Insulin Resistance & Clinical Implications

Prof K M Prasnna Kumar
Prof & Head,
- Dept Of Endocrinology & Metabolism,
M S Ramiah Medical college, Bangalore

Insulin resistance (IR) is insufficient biological/metabolic response to given plasma concentration of insulin. The response to a given dose of insulin may induce plasma glucose reduction of variable degree in different individuals. The person requiring less amount of insulin is Insulin Sensitive & that requiring more is insulin resistant. In other words, a normal amount of hormone produces a subnormal effect & which is individualized & depends on various hormonal & metabolic factors in the individual. IR may be genetically inherited or acquired. Insulin resistance is not static it varies from birth to death, it varies from morning to evening. It can be congenital, genetic or acquired. Recent data has shown conclusively that insulin resistance is the first abnormality and insulin deficiency follows. Thus IR has an important role in the pathogenesis of Type 2 diabetes.

IR is of 2 types: Type A and Type B. Type A is due to genetic defect of insulin receptor & Type B is due to circulating antibodies to insulin receptors.

Syndromes associated with IR are Genetic disorders of Type A i.e. Rabson Mendenhall Syndrome & Leperchaunism.

Immunological Disorders of Type B where there are circulating antibodies to insulin receptors resulting in antaxia & telengiectasia.

Receptor defect could be quantittive ,where the number of receptor for insulin are less ,or a qualitative insulin receptor defect. The insulin resistance could be due to post insulin receptor defects.

Physiological states of IR are pregnancy & puberty. In puberty the pubertal hormones specially the androgens whether they are adrenal androgens or testosterone are responsible for IR. The pathological states responsible for IR are stress, and malignant disease.

Thus a potential diabetic who has inherited IR, acquires obesity, and develops psychological stress due to increasing responsibilities may developt frank diabetes. The genetically acquired IR expresses as diabetes due to obesity, lack of exercise & stress.

The Metabolic factors apart from the above are acidosis, uremia, especially end stage renal disease(ESRD). In early diabetic nephropathy, as albumin is excreted by the kidneys ,insulin and albumin get dissociated. This increases insulin levels in the plasma resulting in reduced insulin requirement. Uremia is a state of IR.

The endocrine disorder characterizing IR are Cushing's Syndrome, Acromegaly, Glucagon tumors, Pheochromocytoma & androgen disorders like PCOD (which is classical state of IR) Polycystic Ovarian Disease is characterized by hyperandrogenism, obesity, anovulation & acanthosis nigricians. Ther are many clinical studies in the last few years regarding the use of metformin in PCOD for induction of Ovulation. Metformin in doses of 1 to 1 ½ gm/day induces ovulation in-patients who are nondiabetic with PCOD. The basis is adrenal androgen induce IR, & IR changes intraovarian milieu. Hyperprolactinemia also increases the IR.Cirrhosis of liver is another cause of IR.

Insulin degradation may be enhanced leading to insulin resistance. Certain patients do not respond to SC Insulin even with very high doses ,but respond to smaller doses of IV insulin. This is SC resistance and normal response to IV insulin. Once euglycemia is achieved, IR is reduced; the patient may respond to SC Insulin.

One of the most important features of IR is Syndrome X where is resistance to insulin stimulating glucose uptake. The features of Syndrome X are

  • Hyperinsulinemia
  • Hypertension
  • Glucose intolerance
  • Increased VLDL decreased HDL
  • Obesity

Now it is well known that Syndrome X is not a conglomeration of disorders but a definite entity. Insulin clamp studies have shown that Asians have higher IR than Europeans. Increasing incidence of diabetes in recent years in Indians in particular and asians in general is because of change in the lifestyle, obesity physical inactivity & stress. By the next year decade or so, DM in India will reach epidemic proportions.

Many patients with HTN have hyperinsulinemia & fasting plasma insulin concentration is very closely related to elevation of blood pressure.

Hyperinsulinemia leads to HTN because of increased renal sodium & water reabsorption Decreased Na/K+ATPase activity. Increased Na/H+ pump activity Increased Intracellular Calcium ion accumulation Stimulation of various growth factors that promote atherosclerosis. Hyperinsulinemia subjects also had higher basal levels of TGL & lower HDL levels, which lead to, increased risk for CAD.

Conclusion of recent data shows that Insulin resistant states can be regarded as antecedent of cardiovascular disease because of its dyslipidemic & hypertensive effect & not necessarily as a direct result of IR or hyperinsulinemia.

To estimate the prevalence of Syndrome X, a study was carried out on 13,672 diabetics at Bangalore at M S ramiah Medical college hospital and Diacon hospital, Bangalore. It was observed that 45% women & 15% men had Syndrome X, 7% women & 5% men had HT with IHD and 50% women and 18% men were obese.

The study concluded that obesity, Hypertension and dyslipidaemia are more common in woman . Syndrome X is more common in women.

Insulin antibodies develop due to impure insulin usage; highly purified/human insulin reduces insulin antibody level in 3 months. Usually, an average individual will require 36 units of insulin / day. In order to identify IR clinically, the guidance used is, if the daily requirement of insulin exceeds 1 unit/kg bodyweight than the patient is said to be insulin resistant.

IR is a key factor in pathogenesis of Type 2 DM, it is partly acquired. It not only leads to Type 2 DM but also to cardiovascular disorders like hypertension, dyslipidemia & atheroscleroses which are the future risk factors for Coronary artery disease morbidity & mortality.