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Eagle Pharmaceuticals – 2006 © 1 • Perhaps the single point that deserves the most emphasis is that insulin resistance is not a disease, but the description of a physiologic state that greatly increases the chances of an individual developing several closely related abnormalities and associated clinical syndromes. • Reaven, G.The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin N Am, 2004, Vol. 33, pp. 283-303. Eagle Pharmaceuticals – 2006 © 2 • Should there be any disturbances to the binding of insulin to the receptors, or of the receptor response to insulin, there will be reduced insulin activity, or insulin resistance. • Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999, Vol. 18, No. 1, pp. 3-10. Eagle Pharmaceuticals – 2006 © 3 • Thus, by definition, insulin resistance is a defect in signal transduction. • Pessin, JE. and Saltiel, AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest, 2000, Vol. 106, No. 2, pp. 165-169. Eagle Pharmaceuticals – 2006 © 4 INSULIN Eagle Pharmaceuticals – 2006 © 5 • First discovered in 1921 by Sir Fredrick Banting and Charles Herbert Best. • One of the smallest proteins in the body that is built from 51 amino acids. Eagle Pharmaceuticals – 2006 © 6 INSULIN PROTEIN Eagle Pharmaceuticals – 2006 © 7 Beta Cells • Insulin is secreted in the pancreas by Beta-cells (-cells) found in the Islets of Langerhans. Pancreas Insulin Eagle Pharmaceuticals – 2006 © 8 • Islets of Langerhans are irregular clusters of endocrine cells that are scattered throughout the tissue of the pancreas that secrete insulin and glucagon. • Editors of the American Heritage® dictionaries, 2000 The American Heritage Dictionary of the English Language, Fourth Ed., Houghton Mifflin Company, Boston. Eagle Pharmaceuticals – 2006 © 9 • Insulin functions in the regulation of the metabolism of carbohydrates and fats, especially the conversion of glucose to glycogen, which lowers the blood glucose level. • Editors of the American Heritage® dictionaries, 2000 The American Heritage Dictionary of the English Language, Fourth Ed., Houghton Mifflin Company, Boston. Eagle Pharmaceuticals – 2006 © 10 Eagle Pharmaceuticals – 2006 © 11 Insulin Glucose • Insulin Receptor Insulin Receptor Glucose Transporters Insulin Receptor Substrates Phosphatidylinositol-3 Kinase Protein Kinase B Eagle Pharmaceuticals – 2006 © 12 KinaseIn biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific target molecules (substrates); the process is termed phosphorylation. An enzyme that removes phosphate groups from targets is known as a phosphatase. Eagle Pharmaceuticals – 2006 © 13 Insulin • Insulin signalling is triggered by binding of insulin to its receptor in the plasma membrane of the cell. • Biddinger, SB. and Kahn, CR. From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol, 2006, Vol. 68, pp. 123-158. Eagle Pharmaceuticals – 2006 © Alpha Units Beta Sub Units 14 Insulin • The receptor phosphorylates several proximal substrates – including members of the insulin receptor substrate (IRS) family. • Bryant, NJ. et al. Regulated transport of the glucose transporter GLUT4. Nature Rev Mol Cell Biol, 2002, Vol. 3, pp. 267-77. Eagle Pharmaceuticals – 2006 © Insulin Receptor Substrate 15 IRS Proteins • The IRS proteins act as important mediators of insulin action. Their regulation serves to augment the specificity of the insulin signalling cascade. • Johnston, AM. et al. Molecular mechanisms of insulin receptor substrate protein-mediated modulation of insulin signalling. FEBS Letters, 2003, Vol. 546, pp. 32-36. Eagle Pharmaceuticals – 2006 © 16 • Tyrosine phosphorylated IRS proteins recruit more effector molecules, such as Phosphatidylinositol-3 Kinase (PI3k). Insulin Receptor Substrate Phosphatidylinositol-3 Kinase • Bryant, NJ. et al. Regulated transport of the glucose transporter GLUT4. Nature Rev Mol Cell Biol, 2002, Vol. 3, pp. 267-77. Eagle Pharmaceuticals – 2006 © 17 Phosphatidylinositol-3 kinase (PI3k) • PI3k has a pivotal role in the metabolic and mitogenic actions of insulin and Insulin Growth Factor 1 (IGF-1). Inhibitors of class 1a PI3k block most metabolic actions of insulin, including stimulation of glucose transport, glycogen and lipid synthesis. • Saltiel, AR. and Kahn, CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 2001, Vol. 414, No. 6865, pp. 799-806. Eagle Pharmaceuticals – 2006 © 18 • PI3k activates the serinethreonine kinase Akt/Protein Kinase B (PKB). Phosphatidylinositol-3 Kinase • Pessin, JE. et al. Signalling pathways in insulin action: molecular targets of insulin resistance, J Clin Invest, 2000, Vol. 106, pp. 165-69. Eagle Pharmaceuticals – 2006 © 19 Akt/PKB • The membrane bound form of Akt in 3T3-L1 adipocytes results in increased glucose transport and persistent localisation of Glucose Transport-4 (GLUT4) to the plasma membrane. • Biddinger, SB. and Kahn, CR. From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol, 2006, Vol. 68, pp. 123-58. Eagle Pharmaceuticals – 2006 © 20 • Insulin stimulates increased glucose transport by causing the redistribution of GLUT4 from an intracellular pool to the cell surface where it acts as a facilitative transporter to enhance entry of glucose into the cell. • Glucose Glucose Transporters Nystrom, FH. and Quon, MJ. Insulin signalling: metabolic pathways and mechanisms for specificity. Cell Signal, 1999, Vol. 11, No. 8, pp. 563-574. Eagle Pharmaceuticals – 2006 © 21 GLUTS (Glucose Transport Proteins) • GLUT1- is widely distributed in foetal tissues. In the adult, it is expressed at highest levels in erythrocytes and also in the endothelial cells of barrier tissues such as the bloodbrain barrier. • GLUT2- is expressed by liver and pancreatic β cells. • GLUT3- is an isoform expressed mostly in neurons where it is believed to be the main glucose transporter isoform. • GLUT4- is the insulin-regulated glucose transporter found in adipose and muscle tissue that is responsible for insulinregulated glucose disposal. Eagle Pharmaceuticals – 2006 © 22 • In the absence of stimulation, GLUT4 is almost completely excluded from the plasma membrane. The addition of insulin, or exercise in the case of muscle cells, causes GLUT4 to shift from its intracellular location to the plasma membrane. • Bryant, NJ. et al. Regulated transport of the glucose transporter GLUT4. Nature Rev Mol Cell Biol, 2002, Vol. 3, pp. 267-77. Eagle Pharmaceuticals – 2006 © 23 • Once the glucose pathway is opened by GLUT4, glucose is polymerised (many sugars linked together) within the cell. Under normal conditions it is then broken down as required to meet the body’s energy needs. Eagle Pharmaceuticals – 2006 © 24 Eagle Pharmaceuticals – 2006 © 25 Receptor Defects Post Receptor Defects Eagle Pharmaceuticals – 2006 © 26 • Over Nutrition • Obesity −Adipose Tissue −Free Fatty Acids • Inflammation −Tumour Necrosis Factor (TNF-) −Interleukin-6 (IL-6) Eagle Pharmaceuticals – 2006 © 27 Eagle Pharmaceuticals – 2006 © 28 Eagle Pharmaceuticals – 2006 © 29 • High carbohydrate diets decrease insulin receptor numbers, probably as a result of increased cellular contact with insulin and resultant insulin receptor down regulation. • Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999, Vol. 18, No. 1, pp. 3-10. Eagle Pharmaceuticals – 2006 © 30 • Diets high in saturated fats and trans fatty acids have been shown to decrease membrane fluidity and decrease insulin receptor binding, thus promoting insulin