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Diabetes Mellitus: How Genetics Informs Research, Patient Care, and Prevention

Fredric E. Wondisford, M.D. Metabolism Division Departments of Pediatrics, Medicine and Physiology Director, JHU-UMD Diabetes Research and Training Center Johns Hopkins University School of Medicine

Outline Diabetes Definitions The Costs New findings from the JHU-UMD DRTC Latest Genetic Findings Obesity Health Disparities

The Insulin Hormone is Made in the Islets of Langerhans

Normal Metabolism Liver

Pancreas

insulin

Muscle

Fat

Type 1 Diabetes Mellitus Liver

Pancreas

insulin

Muscle

Fat

Type 2 Diabetes Mellitus Liver

Pancreas

insulin

Muscle

Fat

Comparison of Diabetes Types T1 DM Insulin Sensitive BMI Low Heritability Low

T2DM Resistant High High

County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2004

Percent 0 - 6.5 6.6 - 8.0 8.1 - 9.4 9.5 - 11.1 > 11.2

County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2005

Percent 0 - 6.5 6.6 - 8.0 8.1 - 9.4 9.5 - 11.1 > 11.2

County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2006

Percent 0 - 6.5 6.6 - 8.0 8.1 - 9.4 9.5 - 11.1 > 11.2

County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2007

Percent 0 - 6.5 6.6 - 8.0 8.1 - 9.4 9.5 - 11.1 > 11.2 www.cdc.gov/diabetes

County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2008

Percent 0 - 6.5 6.6 - 8.0 8.1 - 9.4 9.5 - 11.1 > 11.2

Prevalence of Diabetes in the U.S. by Cause (%) 40-

Prediabetes

30-

20-

T2 DM

10-

T1 DM

02007 ADA data 2007

2010

2020 (est)

Health Care Spending on Diabetes and Related Diseases •Approximately 12% of health care spending in 2009 was used for the care of patients with diabetes.

•Approximately 8% of health care spending in 2009 was used for the care of patients with end-stage kidney disease of which most is caused by diabetes. •Diabetes has a central role in other expensive to care for chronic conditions such as stroke, heart disease, and cancer.

Current estimates are that up to 40% of current U.S. health care costs are related to diabetes

The NIH Funds Diabetes Centers 10 DERCs U WA U Penn U Mass Joslin Yale U Colorado Mass General Columbia, NY UCLA/UCSD Baylor

JHU-UMD DRTC

7 DRTCs Albert Einstein U Michigan Wash U U Chicago Vanderbilt UAB JHU-UMD

17 Centers across the US

The JHU-UMD DRTC is Unique •A joint effort with another major medical center (Johns Hopkins University and the University of Maryland) •A strong focus on childhood obesity and diabetes-where the disease is now starting •A large representation of minority populations in research studies of patients with diabetes and obesity

Type 2 Diabetes Mellitus Liver

Glucose

Pancreas

insulin

Muscle

Fat

A Better Way to Screen for T2 DM

Type 2 Diabetes Mellitus Glucose

Pancreas

X Metformin

Muscle

insulin

Fat

A New Blood Test to See if a Common AntiDiabetic Drug Will Work in T2 DM Patients

How Diabetes and Obesity Cause Infertility: Implications for Patients with PCOS

The Genetics of Diabetes •Candidate Gene Approach uses knowledge about biological pathways to screen for potentially defective genes in patients with diabetes. •Genome-Wide Association Studies (GWAS) rapidly scan markers across the complete human genomes of many people to find gene variations associated with a diabetes.

Science 2007 Vol 316

GWAS and Diabetes: The Good •Most genes do or are predicted to affect the function of the pancreatic beta cell. Some of these genes were already identified by the candidate approach. •Novel pathways in insulin secretion were discovered, which were not found by the candidate approach. •Certain uncommon gene variants may predict which patients will respond to common anti-diabetic drugspharmacogenetic trials underway Florez 2010 Ann NY Acad Sci

GWAS and Diabetes: The Bad •Common genetic variants are not useful in clinical care-personalized medicine. •At best, only 10% of the heritability of T2 DM can be explained by genetic variation based on the studies performed to date-problems in study design •The prime candidate for “Missing Heritability” is a gene-environment interaction.

Florez 2010 Ann NY Acad Sci

Genetics and Environment

60 Years 2.5 Million Years Evolved to avoid starvation

County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2004

Percent 0 - 19.9 20.0 - 24.1 24.2 - 27.2 27.3 - 30.8 > 30.9

County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2005

Percent 0 - 19.9 20.0 - 24.1 24.2 - 27.2 27.3 - 30.8 > 30.9

County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2006

Percent 0 - 19.9 20.0 - 24.1 24.2 - 27.2 27.3 - 30.8 > 30.9

County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2007

Percent 0 - 19.9 20.0 - 24.1 24.2 - 27.2 27.3 - 30.8 > 30.9

County-level Estimates of Obesity among Adults aged ≥ 20 years: United States 2008

Percent 0 - 19.9 20.0 - 24.1 24.2 - 27.2 27.3 - 30.8 > 30.9

Michelangelo’s David: Effect of Environment BMI=22 kg/m22 BMI=38 kg/m

2011 1504

Hypothesis Obesity in U.S. is due to inactivity

County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2004

Percent 0 - 20.0 20.1 - 24.4 24.5 - 28.2 28.3 - 32.7 > 32.8

County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2005

Percent 0 - 20.0 20.1 - 24.4 24.5 - 28.2 28.3 - 32.7 > 32.8

County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2006

Percent 0 - 20.0 20.1 - 24.4 24.5 - 28.2 28.3 - 32.7 > 32.8

County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2007

Percent 0 - 20.0 20.1 - 24.4 24.5 - 28.2 28.3 - 32.7 > 32.8

County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years: United States 2008

Percent 0 - 20.0 20.1 - 24.4 24.5 - 28.2 28.3 - 32.7 > 32.8

Hypothesis Obesity in U.S. is due to inactivity This is not the whole story and perhaps not where the majority of prevention efforts should be directed

Hypothesis Obesity is due to access to inexpensive, high calorie foods

Distribution of Food Stores by HFA Index

Franco et al. Am J Clin Nutr, 2009

Low caloric density foods are common in supermarkets in the suburbs

High caloric density foods are common in convenience stores in the inner-city

Franco et al. J Epidemiol Comm Health 2007

The Principles andRisk Practice of Medicine Cumulative Lifetime for Diabetes in US by Age, Sex, and Ethnicity Sir William Osler 1909

Diabetes Mellitus “It is a disease of the higher class.” “Diabetes is comparatively rare in the colored race….”

Narayan, K.M.V. et al. JAMA 2003;290:1884-1890

What Explains the “Missing Heritability” of T2DM •A diet of excessive calories and the associated obesity causes insulin resistance in the body.

•This produces a stress on the beta cell to make more insulin, which in patients with certain gene variants, causes diabetes. •Excessive or deficient caloric exposure during fetal or early life may also change the expression of these gene variants-epigenetic changes

Primary Prevention For Diabetes •Given that over 98% of all diabetes is type 2, primary prevention efforts must first address obesity. •Exercise alone is helpful but unlikely to curb the high rates of U.S. obesity and T2DM. •Changes in diets coupled with interventions to control appetite (drugs/surgery) are needed.

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