Transcript Insulin Regulation of Hepatic Gluconeogenesis through CREB

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.