Insulin Resistance

INTRODUCTION

The twin epidemic of ‘Diabesity’-diabetes and obesity, all over the world, both in developed and developing countries, has brought the issue of insulin resistance (IR) into new focus of research.

Apart from Type 2 diabetes mellitus (DM), IR is implicated in many other clinical syndromes because of its varied metabolic and mitogenic actions. IR has been found to play important pivotal role in pathophysiology of diabesity.

SOME KEY CONCEPTS

IR is defined as when a normal or higher insulin level fails to produce expected biological response;^[1] predominantly affecting insulin mediated glucose disposal.^[2]

Compensatory hyperinsulinaemia occurs because of excess insulin secretion by islet beta cells to compensate for the peripheral resistance to insulin action.

Metabolic syndrome is the collection of abnormalities that occur in insulin resistant subjects. Some of these abnormalities are due to insulin excess while some are due to resistance to insulin actions.^[2]

HISTORY

Nobel prize was awarded to Best and Macleod in 1923 for discovery of insulin. The theory of IR as cause of Type 2 DM was first postulated by Prof William Falta in 1931 at Vienna which was confirmed by Sir Harold Himsworth in 1936. He observed wide differences in hypoglycaemic effects of similar doses of insulin in different sets of patients with diabetes and suggested that some patients are hyperglycaemic because of resistance to action of insulin rather than from lack of insulin. This was confirmed later in 1960 by Yalow and Berson who reported a set of Type 2 DM patients who were hyperinsulinaemic rather than insulin deficient.^[3]

INSULIN SECRETION

Amount of insulin secreted by beta cells, required for facilitating entry of glucose into the cells and for control of lipolysis and gluconeogenesis, thereby maintaining normal fasting blood glucose is 0.25–1.5 units/hour in basal or fasting state.

Over 50% of total daily insulin is secreted as basal insulin while remaining 50% of secretion is meal related. About 60% of total insulin secreted into portal vein is removed by the liver. In fed state, insulin promotes glycogen and lipid synthesis in muscle cells and suppresses lipolysis and gluconeogenesis from muscle amino acids.

INSULIN RECEPTORS

Insulin action is exerted by binding to insulin receptors. Insulin receptor is a heterotetramer of 2α and 2β glycoprotein subunits linked by disulphide bonds located on the cell membrane.^[4] Insulin molecule binds to the extracellular α subunit, which results in binding of ATP to the intracellular β subunit [Figure 1]. This causes activation of tyrosine kinase enzyme and triggers phosphorylation of the β subunit. This reaction further leads to tyrosine phosphorylation of intracellular substrate proteins known as insulin responsive substrates (IRS). Binding of IRS with other signalling molecules mediates further cellular actions of insulin^[4] such as activation of Phosphoinositol 3 kinase (PI3-K) finally resulting in translocation of Glucose Transporter 4 (GLUT4) to the cell membrane, thus facilitating transport of glucose into the cell. This also brings about other effects of insulin on various metabolic functions such as protein synthesis, glycogen synthesis and antilipolytic effect.

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Figure 1:

Insulin receptor and intracellular signalling (CourtsyRSSDI Textbook of Diabetes Mellitus, 3^rd Edition).

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CELLULAR MECHANISMS OF IR

About 20–30% of reduction in the number of insulin receptors on the target cells is observed in majority of Type 2 DM patients but 1/3 of the patients may not manifest loss of number of receptors; therefore, defective post receptor signalling is considered as the main cause of IR.

Even compensatory hyperinsulinaemia with maximal binding with receptors fails to achieve normal disposal of glucose; hence, the focus is on steps beyond post-receptor binding. Approximately 80% of decrease in insulin stimulated phosphorylation of IRS and 90% decline in PI3-K release have been observed in animals with IR, resulting in non-migration of GLUT4 units to cell membrane. A 50% of decrease in glycogen synthesis is the major defect in glucose disposal at myocyte level.

MAJOR POST-RECEPTOR SITES INVOLVED IN IR

• Tyrosine kinase generation

• P13-K post-binding signal transduction

• Glut 4 translocation

• Glycogen synthesis.

SITES OF IR

DRUGS AND IR

Many commonly used drugs are found to affect insulin sensitivity. Metformin reduces IR in liver and reduces hepatic glucose output. It also reduces IR at peripheral level, but to a lesser extent. Thiazolindeons for example, rosy and pioglitazone, are more potent in reducing peripheral IR. They also promote redistribution of hepatic and visceral adipose fat to the subcutaneous tissues, thereby reducing harmful central obesity. They improve IR in adipose tissue but not in muscle and are shown to be effective in polycystic ovarian syndrome (PCOS).^[10] Use of glitazones is limited by their side effects.

Corticosteroids and oral contraceptives increase IR due to their counter regulatory action. Protease inhibitors used in treatment of HIV result in partial lipodystrophy with increase in abdominal fat and increase in IR with loss of subcutaneous fat.

CLINICAL SYNDROMES ASSOCIATED WITH IR T2DM

IR precedes clinical manifestations of T2DM. It is also seen more commonly in first degree relatives of T2DM patients.^[10] Insulin-mediated GLUT4 translocation is defective, and peripheral glucose uptake by muscle cells and adipocytes is affected resulting in hyperglycaemia.^[10] First phase of insulin secretion is lost early in the course of the disease despite compensatory hyperinsulinaemia. Additional environmental and physiological stresses such as pregnancy, weight gain, physical inactivity and medications may worsen the IR.

UNCOMMON GENETIC DISORDERS ASSOCIATED WITH IR

Many genetic disorders such as Turner’s syndrome, Klinefelter syndrome, Down’s syndrome, progeria, Laurence Moon Bible syndrome, Huntington’s chorea, haemochromatosis, lipodystrophy, and glycogen storage disease are associated with IR.^[12]

MEASUREMENT OF IR

IR can be measured by many research methods as well as by clinical and laboratory parameters. It may be assessed by measuring insulin mediated glucose uptake in the basal or postprandial state or by inference from the relative concentrations of glucose and insulin or by measuring surrogate markers of insulin action.^[13]

RESEARCH METHODS

The clamp studies specifically measure insulin mediated glucose uptake under controlled conditions. These include the euglycaemic clamp (considered the gold standard) and the hyperinsulinaemic clamp. Insulin sensitivity tests and short insulin tolerance tests are comparatively less invasive. Assessments of IR based on mathematical modelling include the Homeostasis Assessment Model^[14] and the Quantitative Insulin Sensitivity Check Index, Continuous Infusion of Glucose with Model Assessment, Frequently Sampled Intravenous Glucose Tolerance Test and minimal modelling are indirect methods of IR measurement.

CLINICAL METHODS

Fasting plasma insulin assay is much simpler method for measuring IR as compared to complex research methods.

FUNCTIONAL MEASURES

IR can also be diagnosed by functional markers such as BMI, serum triglyceride concentration, ratio of triglyceride to HDL cholesterol concentrations and insulin concentration. Cut points of 1.47 mmol/L for triglyceride, 1.8 mmol/L for the triglyceride-HDL cholesterol ratio and 109 pmol/L (16 mIU/L) for insulin are quite specific and sensitive indices for diagnosis of IR.^[15]

CONCLUSION

Apart from genetic or biological causes, social and environmental factors are equally important in causation of IR. Rapid globalisation, urbanisation and industrialisation are responsible for epidemics of obesity, diabetes and related comorbidities.^[13] Dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns need to be addressed seriously if we want to deal with problem of IR.