Disclosure No conflict of interest

1. Bio-Behavioral Mechanisms and Genetics in the Development of Type 2 Diabetes Mellitus: The Moderating Role of Race by Anastasia Georgiades, Ph.D.

2. Disclosure No conflict of interest Supported by NHLBI grants R01HL076020 and P01HL36587

3. Acknowledgements • Richard Surwit, PhD • Redford Williams, MD • Ilene Siegler, PhD, MPH • Jim Lane, PhD • Mark Feinglos, MD • Sharon Minda, MSN • Beverly Brummett, PhD • Stephen Boyle, PhD • Svati Shah, MD • Paul Costa, PhD • John Barefoot, PhD • Cynthia Kuhn, PhD

4. Type 2 diabetes • Over 25 million Americans had diagnosed diabetes in 2010. • The estimated total economic cost of diagnosed diabetes in 2012 was $245 billion. • It is predicted that over 1/3 of the population in the US could have type 2 diabetes by 2050.

5. Worldwide prevalence of Type 2 Diabetes in year 2000 and predicted for 2030 Hossain P et al. N Engl J Med 2007;356:213-215.

6. Age adjusted Percentage of U.S. Population with Diagnosed Diabetes, 1980-2011 by Race and Sex From CDC website: http://www.cdc.gov/diabetes/statistics/prev/national/figraceethsex.htm

7. 2008 1994 2000 2008 1994 2000 No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% Age-adjusted Percentage of U.S. Adults who were Obese (top row) and who had Diagnosed Diabetes (bottom row) Obesity (BMI ≥30 kg/m2) Diabetes CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

8. Risk factors for type 2 Diabetes • Obesity • Inactivity • Family history • Race • Age • Pre-diabetes • Stress?

9. Body mass index (BMI) Weight (kg) BMI = Height squared (m2)

10. Classification of obesity

11. Obesity • 35% of the US population are Normal weight • 35% are Overweight and • 30% are Obese • 4 out of 5 African American women are either overweight or obese.

12. Beyond BMI: The importance of fat distribution • Peripheral vs Central fat depots Pear Apple

13. How to determine central obesity Waist >102 cm (40 in) in men >88 cm (35 in) in women Waist-hip ratio >0.9 for men >0.85 for women

14. More precise estimates of central adipose tissue: measuring Trunk fat with DEXA scan

15. Dual energy X-ray absorptiometry (DEXA) 1 Standard regions of a DEXA scan: 1= head 2= trunk 3= right arm 4= left arm 5= right leg 6= left leg 3 4 2 2 5 6

16. Central adiposity • Adds to the prediction of diabetes (above what can be predicted by BMI) in both men and women • Is particularly predictive of diabetes in African American populations

17. Beyond adiposity • Although over 90% of all type 2 diabetics are obese in the US, not all obese will develop diabetes……

18. Novel hypothetical model • We suggest that individual differences in sympathoadrenal activity may play an important role in the development of impaired glucose regulation.

19. Endogenous glucose production Counter- regulatory hormones Fasting glucose Stress Adiposity Pancreatic -cell function Hypothetical model linking Stress to impaired glucose metabolism Sympathetic activity Lipolysis Free fatty acids Diet/Exercise

20. Free fatty Acids in Glucose Regulation Figure from Bergman R. Orchestration of Glucose Homeostasis: From Small Acorn to the California Oak. Diabetes, 2007;56: 1489-1501

21. Endogenous glucose production Counter- regulatory hormones Fasting glucose Stress Adiposity Pancreatic -cell function Hypothetical model linking Stress to impaired glucose metabolism Sympathetic activity Lipolysis Free fatty acids Diet/Exercise

22. Stress • Stress can be defined as a state of threatened homeostasis, following exposure to adverse forces (stressors). • Stress arises when the individual cannot adequately cope with the demands/threats being made on them.

23. Autonomic nervous system

24. Plausible biobehavioral pathways: • impact health behaviors • and /or • influence counterregulatory hormone activity

25. I. Stress and eating behaviors • Severe stress reduces food intake in animals, while mild stress does not seem to affect food intake. • In humans, acute stress has been found to both increase and decrease food intake. • Chronic life stress may be associated with a high-fat diet and a greater preference for sweet foods. Reference: Torres SJ & Nowson CA, Nutrition, 2007.

