Insulin Resistance

•Metabolic syndrome : (Reaven’s syndrome)

Hyperinsulinaemia

Type 2 diabetes or glucose intolerance

Hypertension

Hypertriglyceridemia

Low HDL

Later additions to the syndrome:

Central obesity

Impaired fibrinolysis

Pro coagulant

Hyperuricaemia

Microalbuminuria

WHO and ATP III have slightly different definitions for the Metabolic syndrome, but it seems like the WHO criteria may identify a greater number of obese adults at risk for CVD. International Journal of Obesity (2005) 29, 668-674 To make definition and screening of patients with the Metabolic syndrome easier, the International Diabetes Federation has come up with a slight variation, including the fasting blood sugar as a satisfactory measure (thus incorporating the ATP III recommendations) Download the latest definition of Metabolic syndrome (IDF consensus statement. PDF format)

The importance of identifying and defining the metabolic syndrome is partly due to the fact that the total cardiovascular risk attributable to the syndrome seems to exceed the sum of the risk from each of the separate components. Diabet Med. 2004 Jan;21(1):52-8. Studies have demonstrated that the prevalence of the metabolic syndrome is associated with worse glycaemia, increasing albuminuria and worsening creatinine clearance even in type I patients. Diabetes Care. 2005 Aug;28(8):2019-24.

It is important to recognize that insulin resistance though loosely used, should be distinguished as insulin resistance in the context of carbohydrate metabolism (inability to stimulate muscle glucose uptake or inability to suppress hepatic glucose production) and insulin resistance in the context of lipid metabolism (inability to suppress lipolysis or inability to facilitate lipogenesis). Also note that insulin-resistance can occur to the actions of insulin on the vascular wall (normally insulin produces nitric oxide-mediated vasodilatation of the peripheral vessels) Am J Physiol. 1994 Aug;267(2 Pt 1):E187-202 as well as at the hypothalamic level (normally insulin increases sympathetic tone through central actions on the hypothalamus with satiety inducing properties), and to its action on platelets (normally insulin has anti-platelet aggregatory effect). In this context, it has to be mentioned that insulin-resistance does not happen with regard to its hypokalaemic and anti-natriuretic actions, Diabetologia. 1991 Apr;34(4):275-81. as well as its actions on the ovary where it stimulates LH production as in the polycystic ovarian syndrome.

Insulin sensitivity is inversely related to BMI above a critical threshold of approximately 120% for ideal body weight. Insulin resistance is common, and is present in almost all obese patients. J Clin Invest. 1980 Jun;65(6):1272-84. Despite this only a small proportion of obese patients end up becoming diabetic, and in fact only a third of patients with impaired glucose tolerance ever progress to type 2 diabetes. This progression is very likely determined by a (?) genetic predisposition to beta cell exhaustion and failure Diabetes Care. 1992 Mar;15(3):318-68. secondary to prolonged insulin resistance. Beta cell "failure" implies multiple defects including a reduction in beta cell mass, a decreased secretory ability of the beta cells secondary to decreased sensitivity and response of the beta cells to usual secretagogues (as glucose) and incretins (GLP-1 and GIP). Lipotoxicity, Diabetes. 1995 Aug;44(8):863-70. glucotoxicity Endocr Rev. 1992 Aug;13(3):415-31, IAPP (islet associated poly peptide- amylin) Diabetes. 1999 Feb;48(2):241-53. and adipokines (cytokines from visceral fat) have all been implicated in the production of these defects although their individual roles in the initiation vs. perpetuation of glucose intolerance and subsequent onset of diabetes in various subgroups of patients is still far from clear.

It is also not yet clear as to whether insulin resistance or insulin secretory defect is the primary pathology (first to arise) in the development of type 2 diabetes, and which one has a stronger genetic component. Their quantitative contribution to the pathology of type 2 diabetes is also not clear from present studies and probably will never be established, as type 2 diabetes seems to be a heterogeneous condition with different subsets showing variable contributions from either of these pathologies depending on genetic and environmental differences. The manifestations of the metabolic syndrome also vary between patients again determined by different factors. Each of the factors may have multiple mechanisms, with hypertension being produced in some through intracellular calcium related mechanisms, while the renal sodium retention might contribute in others.

