1. No category

Are all Type 2 Diabetes Created the Same?:
How Better Understanding Leads to Efficient
Management
Osama Hamdy, MD, PhD, FACE
Medical Director Joslin Obesity Clinical Program
Director of Inpatient Diabetes Program
Joslin 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
Natural History of Diabetes
Diabetes
Relative Function (%)
Obesity
Controllable
Uncontrolled
Hyperglycemia
Hyperglycemia
or
Diabetes
Remission
Controllable
Hyperglycemia
Prediabetes
250 –
Insulin Resistance
200 –
150 –
Diabetes Remission
100 –
50 –
b-cell function
0–
-10
-5
Years before Diabetes
0
5
10
15
20
Years of Diabetes
25
30
Decline in b-Cell Function
With Diabetes Progression: UKPDS
100
Rx: Insulin, Metformin, Sulfonylurea
75
b-Cell
Function
(%)
Is this true?
50
IGT
25
Type 2
Diabetes
Phase I
Postprandial
Hyperglycemia
Type 2
Diabetes
Phase II
0
-12
-10
-6
-2
0
2
6
Type 2 Diabetes
Phase III
10
14
Years From Diagnosis
Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.
Adapted from Lebovitz H. Diabetes Rev. 1999;7:139-153.
UKPDS 16. Diabetes. 1995;44:1249-1258.
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
Lee CW et al. Curr Opin Gastroenterol. 2007;23(6):636-643.
Recovery From Diabetes
Effect of Bariatric Surgery on
Diabetes in Severely Obese Patients
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Control
2 years
Sjöström L et al. N Eng J Med. 2004;351:2683-2693.
Bariatric Surgery
10 years
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.
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
Bergman RN et al. J Clin Invest. 1981;68:1456-1467.
Insulin Resistance is the Core Target
for Intervention
Visceral Fat Accumulation (genetic, ethnic)
Inflammation (subclinical)
Lipotoxicity (increased FFA)
Glucose Toxicity (sig. increased plasma glucose)
Type 2 diabetes
Oxidative Stress
Hypertension
Insulin
Resistance
Endothelial
dysfunction
Coagulation/Fibrinolytic
defects
Atherosclerosis
Hamdy O. Curr Diab Rep. 2005;5(5):317-9.
Dyslipidemia
b3-adrenergic-receptor polymorphism in obese subjects:
Genetic markers for visceral fat and the metabolic syndrome
Genotype
Normal
Heterozygous
Homozygous
Trp/Trp
Trp/Arg
Arg/Arg
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*
BMI
(kg/m2)
Sakane N et al. Diabetologia 1997;40:200-204
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 modify
insulin resistance?
Optimal Improvement of Insulin
Sensitivity
Weight reduction is the prime target
Proper Medical
Nutrition Therapy
(MNT)
• Dietary
Composition
Proper Exercise
• Type
• Duration
Reduction of
Visceral fat
• Hormonal role
• Frequency
Patient adherence and compliance for long-term success
Medications
• Metformin
• TZDs
• SGLT-2 inhibitors
1- Can we Modify Visceral Fat?
Copyright © 2014 by Joslin Diabetes Center. All Rights Reserved.
% Change in insulin Sensitivity Index
Changes in insulin sensitivity after 6-month of
laparoscopic omentectomy in 6 patients with newlydiagnosed Type 2 DM
90
70
84
73.2
Insulin sensitivity measured by hyperinsulinemic
euglycemic clamp method at 0 and 6 months
50
30
33.5
22.6
10
-10
-30Hamdy O. et al, 2008 (Unpublished pilot data)
0.7
-6.8
Percentage Weight Reduction in Patients with Diabetes in
the Real-World Clinical Practice over 5 years (Joslin Why
Duration in Months
WAIT Program)
0.0
0
3M
6M
9M
12M
15M
18M
21M
24M
27M
30M
33M
36M
39M
42M
45M
48M
51M
54M
57M
60M
-2.0
-4.0
-3.5%
Weight Loss (%)
-6.0
-6.4%
-8.0
-10.0
-12.0
***
***
***
-14.0
***
***
***
***
***
***
***
***
***
***
***
14% Remission
21% Stopped insulin
50-60% Reduction in Medications
-16.0
*** p<0.001 (group 1 vs. group 2)
Total Group n=129
Group 1 n=61 (Participants maintained <7% weight loss at 1 year)
Group 2 n=68 (Participants maintained > 7% weight loss at 1 year)
***
***
*** ***
***
***
-9.0%
Effects of Short-term Weight Loss on Insulin
Sensitivity
Obese Patients With Insulin Resistance +/– T2D
Change From Baseline (%)
70
56.8
60
50
40
30
20
10
-7.1
-7.4
-3.1
WGT*
BMI
W-H
0
-10
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.
