Diabetes Update
Betsy Dokken, NP, PhD, CDE
Assistant Professor of
Medicine/Endocrinology
University of Arizona
Outline
• Current understanding of the
mechanisms of the etiology and
pathophysiology of diabetes
• Recent clinical evidence for treatment
of diabetes and co-morbidities
• Future directions
Regulation of Gene Expression
Genetic Model of Disease
Epigenetic regulation of gene expression
Genetics/Epigenetics of T2DM
Genetics/Epigenetics of T2DM
8
Prevalence of Diabetes and
Prediabetes in the United States
CDC and Prevention. National diabetes fact sheet, 2007. http://www.cdc.gov/Diabetes/pubs/pdf/ndfs_2007.pdf.
CDC and Prevention. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.
Prediabetes
35% of US population
Diabetes
8.3% of US population
Pers
on
s (
millio
ns)
Increased incidence of prediabetes from 2007 to 2010
Hyperglycemia
Defects in Type 2 Diabetes
Pancreas
LiverMuscle and Fat
Liver Glucose Insulin Production - Resistance
GlucoseUptake
InsulinResistance-
Progressive Defect in
Insulin Secretion
Insulin binds to its
receptor
Transporters move
to cell membrane
Insulin
Molecularsignals
Insulin Action in Muscle is Impaired in
Insulin Resistance
Glucose enters the cell and is METABOLISED
Glucose transporters
fuse with cell
membrane
Glucose
transporters
Decreased b-Cell Function in Groups
With Diabetes and at High Risk
Natural History of Type 2 Diabetes
Adapted from International Diabetes Center (IDC) Minneapolis, Minnesota
Obesity IFG* Diabetes Uncontrolled Hyperglycemia
50
100
150
200
250
300
350
50
100
150
200
250
Glu
co
se
(mg
/dL
)
Rela
tive
Fu
nc
tio
n (
%)
-10 -5 0 5 10 15 20 25 30
Years of Diabetes
Post-meal Glucose
Fasting Glucose
Insulin Resistance
Insulin Levelb-cell Failure
*IFG = impaired fasting glucose
Regulation of Insulin Secretion
Prevalence of the Insulin Resistance Syndrome
(NCEP)* in the US Population
Risk Factors for Conversion to
Diabetes in Mexican Americans
Treating Insulin Resistance Preserves b-Cell Function
Insulin binds to its
receptor
Transporters move
to cell membrane
Insulin
Molecularsignals
Insulin Action in Muscle is Impaired in
Insulin Resistance
Glucose enters the cell and is METABOLISED
Glucose transporters
fuse with cell
membrane
Glucose
transporters
Effect of Diet and Exercise
on Inflammatory Markers
Dokken B. The kidney as a treatment target for type 2 diabetes. Diabetes Spectrum 2012; 25: 29-36.
SGLT-inhibition prevents glucose reabsorption
(canagliflocin)
Gender Differences Influence Impact of
Type 2 Diabetes on CHD Risk
Patterns of Glucose, Insulin, and Glucagon After Oral Glucose in Type 2 Diabetes
–60 0 60 120 180 240 300
60
30
45
400
Type 2 Diabetes
Normal
0
120
240
360
–60 0 60 120 180 240 300
Delayed and reducedHigh and not suppressed
Postprandial hyperglycemia
Minutes Minutes
–60 0 60 120 180 240 300
Minutes
300
200
100
Mitrakou A et al. Diabetes. 1990;39:1381-1390
Insu
lin (
pmol
/L)
Glu
cago
n (f
mol
/L)
Glu
cose
(m
g/dL
)
Fasting Concentrations of Intact GIP
and GLP-1 and DPP-4 Activity in Patients
With Diabetes
50
GLP-1 helps regulate blood glucose in humans
Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553Adapted from Drucker DJ. Diabetes. 1998;47:159-169
Stomach:Helps regulate
gastric emptying
Promotes satiety and
reduces appetite
Liver:
Glucagon reduces
hepatic glucose outputBeta cells:Enhances glucose-dependent
insulin secretion
Alpha cells: Postprandial
glucagon secretion
GLP-1 secreted upon
the ingestion of food
Pharmacologic Therapy for Type 2 DM
Exenatide: Effects on Glycemic Control in
Combination With Current Oral Therapies
GLP-1 is rapidly degraded by DPP- 4
Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157.
Half-life: GLP-1 ~ 2 minutes.
Food ingestion
GI tract
Intestinalsecretion of
GLP-1 (7-36) amide
DPP-4
GLP-1 (9-36) amide
Incretinaction
DPP-4Inhibitor
Pharmacologic Therapy for Type 2 DM
Effect of Sitagliptin + Metformin on b-Cell Function at 24 Weeks*
Cardiovascular disease and diabetes
Bell DSH. Diabetes Care. 2003;26:2433-41.
Centers for Disease Control (CDC). www.cdc.gov.
Cardiovascular
complications
of DM
~65% of deaths are
due to CV disease
Coronary heart
disease deaths
2- to 4-fold
Stroke risk
2- to 4-fold
Heart failure
2- to 5-fold
POPADAD Trial: Effect of Aspirin Use
on Events in Patients With Diabetes
ADA/AHA/ACC: Recommendations for Use
of Aspirin for Primary Prevention of CV
Events in People With Diabetes
Pignone M, et al. Diabetes Care. 2010;33(6):1395-1402.
Low-dose (75–162 mg/d) aspirin use for
prevention is reasonable for adults with diabetes
and no previous history of vascular disease who
are at increased CVD risk and who are not at
increased risk for bleeding
• 10-yr risk of CVD events >10%
• Most men >50, women
>60 yrs with smoking, HTN,
dyslip, premature CVD fam hx,
albuminuria
Aspirin should not be recommended for CVD
prevention for adults with diabetes at low CVD
risk—potential adverse effects from bleeding
outweigh potential benefits
•10-yr CVD risk
Endothelium is an Endocrine Organ
Diabetes causes endothelial dysfunction, which causes
cardiovascular disease
Blood vessel lined with endothelium Coronary endothelial cells, Dokken Lab,
Charles Piermarini, MS, Physiology
Questions?