Are all Type 2 Diabetes Created the Same?: How Better Understanding Leads to Efficient

Management

Osama Hamdy, MD, PhD, FACEMedical Director Joslin Obesity Clinical Program

Director of Inpatient Diabetes ProgramJoslin Diabetes Center

Harvard Medical School

Type 2 Diabetes Risk Factors• Donna is 65 year old African American lady diagnosed with type 2 diabetes 22 years

ago. • Managed on 3 oral medications plus 90 units of glaragine insulin. Here BMI is 36

Kg/m2 and her A1C 8.3%.

• She enrolled in the Joslin Why WAIT program in 2009 and lost 21 lbs (9.5 Kg) in 12 weeks. She continued to lose weight after the program. Current weight loss is 37 lbs (16.5 Kg).

• Donna stopped all her antihyperglycemic medications and her A1C on 3/2014 was 6%.

What is going on?

Diabetes Today:Pathophysiology

Years of Diabetes

0 –

50 –

100 –

150 –

200 –

250 –

-10 -5 0 5 10 15 20 25 30

Rel

ativ

e Fu

nctio

n (%

)

Obesity Prediabetes

Diabetes

UncontrolledHyperglycemia

Insulin Resistance

Years before Diabetes

Natural History of Diabetes

b-cell function

ControllableHyperglycemia

Controllable Hyperglycemia

or Diabetes

Remission

Diabetes Remission

Is this true?

Adapted from Lebovitz H. Diabetes Rev. 1999;7:139-153.UKPDS 16. Diabetes. 1995;44:1249-1258.

Rx: Insulin, Metformin, Sulfonylurea

-CellFunction

(%)PostprandialHyperglycemia

IGT Type 2DiabetesPhase I

Type 2DiabetesPhase II

Type 2 DiabetesPhase III25

100

75

0

50

-12 -10 -6 -2 0 2 6 10 14

Years From Diagnosis

Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.

Decline in -Cell Function With Diabetes Progression: UKPDS

Lee CW et al. Curr Opin Gastroenterol. 2007;23(6):636-643.

Gastric Bypass (RYGB)

• Advantages• Rapid initial weight loss• Minimally invasive approach is

possible• Longer experience in U.S.• Higher total average weight loss

reported than with LAGB or VBG

Disadvantages• Complications due to

malabsorption are common• Nonadjustable • Higher cost

0%10%20%30%40%50%60%70%80%90%

100%

2 years 10 years

Reco

very

From

Dia

bete

s Control Bariatric Surgery

Sjöström L et al. N Eng J Med. 2004;351:2683-2693.

Effect of Bariatric Surgery on Diabetes in Severely Obese Patients

Are all Type 2 diabetes created the same?

Measurement of Insulin Sensitivity and b-Cell Glucose Sensitivity from the Response to IV Glucose

Bergman RN et al. J Clin Invest. 1981;68:1456-1467.

Bergman RN et al. J Clin Invest. 1981;68:1456-1467.

Measurement of Insulin Sensitivity and b-Cell Glucose Sensitivity from the Response to IV Glucose

Bergman RN et al. J Clin Invest. 1981;68:1456-1467.

Measurement of Insulin Sensitivity and b-Cell Glucose Sensitivity from the Response to IV Glucose

Insulin Resistance is the Core Target for Intervention

Type 2 diabetes Hypertension

Atherosclerosis

Dyslipidemia

Endothelial dysfunction

Coagulation/Fibrinolytic defects

InsulinResistance

Visceral Fat Accumulation (genetic, ethnic)

Inflammation (subclinical)

Lipotoxicity (increased FFA)

Glucose Toxicity (sig. increased plasma glucose)

Oxidative Stress

Hamdy O. Curr Diab Rep. 2005;5(5):317-9.

Genotype Normal

Trp/Trp

Heterozygous

Trp/Arg

Homozygous

Arg/Arg

BMI (kg/m2) 32.3+4.5 33.2+5.9 34.1+1.7

Body Fat% 41.8+2.8 42.9+6.7* 44.8+2.8*

Visceral Fat (cm2) 121+46 178+47** 172+17**

SBP (mmHg) 133+26 141+27 165+32*

BG (AUC) 926+407 1344+635** 1283+32**

F. Insulin (pmol/l) 43+29 72.29** 79+22**

TC (mmol/l) 4.9+0.7 5.4+1.2* 5.9+0.9**

TG (mmol/l)

1.4+0.8 1.3+0.5 2.4+0.8**

HDL (mmol/l)

1.4+0.3 1.3+0.3 1.1+0.1*

Sakane N et al. Diabetologia 1997;40:200-204

b3-adrenergic-receptor polymorphism in obese subjects:

Genetic markers for visceral fat and the metabolic syndrome

Markers of insulin resistance

• High basal insulin and C-peptide• Progressive central adiposity• High CRP (high TNF-a, IL-6, PAI-1)• Skin tags• Acanthosis negricans• Polycystic ovary• High TG and VLDL and low HDL• Increasing blood pressure• Increasing plasma glucose

How to modifyinsulin resistance?