resistance. • Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999, Vol. 18, No. 1, pp. 3-10. Eagle Pharmaceuticals – 2006 © 31 • An acquired loss of PI3k activation in muscle is also seen as a result of a high fat diet. • Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481. Eagle Pharmaceuticals – 2006 © 32 • Picture of centrally obese man Eagle Pharmaceuticals – 2006 © 33 • Obesity is the most common cause of insulin resistance and type 2 diabetes. • Petersen, KF. and Shulman, GI. Eitiology of insulin resistance. Am J Med, 2006, Vol. 119, No. 5a, pp. 10s-16s. Eagle Pharmaceuticals – 2006 © 34 • Central (intra abdominal) deposits of fat are more strongly linked to insulin resistance, type 2 diabetes and cardiovascular disease than are peripheral (gluteal/subcutaneous) fat deposits. • Kahn, BB. and Flier JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol.106, No. 4, pp. 473-481. Eagle Pharmaceuticals – 2006 © 35 • Hotamisligil suggested that obesity appears to be a state of chronic inflammation with increased production of cytokines and other acute-phase reactants that play a crucial role in regulation of systemic insulin action. • Bloomgarden, ZT. Inflammation and Insulin Resistance, Diab Care, 2004, Vol 26(5), pp. 1619-23. Eagle Pharmaceuticals – 2006 © 36 Eagle Pharmaceuticals – 2006 © 37 • Adipocytes have recently been shown to be dynamic endocrine cells that produce and secrete various bioactive molecules (known as adipokines or adipocytokines), some of which affect the insulin sensitivity of other tissues. • Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest, 2006, Vol. 116, No. 6, pp. 1494-1505. Eagle Pharmaceuticals – 2006 © 38 • Insulin resistance that accompanies obesity is attributable, at least in part, to changes in adipokine secretions. • Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest, 2006, Vol. 116, No. 6, pp. 1494-1505. Eagle Pharmaceuticals – 2006 © 39 • The release of a wide variety of molecules including hormones such as leptin, cytokines such as TNF- and substrates such as free fatty acids (FFA’s) allow the adipose organ to play a major regulatory role in energy balance and glucose homoeostasis. • Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481. Eagle Pharmaceuticals – 2006 © 40 Eagle Pharmaceuticals – 2006 © 41 • Elevated FFA’s impair insulin’s ability to suppress hepatic glucose output, stimulate glucose uptake into skeletal muscle and inhibit insulin secretion from pancreatic -cells. • Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481. Eagle Pharmaceuticals – 2006 © 42 • In humans, the triglyceride content of muscle correlates directly with the degree of insulin resistance. • Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481. Eagle Pharmaceuticals – 2006 © 43 Eagle Pharmaceuticals – 2006 © 44 Eagle Pharmaceuticals – 2006 © 45 • Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance. • Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest, 2003, Vol. 112, No. 12, pp. 1821-1830. Eagle Pharmaceuticals – 2006 © 46 • TNF-, IL-6 and undoubtedly other pro- or antiinflammatory cytokines appear to participate in the induction and maintenance of the subacute inflammatory state associated with obesity. • Shoelson, SE. et al. Inflammation and insulin resistance. J Clin Invest, 2006, Vol. 116, No. 7, pp. 1793801. Eagle Pharmaceuticals – 2006 © 47 TNF- • Adipose tissue expression of TNF- is increased in humans and is positively correlated with adiposity and insulin resistance. • Kershaw, EE. and Flier, JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab, 2004, Vol. 89, No. 6, pp. 2548-2556. Eagle Pharmaceuticals – 2006 © 48 • TNF- is raised in adipocytes in obesity and has been shown to: − Inhibit insulin stimulated tyrosine