous glucose production by insulin is impaired - which is an early and distinct metabolic error in Type II diabetes

• This defect is most easily understood as “Insulin resistance of liver”

• This metabolic error is most directly targeted by Metformin(DeFronzo RA et. al.Metabolism, 1989)

Interventions to reduce insulin resistance

Pharmacological Approach

Thiazolidinediones- Rosiglitazone, Pioglitazone

• These drugs promotes insulin-mediated glucose transport in muscles and adipocytes.

• In diabetic patients in whom insulin resistance is strongly believed to be the underlying cause, then these drugs would be the logical choice

(Desouza C et.al., JCOM, 2000)

Insulin Resistance Summary

• A common clinical condition having profound impact on pathogenesis, diagnosis and management of type II Diabetes and IGT.

• Associated or implicated in hypertension, dyslipidemia and atherogenesis

• Presently measured by clinical research tools.

• Early suspicion and detection in obesity, family history, hypertension,dyslipidemia and with impaired FPG.

• Recent marketing of drugs targeting insulin resistance

• Benefits beyond glycemic control need to be proved clinically.

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Insulin Resistance And Its Implications In The Management of Type II Diabetes