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(capita selecta)
Obesity
FFA
Glucose
Type 2 diabetes
The worldwide pandemic of
type 2 diabetes
350
300
prevalence (millions)
World wide diabetes
300
250 221
200
150
150
100
2000 2010 2025
China
Bantu
Polynesian
Polynesian Cook Islands
White US
Black US
Hispanic US
Chinese Mauritius
Asian Indian Fiji
Pima Indian
0 10 20 30 40 50
Prevalence (%)
Top ten countries for estimated number of
adults with diabetes, 1995 and 2025
Country 1995 (millions) Country 2025 (millions)
Rank
1 India 19.4 India 57.2
2 China 16.0 China 37.6
3 U.S. 13.9 U.S. 21.9
4 Russian Fed. 8.9 Pakistan 14.5
5 Japan 6.3 Indonesia 12.4
6 Brazil 4.9 Russian Fed. 12.2
7 Indonesia 4.5 Mexico 11.7
8 Pakistan 4.3 Brazil 11.6
9 Mexico 3.8 Egypt 8.8
10 Ukraine 3.6 Japan 8.5
All other countries 49.7 103.6
70 Women Men
70
60 60
50 50
Percent
Percent
40 40
30 30
20 20
10 10
0 0
1994 1995 1996 1997 1998 1999 2000 2001 1994 1995 1996 1997 1998 1999 2000 2001
BMI
Low
Middle
60 High
Case/10,000 p-yr
40
20 High
Middle
Low
0
Low Middle High
Physical activity
Helmrich. NEJM 325:147-152
IGT is driving the worldwide diabetes
pandemic
50
45
40
% of population
35 IGT
30 Undiagnosed
25 type 2 diabetes
20 Diagnosed
15 type 2 diabetes
10
5
0
20-44 45-54 55-64 65
Age (years)
14 300
8
6
100
4
2
0 0
2.5
p=0.028
2.0 p=0.0001
1.5 Lean
GINF
mmol/m2/min Obese
p=0.016
1.0
0.5
Normal Diabetic
Ludvik et al. Diabetes 1995;44:1121
The continuum of glucose intolerance
Type 2 Disability
Normal IGT Complications
Diabetes Death
Preclinical Clinical
state disease Complications
Birth Death
GLUCOSE TOXICITY
LIPOTOXICITY
Dual defect of type 2 diabetes: treating a
moving target
Insulin Type 2 -cell
Resistance Diabetes Dysfunction
ia
aem
In
su l yc
lin erg
Ac yp
ti o
n -cell Failure H
Insulin
Concentration
Insulin
Resistance
Euglycaemia
Normal IGT Obesity Diagnosis of Progression of
type 2 diabetes type 2 diabetes
DeFronzo et al. Diabetes Care 1992;15:318-68
Typical pathogenic features of hyperglycemia
in type 2 diabetes (2011)
Decreased incretin effect / increase
glucose absorption
Islet cell
Increased lipolysis
and reduced
glucose uptake
Impaired
Islet cell insulin
secretion
Increased hyperglycemia
glucagon
secretion
Increased glucose
reabsorption
Decrease glucose
uptake
Increased hepatic
glucose
production
Neurotransmitter
dysfunction
Kinetic defects in type 2 diabetes
Postprandial hyperglycaemia
12.5
5 mM
Glucose disposal rate
10 10 mM
(mg/kg/min)
7.5
5 mM
5 T50
(min)
Lean 33
2.5 Obese 74
DM 95
0
60 120 180 240 300
Time (min)
9
Conventional
8 Intensive
HbA1C (%)
Treatment
gap
7
6
0
0 3 6 9 12 15
Years from randomisation
Reduction in life expectancy in type 2
diabetes
Age at Marks & Krall Goodkin Panzram &
Diagnosis 1971 1975 Zabel-Langhennig
1981
10/15 (17) 27 -
15-19 16-17 23 -
20-29 12-14 16 -
30-39 10-11 11 -
40-49 8-9 10 7-8
50-59 6-7 6 5-6
60-69 4-5 5 3-4
70+ - - 3
Intervention Risk
Therapy Study Reduction
2
Tuomilehto et al. N Engl J Med 2001;344:1343-50;
3
Chiasson et al. Lancet 2002;359:2072-7;
4
Pan et al. Diabetes Care 1997;20:537-44.
Overview of the Diabetes Prevention Program
Open
risk (%) of
diabetes vs. -20
placebo +
standard
lifestyle -31
-40
advice p<0.01
-60 -58
p<0.01
Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403
Subgroup analyses in the DPP
Age (y) FPG (mmol/L) BMI (kg/m2)
44 59 60 6 .1 7.0 30 <35 35
< < >
25 45 >
5. 3 6.1 22 30
0 0 0
Reduction in diabetes risk
versus placebo (%)
Placebo
Metformin
% patients
50
p=0.011
0
N=70
Duration = 12 months
Probability of 1.0
not having
diabetes 0.9 Lifestyle
intervention
0.8
0.7
Control
0.6
Risk Reduction 58%
0.5
0 1 2 3 4 5 6
Year
Tuomilehto et al. N Engl J Med 2001;344:1343-1349
STOP NIDDM
1.00
Acarbose risk reduction 25%
Cumulative probability
0.90
0.80
Acarbose
0.70
0.60
Placebo
0.50
0.40
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300
Sulphonylurea, metformin
Glucosidase Inhibitors
Glitinides
Thiazolidinediones
Oral combinations
Insulin
*mg/dL
1
American Diabetes Association. Diabetes Care 1999; 22(Suppl 1):S1-S114;
2
European Diabetes Policy Group. Diabetic Medicine 1999;16:716-30;
3
American Association of Clinical Endocrinologists. Endocrine Pract (2002)
8(Suppl. 1):40-82
Choice of agents in current use
Glipizide
Acarbose
Gliclazide
Miglitol
Glimepiride Sulphonylureas Voglibose
Glibenclamide
Meglitinides
Rosiglitazone Repaglinide
Pioglitazone Nateglinide
Site and mode of action of oral
antidiabetic medications
Glucose Biguanides
production Thiazolidinediones
Pharmacological intervention
Adjust therapy to lifestyle (need info on benefits of dual aproach)
Need better definition of lifestyle failure to start drug therapy
Role of drug therapy in children should be evaluated
Need licensed indication for drug treatment in IGT
Metformin & acarbose are suitable candidates (AE overstated)
Type 2 diabetes: treating a
moving target
Progressive hyperglycaemia in type 2
diabetes
9
Diet
Median HbA1C (%)
Insulin
Metformin
7
HbA1C 6.5%
(IDF & AACE goal value)
Sulphonylurea
6
0 2 4 6 8 10
Time from randomization (years)
Sulphonylurea
Metformin
Insulin
40
20
0
3 years 6 years 9 years
Duration of follow-up
60
% Incidence/1000 patient-years
50
40 Myocardial
infarction
30
Microvascular
disease
20
10
0
<6 6-<7 7-<8 8-<9 9-<10 10+
Updated HbA1C (%)
50 90
Cumulative % of patients
80
40 70
61
60
30 48
50
40 32
20
30
18
20
10
10
0 0
< 7.0% < 9.0% <6.5% <7.0% <7.5% <8.0%
HbA1C HbA1C
1
New et al. Diabetologia 2000;43:836-43 2IRIS study. German Diabetes Meeting 2001
Strategy to normalise glucose:
Prediabetes and diabetes