Insulin Resistance: The Pancreatic Scene
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 inabsolute 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.
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.