phosphorylation of the IRS − Stimulate down regulation of the IRS − Stimulate down regulation of insulin-sensitive glucose transporters. • Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999, Vol. 18, No. 1, pp. 3-10. Eagle Pharmaceuticals – 2006 © 49 IL-6 • Adipose tissue IL-6 expression and circulating concentrations are positively correlated with obesity, impaired glucose tolerance and insulin resistance. • Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481. Eagle Pharmaceuticals – 2006 © 50 • IL-6 decreases insulin signalling in peripheral tissues by: – Reducing expression of insulin receptor signalling components – Inducing suppressor of cytokine signalling 3 (SCS3), a negative regulator of insulin signalling. • Kershaw, EE. and Flier, JS. Obesity and insulin resistance. J Clin Endocrinol Metab, 2004, Vol. 89, No. 6, pp. 2458-56. Eagle Pharmaceuticals – 2006 © 51 Over Nutrition IL-6 TNF- Obesity FFA’s & High Fat Diets Eagle Pharmaceuticals – 2006 © 52 Eagle Pharmaceuticals – 2006 © 53 HERBS • Botanical products can improve glucose metabolism and the overall condition of individuals with diabetes not only by hypoglycaemic effect but also by improving lipid metabolism, antioxidant status and capillary function. • Khan, A. et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diab Care, 2003, vol. 26, No. 12, pp. 3215-3218. Eagle Pharmaceuticals – 2006 © 54 Eagle Pharmaceuticals – 2006 © 55 • Cinnamon, also known as Sweet Wood and Gui Zhi is traditionally harvested in Asian countries. It is, perhaps, one of the oldest herbal medicines, having been mentioned in Chinese texts as long as 4000 years ago. • Qin, B. et al. Cinnamon extract potentiates in vivo insulin-regulated glucose utilisation via enhancing insulin signalling in rats. Diab Res Clin Pract, 2003, Vol. 62, pp. 139-48. Eagle Pharmaceuticals – 2006 © 56 • Significant reduction of plasma glucose after four months of treatment was observed in the Cinnamon group but not in the placebo. • Mang, B. et al. Effects of a cinnamon extract on blood glucose in db/db mice. J Ethnopharm, 2006, Vol. 104, pp. 119-123. Eagle Pharmaceuticals – 2006 © 57 • Cinnamon activates insulin receptor kinase and inhibits dephosphorylation of the insulin receptor, leading to maximal phosphorylation of the insulin receptor. • Khan, A. et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diab Care, 2003, Vol. 26, No.12, pp. 3215-3218. Eagle Pharmaceuticals – 2006 © 58 • Results reveal that Cinnamon administration increases the IRS-1/ PI3k association; therefore, this change results in PI3k activation. • Qin, B. et al. Cinnamon extract prevents the insulin resistance induced by a high-fructose diet. Horm Metab Res, 2004, Vol. 36, pp. 119-125. Eagle Pharmaceuticals – 2006 © 59 • Sushruta (6th Century B.C.) and practitioners of Ayurveda have recommended the use of the ‘sala saadi’ group for maturity onset diabetes in addition to dietary restrictions. • Eagle Pharmaceuticals – 2006 © Baskaran, K. et al. Antidiabetic effect of a leaf extract of gymnema sylvestra in NIDDM patients. J Ethnopharm, 1990, Vol. 30, pp. 295-305. 60 • Gymnemic acid inhibits glucose absorption from the small intestine and suppresses the increase in plasma glucose levels. • Porchezhian, E. and Dobriyal, RM. An overview on the advances of gymnema sylvestre: chemistry, pharmacology and patents. Pharmazie, 2003, Vol. 58, No. 1, pp. 5-12. Eagle Pharmaceuticals – 2006 © 61 • Gymnema’s major mode of action is via permeabilisation of -cell plasma membranes, leading to up-regulated loss of insulin from the cells. • Persaud, SJ. et al. Gymnema sylvestra stimulates insulin release in vitro by increased membrane permeability. J Endocrinol, 1999, Vol. 163, pp. 207-212. Eagle Pharmaceuticals – 2006 © 62 Eagle Pharmaceuticals – 2006 © 63 Eagle Pharmaceuticals – 2006 © 64 • In humans there are no descriptions of alpha Lipoic acid (ALA) deficiency; however, lower concentrations have been found in patients with acne vulgaris, neurodermatitis, liver cirrhosis, advanced arteriosclerosis, psoriasis, different types of polyneuropathy, and diabetes. • Konrad, T. et al. Alpha Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diab Care, 1999, Vol. 22, pp. 280-287. Eagle Pharmaceuticals – 2006 © 65 • Findings now demonstrate that oxidants produced by ALA are involved in: – Activation of insulin receptor (Cho, KJ. et al. Alpha Lipoic acid decreases thiol reactivity of the insulin receptor and protein tyrosine phosphatase 1B in 3T3-L1 adipocytes. Biochem Pharmacol, 2003, Vol. 66, pp. 849-858.) – Increased tyrosine phosphorylation of IRS-1 – Activation of PI3k and serine-threonine kinase Akt1 – Translocation of glucose transporters GLUT 1 & 4 (Konrad, D. et al. The antihyperglycemic drug alpha Lipoic acid, stimulates glucose uptake via both GLUT-4 translocation and GLUT-4 activation. Diabetes, 2001, Vol. 50, pp. 1464-1471.) Leading to elevated glucose uptake into 3T3-L1 adipocytes. Eagle Pharmaceuticals – 2006 © 66 alpha Lipoic acid PI3k p38 MAPK Akt GLUT4 Translocation GLUT4 Activation Stimulation of glucose uptake Eagle Pharmaceuticals – 2006 © 67 • In both muscle and adipocyte cells ALA mimics insulin action in stimulating glucose uptake via a pathway requiring PI3k activity. • Estrada, D. et al. Stimulation of glucose uptake by the natural coenzyme alpha Lipoic acid / thioctic acid. Diabetes, 1996, Vol. 45, pp. 1798-1804. Eagle Pharmaceuticals – 2006 © 68 3.5 Troglitazone Insulin 2 Lipoic Acid 1.5 1 Metformin 0.5 0 Control Eagle Pharmaceuticals – 2006 © Co Gly MET La Ins Glyburide TRO mmol/l 3 2.5 69 Eagle Pharmaceuticals – 2006 © 70 • Microscopic analysis showed that Chromium (Cr) treatment for 16hrs increased the basal-state level of GLUT4 in the plasma membrane and insulin’s effect was enhanced in the presence of Cr. • Chen, G. et al. Chromium activates glucose transporter 4 trafficking and enhances insulin stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol dependant mechanism. Mol Endocrinol, 2006, Vol. 20, pp. 857-70. Eagle Pharmaceuticals – 2006 © 71 • Microscopic and biochemical data show clearly that chromium elicits an insulin like accumulation of GLUT4 at the plasma membrane in 3T3-L1 adipocytes. • Chen, G. et al. Chromium activates glucose transporter 4 trafficking and enhances insulin stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol dependant mechanism. Mol Endocrinol, 2006, Vol. 20, pp. 857-70. Eagle Pharmaceuticals – 2006 © 72 Eagle Pharmaceuticals – 2006 © 73 • Alterations of Magnesium (Mg) metabolism induce and/or exacerbate insulin resistance which is confirmed by data in humans, showing that dietary induced Mg deficiency is correlated with insulin resistance. • Barbagallo, M. and Dominguez, LJ. Magnesium metabolism in type 2 diabetes, metabolic syndrome and insulin resistance. Arch Biochem Biophys, 2006, Epub ahead of print. Eagle Pharmaceuticals – 2006 © 74 • Mg depletion induces a severe insulin resistance that is shown to be dependent, at least in part, upon a defective tyrosine kinase activity of the insulin receptors. • Barbagallo, M. et al. Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X. Mol Aspect Med, 2003, Vol. 24, pp. 39-52. Eagle Pharmaceuticals – 2006 © 75 Eagle Pharmaceuticals – 2006 © 76 • Zinc ions have an insulin-like (insulinomimetic) effect. A particularly sensitive target of zinc ions is protein tyrosine phosphatase 1B (PTP 1B), a key regulator of the phosphorylation state of the insulin receptor. • Haase, H. and Maret, W. Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. Biometals, 2005, Vol. 18, No. 4, pp. 333-338. Eagle Pharmaceuticals – 2006 © 77 Eagle Pharmaceuticals – 2006 © 78 • Vitamin D3 not only facilitates the biosynthetic capacity of -cells but also accelerates the conversion of pro-insulin to insulin. • Chiu, KC. et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. AJCN, 2004, Vol. 79, pp. 820-825. Eagle Pharmaceuticals – 2006 © 79 • Observations in the current study suggests that increasing Vitamin D from 10 to 30ng/mL can improve insulin sensitivity by 60%. • Chiu, KC. et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. AJCN, 2004, Vol. 79, pp. 820-825. Eagle Pharmaceuticals – 2006 © 80 • Furthermore, the 60% improvement in insulin sensitivity that results from Vitamin D treatment indicates that it is more potent than either Troglitazone or Metformin treatment. • Chiu, KC. et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. AJCN, 2004, Vol. 79, pp. 820-825. Eagle Pharmaceuticals – 2006 © 81 Eagle Pharmaceuticals – 2006 © 82 • Results show that Biotin increases insulin secretion in normoglycaemic and hyperglycaemic conditions. • Romero-Navarro, G. et al. Biotin regulation of pancreatic glucokinase and insulin in primary cultured rat islets and in biotin-deficient rats. Endocrinol, 1999, Vol. 140, pp. 4595-45600. Eagle Pharmaceuticals – 2006 © 83 • Biotin enhances glucose induced insulin secretion by elevating ATP synthesis in pancreatic Islets of Langerhans. • Sone, H. et al. Biotin enhances ATP synthesis in pancreatic cell islets of the rat, resulting in reinforcement of glucose-induced insulin secretion. Biochem Biophys Res Comm, 2004, Vol. 314, pp. 824-829. Eagle Pharmaceuticals – 2006 © 84 FISH OIL Eagle Pharmaceuticals – 2006 © 85 • Polyunsaturated fatty acids (PUFA’s), especially total n-3 fatty acids, were independently associated with lower levels of pro-inflammatory markers (IL-6, TNF-) and higher levels of anti-inflammatory markers, independent of confounders. Findings support the notion that n-3 fatty acids may be beneficial in patients affected by diseases characterised by active inflammation. • Ferruci, L. et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab, 2006, Vol. 91, pp. 439-446. Eagle Pharmaceuticals – 2006 © 86 Eagle Pharmaceuticals – 2006 © 87 • Exercise training reverses insulin resistance by enhancing the recruitment of GLUT4 to the cell surface. • Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999, Vol. 18, No. 1, pp. 3-10. Eagle Pharmaceuticals – 2006 © 88 Eagle Pharmaceuticals – 2006 © 89 Cinnamon • • • Activates insulin receptor kinase Maximises phosphorylation of insulin receptor PI3k activation Chromium • Increases GLUT4 translocation Eagle Pharmaceuticals – 2006 © 90 alpha Lipoic acid • • • • Activates insulin receptor Increased tyrosine phosphorylation of IRS-1 Activation of PI3k and serine-threonine kinase Akt Translocation of glucose transporters GLUT 1 & 4 Eagle Pharmaceuticals – 2006 © 91 Magnesium • Depletion causes reduced tyrosine kinase activity at the insulin receptor Zinc • Affects phosphorylation at the insulin receptor Eagle Pharmaceuticals – 2006 © 92 Zinc Magnesium alpha Lipoic acid Cinnamon Chromium Exercise Eagle Pharmaceuticals – 2006 © 93 Gymnema • • • Increases insulin release from -cells Inhibition of glucose absorption from small intestine Increases permeabilisation of -cell plasma membranes Eagle Pharmaceuticals – 2006 © 94 Vitamin D • • Facilitates the biosynthetic capacity of -cells Helps with the conversion of insulin to pro-insulin Biotin • Increases insulin secretion Eagle Pharmaceuticals – 2006 © 95 Gymnema Pancreas Biotin Eagle Pharmaceuticals – 2006 © Vitamin D 96 Eagle Pharmaceuticals – 2006 © 97