Understanding the Link between Understanding the Link between Diabetes and Obesity… Diabetes and Obesity…

and What You Can Do About it!and What You Can Do About it!

Kenneth Cusi, M.D., F.A.C.P., F.A.C.E.

Professor of Medicine

Chief, Endocrinology, Diabetes and Metabolism Division

University of Florida, Gainesville, USA

E-mail: Kenneth.Cusi@medicine.ufl.edu

February 16, 2012 - Gainesville, Florida

DIABETESDIABETES When you eat, your body breaks

food down into sugar and sends it into your bloodstream.

Insulin (made in the pancreas) helps get the sugar from the blood into the cells to be used for energy needed for daily life. It’

Insulin like the key that opens the door for the cells.

Diabetes is when the body does not make enough insulin and/or the insulin it makes does not work well. Too much sugar in the blood usually means that a person has diabetes.

K Cusi. Current Diabetes Reports. 2010 Aug;10(4):306-15

What is Pre-DiabetesWhat is Pre-Diabetes??• Pre-diabetes is when a person has too much

sugar in their blood, but not quiet high enough to be called diabetes. (100-125 mg/dl).

• People with pre-diabetes: • Can make changes to their eating habits to help them

lose weight and increase their physical activity to delay or prevent diabetes.

• Eating healthy is for everyone, but it is especially

important for managing or preventing diabetes.

Risk Factors for DiabetesRisk Factors for Diabetes• You are overweight• You rarely excercise• You are 45 or older• You are Hispanic/Latino• You have high blood pressure (140/90 or higher)• Someone in your family has diabetes• You are a woman who has a history of diabetes

during pregnancy or has had a baby weighing more than 9lbs at birth

Hemoglobin Hemoglobin A-1-CA-1-C• The A1C tells you your average blood • glucose levels for the past 2 to 3

months. • Think of it as a blood test that

“memorizes” your blood sugar level.• Your A1C target should be less than 7%.• The A1C test provides your health care

provider with information on how well your diabetes is under control.

Things to do to better to Things to do to better to manage your diabetesmanage your diabetes

• Take your medication as instructed• Monitor my blood glucose more closely and

record results for your health care provider• Develop a plan with your health care provider• Develop a healthy meal plan• Be more active and lose weight

GOOD DIABETES CAREGOOD DIABETES CARE• Be physically active everyday • Meal planning, be mindful of what and

how much you eat• Take your diabetes medications as

prescribed• Check your blood glucose levels. Talk

with your healthcare provider about how often you should

• Visit your healthcare provider as recommended

Objetive for the Objetive for the “Keep on track” booklet“Keep on track” booklet

• Create awareness of the importance of getting your A1C, blood pressure and cholesterol checked

• Take with you to every doctor’s visit to record progress.

• Have a list of emergency contacts

Remember to take care of your Remember to take care of your diabetes by:diabetes by:

• Using a meal plan and being active• Taking your diabetes medications or

insulin• Talking to your healthcare provider if

your plan isn’t working or not meeting your goals.

Molecularmechanismsof lipotoxicity

• ER stress• Inflammatory

response( JNK, NF-)

• Mitochondrial function

• Insulin resistance

FFA

Lipotoxicity

− HGP− NAFLD− NASH

− insulin-mediated− glucose uptake

−-cell apoptosis− insulin secretion− T2DM

− Cardiac function (CHF?)− Risk of ischemia (?)

− Endothelial dysfunction− Pro-atherogenic damage

atherosclerosis

Healthy AdiposeTissue

Hypertrophic DysfunctionalAdipose Tissue

HypoxiaER stress

JNK

NF-Kb

Lipolysis

Necrosis

HypertropyAdipose tissue

insulinresistance

Adiponectin

Systemic effects

?• Genetic• Early life nutritional insults• Chronic over-feeding

Adipokines

Systemic effects

Adipocyte-macrophagecross-talk

Adiposetissue

infiltration

Macrophage cytokines (TNFa, IL-6, CRP, others)

Macrophage“activation”

K Cusi. Current Diabetes Reports. August 2010, 10:306-315

Diagnosis NAFLD & NASHDiagnosis NAFLD & NASH Clinical findings:

Few clinical symptoms (i.e., right upper quadrant discomfort) Requires a high degree of clinical suspicion

Laboratory: May be associated with elevated liver aminotransferases (ALT>AST) May NOT be associated with an elevation in ALT/AST

Imaging: Ultrasound (echogenicity): 65-80% sensitivity for NAFLD

Magnetic ResonanceImaging

Abdominal fat:Visceral and subcutaneous

Liver and Muscle fat

Cardiovascular Disease in NAFLDCardiovascular Disease in NAFLD

0%

20%

40%

60%

80%

CHD CVA PVD All CVD

Without NAFLD NAFLD

Targher G. Diabetes Care 2007;30, 1212-1218N = 2,392

* P < 0.001

**

*

*

??

NEJM 2006, 355, 2297-2307

Mechanism of Action of Thiazolidinediones

TZDinsulin sensitvity lipid storage

Muscle

Muscle

Pancreatic-cellsLiver

FFA and adipocytokines adiponectin

Adipose tissue

???

Directeffects?

K Cusi. New pharmacological approaches in type 2 diabetes mellitus. Edit. Serrano Rios & Gutierrez, Elsevier 2009

64 y.o. CF (IGT) Before After

BMI (kg/m2) 30.9 32.4

FPG (mg/dl) 109 87

ALT (U/L) 43 17

NASH activity score / Fibrosis

5

2

0 (normal)

0 (normal)

Before treatment biopsy

After treatment biopsy

Effect of PioglitazoneEffect of Pioglitazonein NASHin NASH

Cusi K. In Expert Review of Gastroenterology & Hepatology, 2009

Adverse Effects of TZDsAdverse Effects of TZDs

Weight gain

Water retention, CHF, CVD?

Bone loss? (females)

University of Florida/Shands - NASH study Screening for patients with fatty liver Free state-of-the-art metabolic assessments and advice on

long-term management Done by Dr. Cusi and team

VA Gainesville, FL - NASH study Patients with T2DM Vitamin E +/- pioglitazone vs. placebo

Studies of Pioglitazone in Patients with Studies of Pioglitazone in Patients with NASH (by Kenneth Cusi, M.D. and team)NASH (by Kenneth Cusi, M.D. and team)

FOR MORE INFORMATIONFOR MORE INFORMATION

Contact the

American Diabetes Association at:1-800-DIABETES (342-2383) o online at:

www.diabetes.org

Locally call: 210-829-1765

Take care of your risk Take care of your risk factors!factors!