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 <5%

• Men <50, women

<60 yrs with no major add’l

CVD risk factors

Low-dose (75–162 mg/d) aspirin use for

prevention might be considered for those with

diabetes at intermediate CVD risk until further

research is available

• Younger patients with ≥1 risk

factor

• Older pts with no risk factors

• Pts w/ 10-yr CVD risk 5–10%

Recommendation Definition of 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?