2. Diabetes – Status Today Diabetes Reaching Epidemic proportion Monitoring difficulties/complications Economic Implications Prevalence of CAD in the diabetic population, i.e., major abnormalities in ECG, angina, or myocardial infarction (MI) is 24 times than observed in nondiabetics. Prevalence of CCF to which CAD and hypertension contribute, is increased 3- to 4-fold. Uusitupa M, Siitonen O, Aro A, Pyörälä K: Prevalence of coronary heart disease, left ventricular failure and hypertension in middle-aged, newly diagnosed type 2 (non-insulin-dependent) diabetic subjects. Diabetologia 28:22-27, 1985.
3. Diabetes – Roadmap of Today What we know What we may not know What we need to know What we need to do after knowing The different sulfonylureas and relative comparisons Effects of sulfonylureas on cardiac risk factors Aspects of using sulfonylureas in diabetic patients The right approach to the choice of sulfonylureas Today’s review
9. Sulfonylureas – Mechanism Of Action sulfonylureas bind to a subunit of the ß-cell ATP-activated K channel complex (termed the sulfonylurea receptor) This binding reduces the rate of outward flow [efflux] of K+ ions across cell membrane & leads to closure of the channel Kruszynska Y, Olefsky JM. J Invest Med. 1996; 44:413-428. This depolarizes the membrane and triggers opening of voltage-sensitive Ca++ channels, leading to rapid influx of Ca Increased intracellular Ca++ causes an alteration in the cytoskeleton, This stimulates translocation of insulin-containing secretory granules to the plasma membrane and exocytotic release of insulin.
11. Sulfonylureas – what may be Unknown? What is ischaemic preconditioning of myocardium? What is its significance ? Various studies have provided excellent evidence that in diabetic patients, Sulfonylureas bind also to cardiovascular K ATP channels in the myocardium, although less well than to ß-cell K ATP channels chronic inhibition of the K ATP channel in the beta cells of the pancreas with oral sulfonylureas abolishes ischaemic preconditioning of myocardium.
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14. Sulfonylureas – what may be Unknown? inhibit the opening of the potassium channel and promote closure interfere with the myocardial adaptive response Sulfonylureas could potentially disrupt this protective mechanism of ischaemic preconditioning by their presence and interaction with cardiovascular KATP. This could: This abolishing or opposing phenomenon might contribute to the increased cardiovascular mortality in sulfonylurea-treated diabetic patients
15. Sulfonylureas – What Is Unknown? Despite their comparable actions on the pancreatic beta-cell KATP channel, all sulfonylureas are not similar because they strongly differ in their ability to interfere with vascular or cardiac KATP channels A useful pharmacological approach would be to identify -cell-specific sulfonylureas to avoid adverse effects: on the cardiac myocyte, as well as vasculature Why? Thus, what must be done?
16. How Does This Finding Advance Our Knowledge? Initiating / Continuance of long term oral pharmacotherapy Effects on fasting / Postprandial hyperglycaemia concern for benefits beyond the obvious concern for weight gain and hypo-glycaemia Expectations from sulfonylureas Rational Choice of Oral Antihyperglycaemic Agents, By Subhankar Chowdhury, Nilanjan Sengupta- JIMA, Vol. 100, No. 2, February 2002.
48. What Needs to Be Done After Knowing? What Are the Lessons?
49. The Future of Sulfonylureas: What Are the Lessons? Lesser Chances of weight gain / hypoglycaemia Decreased Insulinaemia Improvement In FBS, PPBG & Glycosylated Hb Lesser risks of atherosclerosis Increased Adiponectinaemia Extrapancreatic Effects Beta-Cell specific Preserves Myocardial preconditioning Action on both Phases of Insulin Secretion Rapid and Longer Duration Of Action
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Notas do Editor
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
Slide 2-4 Plasma Insulin After Oral Glucose: Effects of Obesity and Diabetes Following a glucose challenge after overnight fasting, plasma insulin levels are dependent upon obesity as well as diabetes. Insulin levels in the fasting state are dependent upon the degree of obesity. Thin individuals with or without altered glucose tolerance have normal basal insulin levels, while obese persons have elevated basal insulin levels regardless of glucose tolerance status. After a glucose challenge, both thin and obese individuals with type 2 diabetes demonstrate reduced early insulin responses when compared with their respective control groups. However, obese individuals with type 2 diabetes have higher post-glucose insulin levels than do thin individuals with normal glucose tolerance, thus demonstrating the persistence of the effect of obesity on insulin secretion. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest . 1967;46: 1549-1557.