IS
Effects of Short-term Weight Loss on Inflammatory
Markers
Obese Patients With Insulin Resistance +/– T2 DM
Change (%)
NS
P<0.05
NS
NS
P<0.001
P<0.01
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.
2- Role of Medical Nutrition Therapy
Impact of Dietary
Composition on DM
The Impact of Nutrition on Diabetes:
Before the Era of Diabetes Medications
Elliott P. Joslin
Frederick M. Allen
1869-1962
1879–1964
Joslin Clinic
Physiatric Institute
Boston, MA
Morristown, NJ
Joslin Diabetes Diet, 1923
Quantity 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
“Strict diet”: Meats, poultry, game, fish, clear soups, gelatin, eggs, butter, olive oil, coffee, tea
Osler W & McCrae T, The Principles and Practice of Medicine, 1923; Westman EC, Perspect Biol Med, 2006
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
Effects of Low Carbohydrates in Low Calorie Diet on Visceral
Fat and Basal Insulin in Obese Type 2 Diabetic Patients
C
Low Carbs
High Carbs
150
39
62
F
P
35 25
10 26
Serum Insulin
Visceral Fat
100
*
50
Before
Diet
After
Diet
% Decrease in basal Insulin
Visceral Fat (cm2)
0
n= 22
* p<0.05
Miyashita Y et al Diabetes Res Clin Pract. 2004 Sep;65(3):235-41
-10
-20
-30
*
-40
-50
High
Carbohydrates
Low
Carbohydrates
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
Twenty-four–hour plasma glucose response
of subjects to the control (15% protein) and
high-protein (30% protein) diets
Twenty-four–hour triacylglycerol response
of subjects to the control (15% protein) and
high-protein (30% protein) diets.
*Significantly different from control diet, P
< 0.05
*Significantly different from the fasting
control value, P < 0.03
Adapted from Gannon MC et al. Amer J Clin Nutr 2003;78:734-741
3- Gradual, balanced and individualized physical activity
- Duration of exercise
- Type of exercise
- Short versus long-bouts of exercise
- Exercise records/exercise monitor
Visceral Fat
The benefits of
Exercise and or
Increased Physical
Activity include
BP & lipids
Metabolic Control
Physical Fitness & QOL
Maintenance of Weight Loss
Vascular
Resistance
Loss of Muscle Mass (gm/year)
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]
4- Role of Medications
Insulin Sensitizers
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
Metformin
Cell Target
for Metformin
Activation of
AMP Kinase
Cell
Entry
Improves Lipotoxicity
Shu et al. J Clin Invest 2007; 117: 1422-1431
LKB1 and Anti-Tumour Activity
LKB1
Tumour Suppressor
Cheng & Fantus. CMAJ 2005; 172: 213-26
Hawley. J Biol 2003; 2:28
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
Non-surgical Weight Reduction
Testosterone
Growth Hormone
Bariatric Surgery
Visceral
Fat
Very Low Calorie Diet
Metformin
Insulin
Sensitivity
Lipotoxicity
TZDs
Low Carbohydrates
Glucose
Toxicity
Insulin
SGLT2-I
Inflammation
High dose Salicylates
Hamdy O. Joslin Diabetes Center, 2014
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