Optimal Improvement of Insulin Sensitivity

Weight reduction is the prime target

Proper Medical Nutrition Therapy (MNT)

• Dietary Composition

Proper Exercise

• Type

• Duration

• Frequency

Reduction of Visceral fat

• Hormonal role

Patient adherence and compliance for long-term success

Medications

• Metformin

• TZDs

• SGLT-2 inhibitors

Copyright © 2014 by Joslin Diabetes Center. All Rights Reserved.

1- Can we Modify Visceral Fat?

-30

-10

10

30

50

70

90 84

73.2

33.5

22.6

0.7

-6.8

% C

han

ge

in in

sulin

Sen

siti

vity

Ind

ex

Changes in insulin sensitivity after 6-month of laparoscopic omentectomy in 6 patients with newly-

diagnosed Type 2 DM

Insulin sensitivity measured by hyperinsulinemic euglycemic clamp method at 0 and 6 months

Hamdy O. et al, 2008 (Unpublished pilot data)

0 3M 6M 9M 12M 15M 18M 21M 24M 27M 30M 33M 36M 39M 42M 45M 48M 51M 54M 57M 60M

-16.0

-14.0

-12.0

-10.0

-8.0

-6.0

-4.0

-2.0

0.0

****** ***

***

******

*** *** *** *** *** *** *** *** *** *** *** ***

Wei

ght L

oss

(%)

Duration in Months

Total Group n=129Group 1 n=61 (Participants maintained <7% weight loss at 1 year)Group 2 n=68 (Participants maintained > 7% weight loss at 1 year)

*** p<0.001 (group 1 vs. group 2)

*** ***

-9.0%

-3.5%

-6.4%

Percentage Weight Reduction in Patients with Diabetes in the Real-World Clinical Practice over 5 years (Joslin Why WAIT Program)

14% Remission21% Stopped insulin

50-60% Reduction in Medications

Obese Patients With Insulin Resistance +/– T2D

Effects of Short-term Weight Loss on Insulin Sensitivity

WGT* BMI W-H IS-10

0

10

20

30

40

50

60

70

-7.1 -7.4-3.1

56.8

Cha

nge

From

Bas

elin

e (%

)

WGT, weight; BMI, body mass index; W-H, waist-to-hip ratio; IS, insulin sensitivity.*P<0.001.Hamdy O. Diabetes Care. 2003;26:2119-2125.

Obese Patients With Insulin Resistance +/– T2 DM

Effects of Short-term Weight Loss on Inflammatory Markers

NS

P<0.01P<0.001NSP<0.05 NS

IL, interleukin; TNF, tumor necrosis factor; hCRP, human C-reactive protein; PAI, plasminogen activator inhibitor.Hamdy O. Diabetes Care. 2003;26:2119-2125; Monzillo LU. Obes Res. 2003;11(9):1048-1054.

Chan

ge (%

)

Impact of Dietary Composition on DM

2- Role of Medical Nutrition Therapy

The Impact of Nutrition on Diabetes: Before the Era of Diabetes Medications

1869-1962Joslin ClinicBoston, MA

1879–1964Physiatric InstituteMorristown, NJ

Elliott P. Joslin Frederick M. Allen

“Strict diet”: Meats, poultry, game, fish, clear soups, gelatin, eggs, butter, olive oil, coffee, teaOsler W & McCrae T, The Principles and Practice of Medicine, 1923; Westman EC, Perspect Biol Med, 2006

Joslin Diabetes Diet, 1923Quantity of food required by severe diabetic patient weighing 60 Kg

Food Calories (%)

Protein 75 g 300 (17%)

Fat 150 g 1350 (75%)

Carbohydrate 10 g 40 (2%)

Alcohol 15 g 105 (6%)

1795

Response of Fat Mass to Early Calorie Restriction

Bujo LY et al Exp Biol Med 2003; 228:1118-1123

Weight Loss and Glucostatic Parameters Before and After RYGB and VLCD

Jackness C et al. Diabetes. 2013;62(9):3027-32

Relationship Between Insulin Sensitivity and Insulin Secretion Before and After

Interventions

Jackness C et al. Diabetes. 2013;62(9):3027-32

Before Diet

After Diet

50

100

150

Series1

-50

-40

-30

-20

-10

0

High Carbohydrates

Low Carbohydrates

Visc

eral

Fat

(cm

2 )