Fasting Eur J Clin Invest. 2000 Jan;30(1):45-52. and postprandial Metabolism. 1992 Mar;41(3):264-72. plasma free fatty acid levels are higher in patients with obesity and insulin resistance syndrome. In fact, epidemiological studies seem to suggest that higher plasma FFA levels are independent predictors of progression to type 2 diabetes. Diabetologia. 1997 Sep;40(9):1101-6. The increased fatty acids induce apoptosis through excess nitric oxide production. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498-502. Increased lipolysis of triglyceride rich lipoproteins intravascularly as well as in the adipose tissues, along with decreased uptake by liver, adipose tissue, and other organs contributes to this excess FFA levels in the insulin resistant subject, such that the FFA turn over is higher in obese individuals. Endocr Rev. 2002 Apr;23(2):201-29 A resistance to insulin's suppressive action on the hormone sensitive lipase in adipose tissue is probable, Metabolism. 1992 Mar;41(3):264-72 accounting for the increased lipolysis in the insulin resistant individual although this has not been consistently borne out in all studies. Am J Physiol 263:E79–E84 Augmented TNF α expression seems to facilitate increased circulating FFA through antagonism of the antilipolytic properties of insulin. Diabetes Obes Metab. 2001 Aug;3 Suppl 1:S11-9. The alternative hypothesis is that while hormone sensitive lipase remains sensitive to insulin action, the increasing amount of fat mass overwhelms insulin's suppressive effect on HSL. In keeping with this notion is that when normalized per total body fat, lipolysis is normal or reduced in the obese. Acta Med Scand. 1969 Apr;185(4):351-6.

Abnormalities in Fatty Acid binding proteins (FABP-2) could result in increased intestinal fat absorption resulting in higher fatty acid levels, Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1606-10 and insulin resistance Clin Biochem. 1998 Nov;31(8):609-12 although these polymorphisms and their fat absorptive effects is restricted to specific populations, J Clin Invest. 1995 Mar;95(3):1281-7. with inconsistencies in studies with regard to enhancement of intestinal fat absorption. Metabolism. 2001 Apr;50(4):473-6. On a similar note, defects or deficiency of fatty acid receptors or transporters (e.g. CD36, a scavenger receptor) could result in defective uptake of fatty acids into adipose tissue J Biol Chem. 2000 Oct 20;275(42):32523-9. with resultant higher serum free fatty acid levels and induction of insulin resistance in rodents, Lancet. 2001 Mar 3;357(9257):651-2. as well as in some human populations. Lancet. 2001 Mar 3;357(9257):686-7, although its physiological relevance if any, still remains unclear. Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1072-9. ASP or acyl stimulation protein is another adipocyte derived factor that may play a role in determining fatty acid esterification through a PKC-dependent pathway. J Biol Chem. 1999 Jun 25;274(26):18243-51. Although increased in obesity, its physiological contribution to the elevated FFA levels remains to be clarified. GPR40, a free fatty acid receptor on pancreatic beta cells may function as a signalling molecule and regulate insulin secretion Hepatol Res. 2005 Oct 5 and may be involved in the secretory abnormalities mediated by free fatty acids that accompany insulin resistance.

Normally, during an overnight fast the liver is the major contributor to plasma glucose through glycogenolysis and gluconeogenesis. This basal hepatic glucose production is increased in type 2 diabetics due to incomplete suppression of endogenous glucose production by the liver. Metabolism. 1988 Jan;37(1):15-21 This is despite the fasting hyperinsulinaemia, reflecting the insulin-resistance to carbohydrate metabolism in the liver. This increased HGP is predominantly due to gluconeogenesis (proved by deuterated water and MRI).
So what causes this insulin resistance in the liver? Hepatic fatty infiltration has been closely correlated to hepatic insulin resistance, independent of general obesity. J Biol Chem. 2000 Mar 24;275(12):8456-60. Ectopic fat storage hypothesis assumes that overwhelming of the adipocyte storage space diverts triglycerides to the liver (and muscle) producing steatohepatitis resulting in resistance to insulin action at this site. Ann N Y Acad Sci. 2002 Jun;967:363-78. In this context, it is important to note that insulin is unable to suppress hepatic glucose production in mice lacking the insulin receptor in the liver. Mol Cell. 2000 Jul;6(1):87-97.

Resistance to insulin's actions on lipid metabolism in the liver results in a lack of suppression of VLDL output by the liver. This excess VLDL production by the liver is partly due to increased substrate (NEFA) delivery of to the liver from unsuppressed lipolysis in the adipose tissue due to local insulin resistance at that site, and partly due to a hepatic defect in suppression of VLDL production. Diabetologia. 1997 Apr;40(4):454-62. This excess triglyceride (VLDL) production by the liver results in increased CETP-mediated transfer of triglycerides to HDL, thus converting HDL to HDL3. The increased transfer of triglycerides to HDL results in its increased clearance from circulation by hepatic lipase producing the characteristic profile in insulin resistant states. Triglyceride transfer also occurs from VLDL to LDL, thus making LDL also more susceptible to hepatic lipase, converting it into the smaller dense LDL particles which is atherogenic.

