Diabetes in Asian American and Pacific IslandersFocus on

Diabetes in Asian American and Pacific Islanders-Focus on Type 1 Diabetes George L. King, MD Director Asian American Diabetes Initiative Research Director Joslin Diabetes Center Professor of Medicine Harvard Medical School

Two Main Types of Diabetes Type 1 diabetes Type 2 diabetes 5 -10% of total (Rare in Asians) >90% of total (>95% in AA) Common in children (A Minority in East Asian Mostly in adults, but increasing in children Children) Insulin Requiring Auto-immune Destruction of the Islets, HLA DR 3/4 or LADA (0 nly 1/3 of AA’s) Rare fulminating type in Asians Not insulin requiring Insulin resistant associated with obesity , inflammation and inactivity

Diabetes is Reaching Epidemic Levels 26. 5 32. 9 24% 2000 = 14. 2 2010 = 17. 5 23% 9. 4 14. 1 50% 1. 0 1. 3 33% 15. 6 22. 5 44% IDF, WHO Data 84. 5 132. 3 57% World 2000 = 151 million 2030 = 435 million Costs 2010 = $376 billion

Incidence rates of type 1 diabetes in children

Incidence of T 1 DM (children less than age 15 - per 100, 000/year) Finland 29 Sweden 25 US 18 Cuba 3 Japan 2 (Diabetes Metab Rev 1989, 5: 571) In the U. S. about 1 in 400 children have T 1 DM. Although there is a peak in adolescence, the average of onset is about age 30. The incidence continues to climb.

Incidence Type 1 DM Incidence in Various Countries & in the U. S. USA Diabetes in America, 2 nd Edition, Pg. 42 Diabetes Care, Volume 16, Number 5, May 1993

Type-specific proportions of prevalent cases of diabetes according to age group (A, 0– 9 years; B, 10– 19 years) and race/ethnicity. et al. Pediatrics 2006; 118: 1510 -1518 © 2006 by American Academy of Pediatrics

Human pancreas: 85 gm Islet mass: 2% About one million islets About one billion beta cells (Insulin)

Normal Mouse Islet - Insulin PAP Stain Beta Cells Alpha and Delta Cells Bonner-Weir

Processing of Proinsulin to Insulin and C-Peptide Lodish

Glucose GLUT 2 GK G G 6 P K/ATP Ca K VDCC ATP/ ADP Ca 1 ? ? Mitoch 2 Exocytosis of insulin 1. K/ATP dependent pathway 2. K/ATP independent pathway

Insulin and glucagon secretion in response to a meal NEJM 1970, 283: 109

Normal Pre-diabetic Type 1 Diabetes

First Demonstration of Increased Insulin Secretion in Obesity Important first evidence of increased secretion in response to demand. Karam, J. H. , Grodsky, G. M. , and Forsham, P. H. 1963. Excessive insulin response to glucose in obese subjects as measured by immunochemical assay. Diabetes 12: 196204.

Natural History of Type 1 Diabetes PUTATIVE ENVIRONMENTAL TRIGGER CELLULAR (T CELL) AUTOIMMUNITY HUMORAL AUTOANTIBODIES BETA CELL MASS (ICA, IAA, Anti-GAD 65, IA 2 Ab, etc. ) LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) GENETIC PREDISPOSITION GLUCOSE INTOLERANCE INSULITIS BETA CELL INJURY (OGTT) “PRE” DIABETES CLINICAL ONSET DIABETES TIME

Natural History of Type 2 Diabetes Insulin Sensitive Contributing Factors Obesity Diet Sedentary Lifestyle Increasing Age Genetics Perinatal Factors Inflammation Normoglycemia Hyperglycemia Insulin Resistant Compensatory Hyperinsulinemia Cell Decompensation Relative Insulin Deficiency Cell Failure Impaired Glucose Tolerance or ‘Prediabetes’ Type 2 Diabetes Risk of Cardio-vascular Complications

Autoimmune destruction of cells results in atrophic islets Spontaneous diabetic NOD mice; glucagon stain

Killing Beta Cells Autoreactive T Cell Inflammation Regulatory T Cell Killing Cytokines Granzyme Perforin Beta Cell

Genetics HLA accounts of about 60% of the genetic risk. 95% of all patients, who develop diabetes before the age of 30 have susceptibility haplotypes DQB 1*0302 A 1*0301 -DRB 1*04 and DQB 1*0201 A 1*0501 -DRB 1*03 except East Asians Other individual genes are much less influential (IDDM 2 -18). Notable candidates IDDM 2: Insulin IDDM 12: CTLA-4

Frequency of Risk HLA Category for Type 1 Diabetes in Various Ethnic Populations Rewers M, et al. Diabetologia. 1996; 39(7): 807 -12.