% D

ecre

ase

in b

asal

Insu

lin

Miyashita Y et al Diabetes Res Clin Pract. 2004 Sep;65(3):235-41

Effects of Low Carbohydrates in Low Calorie Diet on Visceral

Fat and Basal Insulin in Obese Type 2 Diabetic Patients C F P

Low Carbs 39 35 25High Carbs 62 10 26

n= 22* p<0.05

*

*

Visceral Fat Serum Insulin

Twenty-four–hour plasma glucose response of subjects to the control (15% protein) and high-protein (30% protein) diets

*Significantly different from control diet, P < 0.05

Twenty-four–hour triacylglycerol response of subjects to the control (15% protein) and high-protein (30% protein) diets.

*Significantly different from the fasting control value, P < 0.03

Adapted from Gannon MC et al. Amer J Clin Nutr 2003;78:734-741

The Metabolic Effect of Different Protein/Carbohydrates Ratios in Type 2 DM

Protein to carbohydrate to fat: 30:40:30 Versus 15:55:30

-40% Reduction

Visceral Fat

BP & lipids

Metabolic ControlPhysical Fitness & QOLMaintenance of Weight Loss

Vascular Resistance

The benefits of Exercise and or

Increased Physical Activity include

3- Gradual, balanced and individualized physical activity - Duration of exercise

- Type of exercise- Short versus long-bouts of exercise- Exercise records/exercise monitor

Diabetes, a Common Comorbidity, Significantly Accelerates Loss of Muscle

Mass, Strength and Quality

p<0.05*Park SW, et al. Diabetes Care 2009;32:1993-1997.

Loss of Total Muscle Mass[g/ year]

Loss

of M

uscl

e M

ass

(gm

/yea

r)

*

*

Insulin Sensitizers

4- Role of Medications

Metformin - Recommended first line therapy

• Why?

• Improves insulin sensitivity• Effective reduction in A1c (1-1.5%)• No hypoglycemia or weight gain• Inexpensive• Long-term safety• Reduction in CV risk & Mortality• May also reduce mortality and cancer risk

Cell Entry and Mechanism of Metformin

Shu et al. J Clin Invest 2007; 117: 1422-1431

Metformin

Cell Entry

Cell Targetfor Metformin

Activation of AMP Kinase

Improves Lipotoxicity

LKB1 and Anti-Tumour Activity

Cheng & Fantus. CMAJ 2005; 172: 213-26Hawley. J Biol 2003; 2:28

LKB1

Tumour Suppressor

Thiazolidinediones (TZDs)

• Highly efficacious in reducing insulin resistance and plasma glucose without hypoglycemia

• Improves lipotoxicity and hence improves insulin sensitivity• Proliferates fat cells that scavenger FFA

• Side effects limiting use: weight gain, edema• Increased bone fracture rates in women• Cardiovascular issues incompletely resolved:

– Clear data for CHF contraindication– Ischemic CVD: Remained a question mark for long time (FDA cleared it)

• Bladder cancer risk incompletely resolved– Any effect is likely dose- and duration-dependent– Restrictions on pioglitazone use

Sodium-Glucose-Cotransporter-2 (SGLT2) Inhibitors: The Latest Class of Oral Agents

• Canagliflozin and Dapagliflozin are the first FAD approved SGLT-2 In• Lowers blood glucose by blocking the reabsorption of glucose by the

kidney and increasing excretion of glucose into the urine• Improves glucose toxicity and hence improves insulin sensitivity and b-

cell function• Low risk of hypoglycemia and induce weight loss

• Potential side effects:– Urinary tract infections– Genital infections– Orthostatic hypotension/dizziness– Increase LDL– Dehydration and electrolytes disturbance

Targeting Insulin Resistance

Bariatric Surgery

Testosterone

High dose Salicylates

Low CarbohydratesVery Low Calorie Diet

TZDs

VisceralFat

Metformin

Hamdy O. Joslin Diabetes Center, 2014

LipotoxicityGlucose Toxicity

Inflammation

Growth Hormone

InsulinSGLT2-I

Non-surgical Weight Reduction

Insulin Sensitivity

Exercise

Summary and Take Home Messages

• Insulin resistance is the core problem in overweight and obese patients with type 2 diabetes

• Reduction of body weight improves insulin sensitivity, prevents diabetes and may reverse the progressive course of type 2 diabetes

• Remission of type 2 diabetes is possible through significant weight reduction by surgical and non-surgical interventions

• Changing dietary composition with the addition of strength exercise reduce visceral fat and improve metabolic control

• Clearing lipotoxicity or glucose toxicity improves insulin sensitivity

• Insulin sensitizers, particularly metformin, are essential in managing type 2 diabetes

Thank You