Interestingly people with IGT have normal HGP and normal fasting glucose despite marked fasting hyperinsulinaemia. This is probably due to the high post absorptive plasma insulin levels being sufficient to overcome the hepatic insulin resistance thus maintaining the basal HGP normal. The high post absorptive plasma insulin levels in this setting is attributed to the defective first phase insulin response resulting in hyperglycemia which stimulates a higher than usual second phase response of insulin secretion.

Skeletal muscle in T2 diabetes is resistant to insulin action. There is a 50% reduction in the ability of insulin to increase muscle glucose disposal in type 2 diabetes. This muscle insulin resistance is well established in IGT individuals as well.

Yet, muscle insulin receptors are not crucial to facilitate muscle uptake of glucose, as hyperglycaemia itself can produce glucose uptake in muscles. In keeping with this, rats with tissue specific deletion of the muscle insulin receptor have normal glucose and insulin concentrations. Mol Cell. 1998 Nov;2(5):559-69. Note that the number of insulin receptors and transporters as GLUT4 and the affinity of insulin for receptors in muscle are mostly normal despite insulin resistance. Instead multiple intracellular signalling defects have been identified as the cause of defective insulin action at the muscular level, namely:

1. Defective insulin receptor tyrosine phosphorylation so that Insulin is unable to activate the insulin receptor.
2. Defective IRS-1 (Insulin receptor substrate) phosphorylation and PI-3 (Phosphatidyl Inositol) activation by insulin.
3. Impaired ability of PI-3 to induce GLUT4 translocation.
4. Other defects as defective muscle glucose phosphorylation by hexokinase 2 are also well described in IGT and diabetes.

All these provide various areas to target with drug therapy partly due to the fact that it is not yet clear whether they are causal or merely an effect of the insulin resistance state.

Skeletal muscles, like adipose tissue, also possess lipoprotein lipase, the activity of which is normally suppressed by insulin. Metabolism. 1991 Feb;40(2):214-6. In insulin resistance, this activity is increased which could contribute to the increased muscle triglyceride content, Metabolism. 1995 Jun;44(6):786-90. with resultant muscle insulin resistance. In fact, skeletal muscle insulin sensitivity correlates closely with intramyocellular fat. Diabetologia. 2001 Jul;44(7):824-33.

All patients by the time they reach IGT have some degree of insulin secretory defect, since the pancreas has a huge reserve and hence coping ability normally. Although there is a relative deficiency initially, by the stage when fasting glucose rises above about 11.1 mmol/L (200 mg/dl) the deficiency of insulin is in absolute terms. It makes sense to assume that the pancreatic beta cell failure is secondary to insulin resistance of a prolonged duration, with higher insulin resistance probably producing earlier failure in a susceptible individual. Physiol Rev. 1995 Jul;75(3):473-86 The demonstration of offsprings of type 2 diabetics being insulin resistant and hyperinsulinaemic is in keeping with this. Ann Intern Med. 1990 Dec 15;113(12):909-15. But in recent times a new assumption has been proposed, where the beta cell failure is thought to be the primary genetic defect, and the resulting hyperglycaemia contributing to glucotoxicity and later, insulin resistance. Endocr Rev. 1998 Aug;19(4):491-503. Demonstration of first degree relatives of type 2 diabetics with normal glucose tolerance but reduced insulin responses in the absence of insulin resistance seems to be the strongest argument for this hypothesis. Metabolism. 2000 Oct;49(10):1318-25. Also, a 37% deficit in early insulin response has been demonstrated in pre-diabetic subjects compared to non-diabetic subjects. Diabetes Care. 2003 Mar;26(3):868-74. HOMA assessment of beta cell function undertaken in the UKPDS study supports this by showing that beta cell function is already reduced by 50% at the time of diagnosis of type 2 diabetic state. Diabetes. 1995 Nov;44(11):1249-58. The relentless progression despite modalities to target insulin resistance (metformin) further lends credence to this theory of a primary beta cell pathology. The process by which a pancreatic dysfunction as the primary pathology could lead to insulin resistance as a secondary event is difficult to explain. I would like to postulate that a relative deficiency of insulin could upset the hepato-portal insulin to glucagon ratio which might impact on fatty acid release in the periphery due to excessive glucagon action. The increased fatty acid release could result in hepatic steatosis and increased myocellular lipid content with development of insulin resistance? (personal view). While much is known about the various factors determining insulin resistance, much less is known about factors determining insulin secretory ability or insulin secretory failure, which probably stems from the fact that the hyperglycaemic clamp allows a reasonably accurate measurement of insulin sensitivity while no such gold standard exists to measure insulin secretory ability.