Table 3. Screening results in different ethnic groups in the three US centers Race/Ethnicity Asian-Americans Hispanic Americans African-Americans Caucasian Other* 3715 6611 9231 38 240 8409 6 10 14 58 13 Genotype A (DR 3/4) 0. 2 1. 9 0. 5 2. 3† 0. 9 Genotype B (DR/4/4) 0. 1 1. 9‡ 0. 2 0. 9 0. 5 Genotype C (DR 4/8) 0. 1 2. 2‡ 0. 1 0. 5 0. 6 Genotype D (DR 3/3) 0. 5‡ 0. 8 0. 6‡ 1. 3 0. 6 0. 9‡ 6. 9 1. 3‡ 5. 0 2. 5 6 14 15 27 NA Relative Incidence (vs. Caucasians) (%) 22 52 56 100 NA Relative eligibility (vs. Caucasians) (%) 18 138 26 100 NA Weighted eligibility rate (%) 81 266 47 100 NA Screened (n) Percentage of screened: average Eligible (%) All genotypes Incidence of T 1 D § *Native Americans, Pacific Islanders, multiracial, or unknown † Uncorrected p < 0. 01 (chi-square test) vs. total for all ethnicities ‡ Uncorrected p < 0. 001 (chi-square test) vs. total for all ethnicities § Incidence per 100 000/yr Hagopian WA, et al. Pediatric Diabetes. 2011 May 12. doi: 10. 1111/j. 1399 -5448. 2011. 00774. x. [Epub ahead of print]

Disease susceptible HLA-haplotypes Japanese (DR 4) (DR 9) Caucasians (DR 3) (DR 4) DRB 1*0405 -DQB 1*0401 DRB 1*0901 -DQB 1*0303 DRB 1*0301 -DQB 1*0201 DRB 1*0401 -DQB 1*0302

Figure 1. Frequencies of type 1 diabetes in siblings of probands with type 1 diabetes as compared with prevalence of type 1 diabetes in general population. Ikegami H, et al. Ann. NY Acad Sci. 2006; 1079: 51 -59.

Association of CTLA 4 with autoimmune diseases (Caucasian populations) Odds ratio (95% CI) Graves’s disease 1. 51 (1. 31 -1. 75) Hashimoto thyroiditis Type 1 diabetes 1. 45 1. 14 (1. 17 -1. 80) (1. 07 -1. 21) SNP: +6230 G>A (rs 3087243) Ueda H et al. Nature 2003

Islet Cell Antibodies 1. Insulin 2. Glutamic acid decarboxylase (GAD) 3. ICA 512 (insulinoma-associated antigen-2 [IA-2]) (Phogrin). 4. Zinc transporter 8 (SLC 30 A 8) These antibodies are not cytotoxic but are good markers of disease progression

Diabetes 1996, 45: 926 -933.

Auto-Antibodies to Islet and GAD in Type 1 Diabetes Media, 17(295) 2000

AADI’s Study to Differentiate Type 1 and 2 Diabetes in Asian-Americans Type 1 Diabetes (n=10) 25. 4 ± 4. 5 Type 2 Diabetes (n=9) 31. 7 ± 6. 3 Controls (n=11) 26. 3 ± 4. 3 ANOVA p value 0. 023 Gender male (%) 3(30%) 3(33. 3) 5(45. 5) 0. 74 Years with DM (yrs) 6. 1 ± 4. 0 3. 0 ± 3. 4 N/A BMI (kg/m 2) 23. 4 ± 1. 7 24. 5 ± 3. 6 23. 3 ± 3. 9 0. 650 A 1 C% 6. 9 ± 1. 1 7. 0 ± 1. 6 5. 2 ± 0. 3 0. 001 0. 85 ± 0. 02 0. 89 ± 0. 53 0. 89 ± 0. 07 0. 150 Age (yrs) Waist to Hip Ratio Adiponectin (ug/ml) Cholesterol HDL (mg/dl) 16. 6 ± 5. 6 7. 3 ± 3. 5 8. 6 ± 5. 1 <0. 0001 60. 8 ± 10. 6 47. 8 ± 16. 1 47. 5 ± 10. 7 0. 038 C-peptide (ng/ml) 0. 14 0. 15 2. 29 1. 57 1. 35 1. 21 0. 001 CRP (ng/ml) 2. 68 ± 2. 35 1. 31 ± 1. 11 0. 814 ± 1. 02 0. 048 0. 54 ± 0. 19 1. 09 ± 0. 35 0. 77 ± 0. 26 0. 0003 7. 62 2. 59 5. 43 2. 7 8. 61 2. 37 0. 032 Total Body Fat (%) 23. 8 ± 8. 4 27. 5 ± 5. 4 25. 9 ± 5. 4 0. 476 Trunk Fat (%) 21. 5 ± 8. 0 28. 8 ± 6. 7 25. 3 ± 6. 2 0. 094 Trunk Fat (kg) 6. 1 ± 2. 1 10. 3 ± 4. 3 8. 0 ± 3. 7 0. 046 GAD Ab+ Subjects* 30% 0% 0% 0. 079‡ IA 2 Ab+ Subjects* 20% 11% 0% 0. 379‡ FFA (m. Eq/l) GDR (mg/min/kg) Baseline Values, GDR=Glucose Disposal Rate

Type 1 Diabetes in AAPI < 5% of total (Rare in AAPI) Common in children (A Minority in East Asian Children) Insulin Requiring and Sensitive Auto-immune Destruction of the Islets, HLA DR 3/4 (0 nly 1/3 of AA’s) Auto-immunity as a cause can only explain 1/3 of the cases. What is the cause for the other 2/3 of Type 1 DM in Asians, Asian-Americans and Pacific Islanders ?

Asian American Diabetes Initiative (AADI) Joslin Diabetes Center Dr. William Hsu Chihiro Hernandez Karen Lau