26. II. Stress and Epinephrine: known effects on Glucose metabolism • Hyperglycemia can be induced by exposure to stress or by injection of epinephrine in animals, a response that is exaggerated if obesity is present (Surwit RS & Williams PG,Psychosom Med, 1996). • It has been proposed that catecholamines acting on central adipose tissue may be an important contributing factor to abnormalities in glucose metabolism in humans (Bergman RN, Diabetes, 2007)

27. Sympathoadrenalactivity • Diabetes research to date has focused on the role of adipose tissue in relation to metabolic dysregulation. • No previous study has examined if individual differences in counterregulatory hormone regulation influences glucose metabolism. • We propose that sympathoadrenal activity and central adiposity are both key factors in the development of impaired glucose metabolism.

28. Central Hypothesis High Epinephrine Sympathoadrenal activity (plasma epinephrine) will interact with central adipose tissue to produce impaired glucose metabolism Impaired glucose metabolism High Central Adiposity

29. Study 1 • 30 healthy women underwent an intravenous glucose tolerance test (IVGTT). • The participants had glucose, insulin and plasma EPI levels measured during the IVGTT.

30. Aim 1 To examine if epinephrine response to the glucose bolus interact with obesity to determine fasting glucose levels.

31. Results: EPI change during IVGTT was associated to Fasting Glucose in Obese Women (BMI>30) r=.76, p=.001

32. Aim 2 To examine if epinephrine response to the glucose bolus interact obesity to determine endogenous glucose levels during the IVGTT.

33. Results: Increases in EPI in response to the glucose bolus were associated with higher endogenous glucose levels during an IVGTT among obese women (BMI>30)

34. Study 2 • 70 healthy African American women (mean age 29±8 yrs) underwent an oral glucose tolerance test and a dual energy X-ray absorptiometry (DEXA) scan. • The participants also had glucose, insulin and plasma EPI levels measured during a psychological stress protocol.

35. Aim 1 To examine if plasma epinephrine levels interact with central adipose tissue to determine fasting glucose levels.

36. Women with high trunk fat and high EPI levels have significantly higher fasting glucose Surwit et al. 2010, Obesity

37. Aim 2 To examine if plasma epinephrine levels interact with central adipose tissue to determine glucose levels during stress.

38. Glucose levels during an Anger Recall task

39. Hypothesis testing • If central adipose tissue is sensitive to the effects of epinephrine, then centrally obese individuals may have lower of epinephrine in order to keep their glucose levels normal.

40. Study 1. Participant characteristics

41. Plasma Epinephrine Levels Decrease with Increasing Central Adiposity in Individuals with Normal Fasting glucose (<95mg/dl) Further support for our Hypothesis Georgiades et al., submitted to Diabetes Care

42. Conclusion Our studies suggest that the interaction of high central adiposity and enhanced sympathoadrenal activity contribute to both chronic and acute glucose changes. As African American women have significantly higher prevalence of central adiposity compared to white women, they may be particularly valuable to the effects of stress hormones on glucose metabolism.

43. Genetics Aim: To identify genotypes that are associated with • increased adiposity • increased sympathoadrenal activity • impaired glucose metabolism

44. Endogenous glucose production Counter- regulatory hormones Stress Adiposity Pancreatic -cell function Hypothetical model linking Stress to Impaired Glucose metabolism: associations to Genetic markers Genetics Sympathetic activity Lipolysis Impaired glucose metabolism Free fatty acids Diet/Exercise

45. Candidate genes • DRD2 (dopamine receptor) • HTR2C (serotonin receptor)

46. 1. The DRD2 gene • Encodes the D2 subtype of the dopamine receptor. • The DRD2 gene has been most associated with neuropsychiatric disorders but it has also been suggested to be involved in eating behaviors.

47. DRD2 snpRS4274224 • The DRD2 snp RS4274224 is associated with coronary artery disease among African Americans in the CATHGEN study. • The same snp was tested for associations with central adiposity in 2 separate studies: the PPG2 and the Caregiver study

48. DRD2 snpRS4274224 was associated with central adiposity among African Americans PPG2 study Caregiver study

49. DRD2 snpRS4274224 was also associated with Caloric intake in African American women

50. Total Caloric Intake, Waist circumference and % Trunk fat by race and sex groups in PPG2 Total Caloric intake Waist Circumference % Trunk fat