The primary defect in the beta cell could involve multiple aspects of insulin synthesis and secretion which might under genetic control. Normally, insulin secretion involves recognition of hyperglycaemia by the pancreas (glucose sensing), glucose metabolism in the pancreatic cells, depolarisation of the beta cell plasma membrane (closure of potassium channels), movement of preformed secretory granules to the plasma membrane (involving microtubules and microfilaments), followed by release of its contents (insulin, proinsulin, C peptide) through fusion of the membranes (calcium influx). One or more of these steps can be defective in a particular individual depending on the genetic defect. Genetic defects have been described for the glucokinase gene, glucose transporter 2 (GLUT-2), the insulin gene, the sulphonylurea receptor and the mitochondrial genome. Diabetologia. 1996 Apr;39(4):375-82. Genetic defects causing defective insulin action have also been identified including those for GLUT-4, IRS-1. hexokinase II, FABP etc. While genetic analysis can be effective in identifying defective genes in monogenic forms of diabetes, the mystery of polygenic diabetes (type 2) still remains unraveled due to the heterogeneity of the genotypes and the variable phenotypes in different populations. Identification of a candidate gene(s) for type 2 diabetes by association would then have to be the demonstrated to have a pathogenic role by quantitatively relating it's malfunction to the insulin resistance or insulin deficiency in vivo. Yet, it still remains unclear as to whether an insulin secretory defect or insulin resistance contributes predominantly to the pathogenesis of type 2 diabetes.

Non-genetic factors may also play a role in the pancreatic endocrine dysfunction. Down regulation of glucose transporters or oxidative stress- induced alteration of transcription factors induced by hyperglycaemia (glucotoxicity) Endocrinology. 2002 Feb;143(2):339-42. and impairment of beta cell function by free fatty acids Diabetes. 2004 Feb;53 Suppl 1:S119-24. especially in those with polymorphisms of the PPAR gamma receptors in the beta cells Diabetes. 2001 May;50(5):1143-8. are also likely to play a role in the beta cell dysfunction. Hyperglycaemia for 5 days has been shown to produce increased beta cell apoptosis similar to that of overt diabetic state, Diabetes. 2001 Jun;50(6):1290-301. implicating glucotoxicity as a potent factor for beta cell dysfunction. Hyperglycaemia results in increased production of reactive oxygen species as superoxide which can activate the UCP-2 (uncoupling protein) with resultant impaired ATP generation and insulin secretion. J Clin Invest. 2003 Dec;112(12):1831-42 In keeping with the lipotoxicity theory, lipid infusion in subjects with a family history of type 2 diabetes reduced the first phase response of insulin by 25% compared to controls and the second phase by 42%. Diabetes. 2003 Oct;52(10):2461-74. While an increase in free fatty acids over a short duration as 6 hours increases insulin secretion, longer exposure seems to decrease the AIR (acute insulin response) by up to 50%. Diabetologia. 1995 Nov;38(11):1295-9. A decreased response of the beta cells to gut incretin hormones is thought to contribute to the pancreatic endocrine secretory dysfunction, as show by reduced effect of GIP (glucose dependent insulinotropic peptide) on insulin stimulation. A reduced response to the predominant incretin GLP-1 has also been described. Islet Amyloid PolyPeptide (IAPP) is found to be deposited in up to 90% of type 2 diabetic patients as opposed to 10% of non- diabetic patients. The contribution of Islet amyloid deposition towards this beta cell secretory dysfunction Nature. 1994 Apr 21;368(6473):756-60 is still open to discussion, Diabetes Res. 1988 Dec;9(4):151-9. but is generally thought to be representative of a degenerative process or a secondary effect of hyperglycaemia Diabetes. 2003 Jan;52(1):102-10. rather than a primary pathology. Yet increased fat intake seems to be associated with higher islet amyloid associated polypeptide deposition in experiments with transgenic mice expressing human IAPP. Diabetes. 2003 Feb;52(2):372-9. It remains to be clarified whether the size of the fibrils of amyloid polypeptide can specifically influence apoptosis rates in human pancreatic tissue invivo. Diabetes. 1999 Mar;48(3):491-8. TNF α apart from contributing to insulin resistance may also inhibit insulin signalling pathways through stimulation of IL-1 release from intraislet macrophages in turn inducing nitric oxide (free radical) production by beta cells. J Biol Chem. 1999 Jun 25;274(26):18702-8. The acute phase response of insulin (0-10 minutes) to food is impaired when the fasting glucose increases above 6.4 mmol/L accounting for the impaired suppression of hepatic glucose production (HGP) described above. But in IGT and the early stages of T2DM, the later insulin response (60-120 minutes) remains high and seems to be a compensatory effort to control postprandial hyperglycaemia. Proinsulin processing in the pancreas seems to be dysregulated in type 2 diabetes with increased proinsulin to insulin ratios, which correlates with beta cell dysfunction and is in fact predictive of type 2 diabetes development. Am J Med. 2003 Apr 15;114(6):438-44. Aging is associated with a reduction in mitochondrial function and oxidative phosphorylation. Reduction of ATP generation by oxidative phosphorylation could compromise the beta cell secretory ability over time. This could be superimposed on environmental stressors as obesity to result in pancreatic endocrine insufficiency.

