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Two very different types of diabetes

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Two very different types of diabetes

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    1. Two very different types of diabetes

    2. Evolution favors predisposition toward obesity (thrifty genotype) If these figurines represent realistic portrayals of human bodies, these were certainly obese. It tells us that although increased prevalence of obesity is recent, its existence itself is not. In fact, it is very likely that eons of evolution has selected for a set of “thrifty genes” that predispose each and every one of us to develop obesity. The high incidence of obesity in recent years should not be a surprise. Becoming obese is a normal physiological response to ready availability of food. Per se it is not a disease in the sense that something is abnormal. The central question is this: if development of obesity and insulin resistance are normal physiological processes, how can one design a therapy that does not reverse normal physiological processes and millions of years of evolution? The answer I believe lies in the understanding of the molecular and metabolic basis of this predisposition toward obesity. That is the long term goal of my studies. Human body has its own logic. Many of the drugs used to treat diabetes actually goes against this logic. For example, thiazolidinediones can improve insulin sensitivity, but often make people more obese. I feel that if we can better understand how the body regulates energy homeostasis, we can develop therapeutic regimens that will make more sense, and perhaps more effective as well. So, how does one begin to approach this problem. A good place is to identify genes that participates in energy balance regulation. If these figurines represent realistic portrayals of human bodies, these were certainly obese. It tells us that although increased prevalence of obesity is recent, its existence itself is not. In fact, it is very likely that eons of evolution has selected for a set of “thrifty genes” that predispose each and every one of us to develop obesity. The high incidence of obesity in recent years should not be a surprise. Becoming obese is a normal physiological response to ready availability of food. Per se it is not a disease in the sense that something is abnormal. The central question is this: if development of obesity and insulin resistance are normal physiological processes, how can one design a therapy that does not reverse normal physiological processes and millions of years of evolution? The answer I believe lies in the understanding of the molecular and metabolic basis of this predisposition toward obesity. That is the long term goal of my studies. Human body has its own logic. Many of the drugs used to treat diabetes actually goes against this logic. For example, thiazolidinediones can improve insulin sensitivity, but often make people more obese. I feel that if we can better understand how the body regulates energy homeostasis, we can develop therapeutic regimens that will make more sense, and perhaps more effective as well. So, how does one begin to approach this problem. A good place is to identify genes that participates in energy balance regulation.

    3. The United States is a large country

    4. Obesity Trends* Among U.S. Adults BRFSS, 1985

    5. Obesity Trends* Among U.S. Adults BRFSS, 1986

    6. Obesity Trends* Among U.S. Adults BRFSS, 1987

    7. Obesity Trends* Among U.S. Adults BRFSS, 1988

    8. Obesity Trends* Among U.S. Adults BRFSS, 1989

    9. Obesity Trends* Among U.S. Adults BRFSS, 1990

    10. Obesity Trends* Among U.S. Adults BRFSS, 1991

    11. Obesity Trends* Among U.S. Adults BRFSS, 1992

    12. Obesity Trends* Among U.S. Adults BRFSS, 1993

    13. Obesity Trends* Among U.S. Adults BRFSS, 1994

    14. Obesity Trends* Among U.S. Adults BRFSS, 1995

    15. Obesity Trends* Among U.S. Adults BRFSS, 1996

    16. Obesity Trends* Among U.S. Adults BRFSS, 1997

    17. Obesity Trends* Among U.S. Adults BRFSS, 1998

    18. Obesity Trends* Among U.S. Adults BRFSS, 1999

    19. Obesity Trends* Among U.S. Adults BRFSS, 2000

    20. Obesity Trends* Among U.S. Adults BRFSS, 2001

    29. Insulin is the principal regulator of blood sugar (glucose) levels

    30. Glucose transport (GLUT) protein: Catalyzed “downhill” movement of glucose into or out of a cell.

    31. Insulin regulates glucose uptake by altering the distribution of GLUT4 within the fat and muscle cell.

    32. Insulin resistance often leads to diabetes

    33. Type II Diabetes Mellitus and Obesity The question must be asked in a telelogical manner. -type II, or adult-onset, diabetes is a major disease that afflicts tnes of millions of people world wide, and particularly in affluent countries. This is so because in most cases, type II diabetes is intimately linked to obesity. -Although obesity per se is not a disease, it is associated with many of the major killers of today. Obesity is an intimate part of the metabolic syndrome X that include many leading causes of death. That is the biggest reason to study obesity. -In order to understand pathogenesis of diabetes, we must study how obesity promotes insulin resistance -Recently the incidence of obesity has been at a very sharp increase in our population. The next series of slides depicts graphically how serious is this problem. The question must be asked in a telelogical manner. -type II, or adult-onset, diabetes is a major disease that afflicts tnes of millions of people world wide, and particularly in affluent countries. This is so because in most cases, type II diabetes is intimately linked to obesity. -Although obesity per se is not a disease, it is associated with many of the major killers of today. Obesity is an intimate part of the metabolic syndrome X that include many leading causes of death. That is the biggest reason to study obesity. -In order to understand pathogenesis of diabetes, we must study how obesity promotes insulin resistance -Recently the incidence of obesity has been at a very sharp increase in our population. The next series of slides depicts graphically how serious is this problem.

    34. Adipose tissue: a producer of many important hormones that regulate sugar and fat metabolism • Tumor necrosis factor-a (TNF- a) • Leptin • Acrp30/Adiponectin • Resistin

    35. Acrp30/ Adiponectin - A Major Adipocyte- Specific Hormone

    41. Incubation of rat extensor digitorum longus (EDL) muscle with Acrp30/ adiponectin for 30 min. led to two-fold increases in AMPK activity and phosphorylation of AMPK on Thr 172 and acetyl CoA carboxylase (ACC) on Ser-79.

    42. Incubation of rat extensor digitorum longus (EDL) muscle with Acrp30/Adiponectin (2.5 µg/ml) for 30 minutes activates both AMPK and ACC phosphorylation

    44. APM1 (Acrp30) is decreased in individuals with type II diabetes and coronary artery disease Nondiabetic Diabetic Diabetic with coronary     artery disease

    45. Fat tissue from obese mice or humans is resistant to insulin

    46. Why is fat tissue from obese mice or humans is resistant to insulin?

    47. Physiological Relevance of TNF-a TNF-a is highly induced in adipose tissues of obese animals and human subjects TNF-a induces insulin resistance both in cell culture and in experimental animals The absence of either TNF-a or its receptors improves the action of insulin in mice

    48. The Role of TNF-a in Inducing Insulin Resistance

    49. TNF-a treatment of adipocytes leads to downregulation of GLUT4 glucose transporter and Acrp30/ adiponectin messenger RNAs

    50. TNF-? administration to rats leads to induction of insulin resistance: insulin tolerance test

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