Insulin Resistance: The Biochemical Scene
THE BIOCHEMICAL SCENE
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.
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.