Over and above these functional abnormalities, the beta cell mass is also noted to be decreased. In fact, reduction of pancreatic beta cell mass by up to a third is well recognised in type 2 diabetics compared to non-obese individuals, Diabetes Res. 1988 Dec;9(4):151-9. although this cannot in isolation explain the 80% reduction in secretory function seen in type 2 diabetics. The α cell mass has in fact been shown to be slightly increased in type 2 diabetics. Diabetologia. 1983 May;24(5):366-71 with impaired suppression of glucagon by hyperglycaemia. Hyperglucagonaemia is a characteristic feature in type 2 (and type I ) diabetes. Despite these, the changes in the α cells are thought to be secondary to the hyperglycaemia as these are reversible on restoring euglycaemia.

In insulin resistant states as type 2 diabetes mellitus, the fat cells are resistant to insulin, both for glucose uptake and suppression of lipolysis. J Clin Endocrinol Metab. 1985 Nov;61(5):807-11 The latter defect results in increased lipolysis in adipose tissue with chronically elevated free fatty acids (FFAs) which in turn impairs insulin secretion, decreases glucose uptake in muscles, J Clin Invest. 1983 Nov;72(5):1737-47. stimulates hepatic gluconeogenesis, increases hepatic VLDL production and induces hepatic and muscular insulin resistance. J Biol Chem. 2000 Mar 24;275(12):8456-60. Thus the adipocyte defect might be more crucial in the pathogenesis of insulin resistance? Read further about the role of adipose tissue........Insulin and glucose normally stimulates adipocyte lipoprotein lipase activity while reducing muscle lipoprotein lipase activity, thus directing fatty acids towards adipose tissue rather than muscles. In obese patients, activation of lipoprotein lipase in adipose tissue is delayed while LPL activity in muscle is increased, Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7522-7. resulting in increased lipid accumulation in muscles (increased intramyocellular lipid), with development of the ectopic fat storage syndrome. The role of fatty acid transporter protein (CD36) in regulation of fatty acid uptake in tissues, with implications on development of insulin resistance in states of deficiency Lancet. 2001 Mar 3;357(9257):686-7 remains to be clarified.

Increased reductase activity of 11 beta HSD levels in fat seems to contribute to locally raised cortisol levels which could facilitate increased adipocyte proliferation with resultant adverse effects. Dysregulation of 11β HSD1 in human obesity has been described and seems to be tissue specific. Increasing BMI is associated with impaired 11β-HSD1 activity, with the degree of impairment correlating with visceral fat mass. J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61. This down-regulation of 11 β HSD1 activity in the obese could be protective against development of insulin resistance. Type 2 diabetic patients do not show this BMI related change in 11 β HSD1 activity J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61 and it can be postulated that a lack of down-regulation of 11 β HSD1 in obese patients could facilitate development of diabetes.

Normally insulin produces nitric oxide dependent vasodilatation of the peripheral resistance vessels. Am J Physiol. 1994 Aug;267(2 Pt 1):E187-202 Endothelium dependent vasodilatation has been shown to be defective in insulin resistant states. Eur J Clin Invest. 2001 Dec;31(12):1013-4. Hyperinsulinism which characterises insulin resistance is thought to produce vascular damage with predilection for atherosclerosis though induction of vascular smooth muscle proliferation. The hyperinsulinism of insulin resistance stimulates the MAP kinase pathway excessively, resulting in increased growth and proliferation of vascular smooth muscle cells, with increased collagen formation and release of growth and chemotactic factors which facilitate atherosclerosis. Lowering of hyperinsulinaemia using modalities as metformin would thus be expected to improve atherosclerosis related macrovascular disease as opposed to exogenous insulin or insulin secretagogue therapies, as demonstrated in the UKPDS trial. Lancet. 1998 Sep 12;352(9131):854-65. Insulin normally decreases vagal tone while increasing sympathetic drive, and hence hyperinsulinism might contribute to the increased sympathetic drive seen in insulin-resistant obese J Clin Invest. 1994 Jun;93(6):2365-71. or perhaps not? J Clin Endocrinol Metab. 2001 Mar;86(3):1403-9

Insulin normally inhibits platelet aggregation. Diabetes Care. 1998 Jan;21(1):121-6 Platelet vascular mechanism are activated in diabetes mellitus evidenced by increase in beta thromboglobulin, platelet factor 4, thromboxane A4 and B2, ICAM 1 and E- selectin and decreased prostaglandin12. Platelets in diabetics have an increased sensitivity to activation under high shear stress. The increased procoagulant nature of the platelets is demonstrated by an increased tendency to ADP induced aggregation.

Fibrinogen levels are raised in diabetes mellitus. Levels are particularly raised due to chronic hypersecretion in those with prolonged poor metabolic control. Hence improved diabetic control should theoretically decrease fibrinogen levels and improve the coagulant status.

Increased fibrinogen levels increase blood viscosity with increased tissue deposition of bigger fibrin clots with stimulation of atherosclerosis. Glycated fibrinogen deposition is probably greater than fibrinogen itself. due to decreased susceptibility to plasmin. These could have impact on macro and microvascular disease initiation and progression. Metformin may have a positive influence on the fibrin structure and the cross linking of fibrin by factor 12 . This improves the hypofibrinolytic state of diabetes.

High levels of plasminogen activator inhibitor which inhibits fibrinolysis is a feature of type 2 diabetes mellitus. This is an added risk factor for macrovascular disease. Although both t-PA and PAI-1 activity are increased in diabetics, the latter is clearly overpowering due to the net reduction of the free fibrinolytic activity. It is interesting to note in this juncture that in type 1 diabetics without complications PAI-1 activity is normal but when complications occur, the levels are usually high. Metformin reduces PAI-1 by 20%.

The knowledge of the multiple sites of insulin resistance as well as the multiple abnormalities associated with insulin resistance ( low HDL, high triglycerides, hypertension, obesity, increased platelet aggregation, increased procoagulant tendency) with or without hyperglycaemia, should prompt a multi-pronged approach to treating this multi-faceted disease.

Body weight is the commonest and easily measurable indicator of insulin resistance. Combating obesity brings immense benefits as sited elsewhere in this site. Most studies (DPP, Finnish DPS, Da Qing, XENDOS) have demonstrated the positive effect of weight loss on improved glucose tolerance with prevention of progression of IGT to T2DM. . In the XENDOS study involving 3304 patients (80% with IGT) for 4 years, the orlistat group had a 37% risk reduction in progression from IGT to T2DM (weight reduction in placebo and orlistat group: 7.5 vs. 11.4 kg; Conversion rate from IGT to T2DM in placebo and orlistat groups: 9% vs. 6.2% respectively) Diabetes Obes Metab. 2003 Sep;5(5):356. Weight loss improves vascular response to L- arginine, reduces fasting insulin concentrations, and reduces IL 6 and TNF α levels. Increasing the dietary carbohydrate with lowering of dietary fat has been shown to improve glucose tolerance secondary to an increase in insulin secretion and an improvement in insulin sensitivity in older people J Clin Endocrinol Metab. 1988 Nov;67(5):951-7. and type 2 diabetics. N Engl J Med. 1971 Mar 11;284(10):521-4.

Both aerobic and resistance training exercises improve insulin sensitivity, but the beneficial effects of exercise tend to decrease after a few days of inactivity. Studies have shown that physical activity N Engl J Med. 1991 Jul 18;325(3):147-52 and fitness levels Ann Intern Med. 1999 Jan 19;130(2):89-96 are inversely associated with incidence of type 2 diabetes independent of BMI. So, how does exercise produce an improvement in insulin resistance? Regular exercise may increase translocation of GLUT-4 glucose transporters in skeletal muscle cells partly related to the increased skeletal muscle blood flow J Clin Endocrinol Metab. 1995 Aug;80(8):2437-46. and AMPK (5'adenosine monophosphate activated protein kinase) activation Diabetes. 1999 Aug;48(8):1667-71. thus improving glucose uptake. The ability of insulin to increase skeletal muscle blood flow seems to be improved with exercise in normals and insulin resistant subjects. Diabetes. 1995 Sep;44(9):1010-20 , and the increased blood flow may improve local availability of insulin as well. Exercise has been associated with increased release of local bradykinin which may have stimulatory effects on glucose uptake. Diabetes. 1998 Apr;47(4):550-8 Exercise without weight loss significantly reduces visceral fat compared to controls. Exercise-induced weight loss reduces total fat to a greater extent than diet induced weight loss.

Metformin has been shown to improve muscle insulin sensitivity measured with the euglycaemic insulin clamp in type 2 diabetics. Metformin also improves insulin sensitivity and normalises glycogen synthesis in the muscle in insulin resistant normoglycaemic first degree relatives of individuals with type 2 diabetes mellitus. Metformin may activate AMP kinase leading to enhanced basal and insulin stimulated glucose transport in muscle

Metformin improves hepatic insulin sensitivity. Basal HGP was decreased by 20% in T2DM treated with metformin- interestingly despite a reduction in fasting plasma insulin. Metformin does this by improving insulin receptor tyrosine phosphorylation and enhances glucose transport. Activation of AMP kinase in liver causes inhibition of hepatic glucose production and decreased expression of a number of genes involved in hepatic free fatty acid and VLDL synthesis. The VLDL synthesis reduction may also be partly mediated through a decrease in acetyl Co A carboxylase activity. All these could be involved in the efficacy of metformin in retarding the progression of IGT to T2DM as shown in the DPP study. Combating insulin resistance with decreased FFA and VLDL synthesis could explain the cardiovascular mortality reduction in obese diabetics demonstrated in the UKPDS. Read more on Metformin

Rosiglitazone and Pioglitazone are the major players in this group at present. Thiazolidinediones improve insulin sensitivity in both liver and muscle. They (rosiglitazone and pioglitazone) augment insulin stimulated muscle glucose uptake and enhance basal and insulin mediated suppression of HGP. Improvement in glycaemia may contribute to improved beta cell function.

Both thiazolidinediones were shown to produce a 35% increase in insulin mediated muscle glucose disposal in T2DM patients using a euglycaemic insulin clamp. Treatment of T2DM with rosiglitazone almost completely reversed the severe impairment in IRS-1 tyrosine phosphorylation, and markedly increased PI-3 kinase activity. This closely correlated with improvement in muscle insulin sensitivity and muscle glycogen synthesis measured with euglycaemic clamp. The above mechanisms imply that thiazolidinediones may be effective in preventing/delaying progression of IGT to T2DM.

The thiazolidinediones also seem to enhance insulin secretion probably through increasing glucose uptake by the beta cell. Diabetologia. 1995 Jan;38(1):24-30. They have also been shown to preserve beta cell function in diabetic animal models. The beneficial effect of thiazolidinediones may partly be related to the favourable fat redistribution since this happens despite a consistent finding of weight gain! They reduce hepatic and visceral fat, while increasing subcutaneous fat. The effect on intramyocellular fat is controversial with studies for and against such an action. Thiazolidinediones seem to consistently lower the plasma FFA concentration by 25-35%. Diabetes Care. 2001 Apr;24(4):710-9. This reduction in free fatty acid levels may be brought about partly by improving insulin sensitivity and partly through suppression of TNF alpha expression in adipose tissue -which normally facilitates lipolysis- by thiazolidinediones. Diabetes Obes Metab. 2001 Aug;3 Suppl 1:S11-9. A direct protective effect of beta cells from lipotoxicity seems to be offered by glitazones in in vitro studies. Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E560-7

Triglyceride accumulation in beta cells of pancreas causes in increase in fatty acyl coA levels with increased ceramide synthesis which increases NO resulting in beta cell apoptosis. It is proposed that improvement of triglyceride content in the pancreatic beta cells brought about by thiazolidinedione therapy in the rats might explain the decreased beta cell apoptosis with the possibility of preservation of pancreatic islet function for longer. J Biol Chem. 1998 Feb 6;273(6):3547-50. The increased proinsulin to insulin ratios, which correlates with beta cell dysfunction and is predictive of type 2 diabetes development, Am J Med. 2003 Apr 15;114(6):438-44. is also improved by thiazolidinediones. Diabet Med. 2004 Jun;21(6):568-76.

In the thiazolidinedione arm of DPP (troglitazone) where patients were exposed to the drug for 10 months, there was a 23% decrease in the conversion rate of IGT to T2DM.

TRIPOD study involving 235 women with a history of GDM (two third with IGT), where the women were treated with troglitazone for 30 months, the drug did better than placebo (12.3% per year converting from IGT to T2DM in the placebo group as opposed to 5.4% in the troglitazone group; p<0.001) Diabetes Metab. 2003 Nov;29(5):547-53. The PIPOD study using pioglitazone will be looking at similar benefits.

Ongoing studies with the combination of Rosiglitazone and Ramipril (DREAM trial-Diabetes REduction Approaches with Ramipril and Rosiglitazone-4000 IGT patients with established CVS disease for 3 years) will hopefully clarify the role of these drugs in combating insulin resistance and glucose intolerance. Diabetologia. 2004 Sep;47(9):1519-27.

Among the sulphonylureas, the third generation sulphonylurea (Glimiperide) seems to have a more favourable cardiovascular profile. Horm Metab Res. 1996 Sep;28(9):496-507. Glimiperide seems to improve glycaemia to similar levels as the second generation sulphonylureas despite lower insulinotropic activity. Diabetes Res Clin Pract. 1995 Aug;28 Suppl:S115-37. This is thought to imply extra-pancreatic effects of Glimiperide through favouring peripheral glucose uptake as well as by augmenting first phase insulin secretion. Pharmacotherapy. 2004 May;24(5):606-20.

The term Glucotoxicity has been coined to explain the beta cell failure as well as peripheral insulin resistance in type 2 diabetes. Sulphonylureas may partly exert their beneficial effect through improvement of glucotoxicity. Glucotoxicity implies chronic elevation of plasma glucose levels inducing insulin resistance and impairing beta cell function by local toxicity. High levels of glucose down-regulates the glucose transport system in the muscle while up-regulating glucose-6- phosphatase in the liver with increased hepatic glucose production, both contributing to insulin resistance at the respective sites. An ongoing study with Nateglinide should address the issue of postprandial glucose reduction and improvement in insulin resistance effects. The fact that glycaemic control did not produce statistically significant improvement in Cardiovascular outcomes in the UKPDS suggests that tackling the glycaemic abnormality is probably not the whole answer to insulin resistance management.

ACE Inhibitors improve muscle blood flow and increase muscle glucose uptake (increase GLUT4 activity). FEBS Lett. 2004 Oct 22;576(3):492-7. They suppress brain sympathetic activity thus improving insulin sensitivity. They may have an effect on the tissue ACE demonstrated in pancreatic beta cells. Increasing the bradykinin and prostaglandins in the muscle has been shown to improve insulin sensitivity of muscle and this could be a possible mechanism. Diabetes. 1998 Apr;47(4):550-8 Counteracting the deleterious effects of Angiotensin II in the adipose tissue, and recruiting new adipocytes by facilitating adipocyte differentiation could be yet another mechanism of action of ACE inhibitors. Diabetes Metab. 2004 Dec;30(6):498-505.

Agents to improve insulin signalling, using activators of insulin receptor tyrosine kinase activity Science. 1999 May 7;284(5416):974-7. might become possible in the future. Reducing free fatty acid levels using agents (etomoxir) to inhibit carnitine palmitoyl transferase I (CPT-1) has the potential to improve plasma triglyceride levels Metabolism. 1991 Nov;40(11):1185-90 and producing modest improvements in glycaemia through inhibition of hepatic gluconeogenesis, although this could potentially pose problems with poor response to hypoglycemia. Vanadium compounds have been shown to hold some promise in decreasing endogenous glucose production as well as increasing peripheral glucose disposal with reduction in lipolysis. J Clin Invest. 1995 Jun;95(6):2501-9. Glucagon antagonists to counter the actions of glucagon is another potential area for research in this field. Expert Opin Ther Targets. 2005 Jun;9(3):593-600. Since reactive oxygen species as superoxides are recognised to produce functional beta cell impairment, J Clin Invest. 2003 Dec;112(12):1831-42 antioxidants could theoretically hold promise to preserve beta cell function.

Various questions have troubled the medical community for sometime. Is insulin resistance the consequence of obesity? Or does insulin resistance lead to obesity? Did the obese individual have a NEED for insulin resistance as a protective phenomenon? Or in other words, is insulin resistance a good thing that has gone terribly wrong?

The lipotoxicity hypothesis assumes the latter view. Excess carbohydrates are stored as glycogen normally. When glycogen stores are replete, further fate of the carbohydrates is entry into the lipogenic pathway (conversion to acetyl coA and then malonyl CoA). Malonyl coA inhibits fatty oxidation (lipolysis) by beta-oxidation, through inhibition of the CPT-1 (carnitine palmitoyl transferase 1) enzyme, while favouring fat deposition ( lipogenesis), while the cell which is insulin sensitive continues to utilize glucose for its energy needs. The proposed disadvantage of this scenario is that the fat that does not undergo beta oxidation here, can be metabolised by other pathways leading to toxic products facilitating apoptosis and lipotoxicity. Annu Rev Med. 2002;53:319-36. Development of insulin resistance (to the uptake of glucose into cells) results in diversion of the stored triglycerides into the preferred beta oxidation pathway avoiding generation of toxic substances including nitric oxide and ceramide. Trends Endocrinol Metab. 2003 Nov;14(9):398-403. But if this was to be as simplistic as it sounds, insulin resistance would have ultimately produced total lipolysis thus limiting the fat accumulation and restoring insulin sensitivity! It is important to realise that it is postulated that insulin resistance in this context may be selective for glucose uptake and not for lipogenesis. In other words, the cell remains sensitive to the lipogenic action of insulin through mechanisms as SREBP1c up regulation, Endocr Rev. 2002 Apr;23(2):201-29. facilitating continued deposition of fat as long as excess dietary supply of carbohydrates or calories is maintained.