Clinical Presentation of Type 2
Diabetes
1
Risk Factors for Prediabetes
and Type 2 Diabetes
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•
•
•
•
•
•
•
•
Family history of diabetes mellitus
Cardiovascular disease
Being overweight or obese
Sedentary lifestyle
Nonwhite ancestry
Previously identified impaired glucose tolerance, impaired fasting
glucose, and/or metabolic syndrome
Hypertension
Increased levels of triglycerides, low concentrations of high-density
lipoprotein cholesterol, or both
History of gestational diabetes mellitus
Delivery of a baby weighing more than 4 kg (9 lb)
Polycystic ovary syndrome
Antipsychotic therapy for schizophrenia and/or severe bipolar disease
2
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Development of Type 2 Diabetes
Depends on Interplay Between Insulin
Resistance and β-Cell Dysfunction
Genes &
environment
Genes &
environment
Insulin
resistance
Normal
β-Cell
Function
Compensatory
hyperinsulinemia
No
diabetes
Insulin
resistance
Abnormal
β-Cell
Function
Relative
insulin
deficiency
Type 2
diabetes
3
Gerich JE. Mayo Clin Proc. 2003;78:447-456.
Etiology of β-cell Dysfunction
Genetic predisposition
Lean phenotype
Obese phenotype
IGT, IFG
Elevated FFA
Initial glucolipoadaptation
(increased FFA usage)
Oxidative stress and
glucotoxicity
Hyperglycemia
Cellular lipid synthesis
and glucolipotoxicity
Glucolipotoxicity and glucotoxicity
Progressive -cell failure and type 2 diabetes
4
Poitout V, Robertson RP. Endocrine Rev. 2008;29:351-366.
Progression to Type 2 Diabetes:
“Falling Off the Curve”
500
400
Nonprogressors
NGT
300
NGT
NGT
20 0
IGT
NGT
Progressors
100
DIA
0
0
1
2
3
4
5
Glucose disposal (insulin sensitivity)
(mg/kg EMBS/min)
5
NGT=normal glucose tolerance; IGT=impaired glucose tolerance; EMBS=estimated metabolic body size.
Weyer C et al. J Clin Invest. 1999;104:787-794.
Pathophysiology of T2DM
Organ System
Defect
Major Role
Pancreatic beta cells
Decreased insulin secretion
Muscle
Inefficient glucose uptake
Increased endogenous glucose
secretion
Liver
Contributing Role
Adipose tissue
Increased FFA production
Digestive tract
Decreased incretin effect
Pancreatic alpha cells
Increased glucagon secretion
Kidney
Increased glucose reabsorption
Nervous system
Neurotransmitter dysfunction
6
DeFronzo RA. Diabetes. 2009;58:773-795
Natural History of Type 2 Diabetes
Years from
diagnosis
–10
–5
Onset
0
5
10
15
Diagnosis
Incretin effect
-Cell function
Insulin resistance
Insulin secretion
Postprandial glucose
Fasting glucose
Microvascular complications
Macrovascular complications
Prediabetes
7
Type 2 diabetes
Figure courtesy of CADRE.
Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349;
UKPDS Group. Diabetes. 1995;44:1249-1258
UKPDS: -cell Loss Over
Time
-Cell Function (%)
100 –
75 –
50 –
25 –
Impaired
Glucose
Tolerance
0 –l
l
-12
-10
Postprandial
Hyperglycemia
l
-6
Type 2 Diabetes
l
-2
l
0
l
2
l
6
l
10
l
14
Years from Diagnosis
8
Dashed line = extrapolation based on Homeostasis Model Assessment (HOMA) data.
Data points from obese UKPDS population, determined by HOMA model.
Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.
Normal Glucose Homeostasis and Pre- and
Postmeal Insulin and Glucagon Dynamics
Insulin
(µU/mL)
120
90
60
30
0
Glucagon
(pg/mL)
140
130
120
110
100
90
Glucose
(mg %)
Normal (n=11)
Meal
360
330
300
270
240
110
80
-60
9
0
60
120
180
Premeal
Postmeal
 Insulin
 Insulin
 Glucagon
 Glucagon
 HGP
 HGP
Just enough
glucose to meet
metabolic needs
between meals
Modest
postprandial
increase with
prompt return to
fasting levels
240
Time (min)
Müller WA, et al. N Engl J Med. 1970;283:109-115.
Hyperglycemia in Type 2 Diabetes Results from
Abnormal Insulin and Glucagon Dynamics
Insulin
(µU/mL)
120
90
60
30
0
Glucagon
(pg/mL)
140
130
120
110
100
90
Glucose
(mg %)
Normal (n=11)
T2DM (n=12)
Meal
360
330
300
270
240
Premeal
Postmeal
 Insulin
 Insulin
 Glucagon
 Glucagon
 HGP
 HGP
 FPG
 PPG
110
80
-60
10
0
60
120
180
240
Time (min)
Müller WA, et al. N Engl J Med. 1970;283:109-115.
Acute Insulin Response Is
Reduced in Type 2 Diabetes
1st
2nd phase
20 g glucose infusion
120
Normal (n=85)
Type 2 diabetes (n=160)
Plasma IRI
(µU/ml)
100
80
60
40
20
0
-30
0
30
60
90
120
Time (minutes)
11
IRI=immunoreactive insulin.
Pfeifer MA, et al. Am J Med. 1981;70:579-588.
Defective Insulin Action in
T2DM
12
6
Leg Glucose Uptake
(mg/kg leg wt per min)
Total Body Glucose Uptake
(mg/kg • min)
7
5
4
3
2
8
4
P<0.01
1
0
0
Normal
T2DM
0 20
60
100
140
Time (minutes)
180
12
DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155.
Elevated Fasting Glucose in
Type 2 Diabetes Results From
Increased HGP
4.0
Basal HGP
(mg/kg • min)
3.5
r=0.85
P<0.001
3.0
2.5
Control
2.0
T2DM
100
200
FPG (mg/dL)
300
13
DeFronzo RA, et al. Metabolism. 1989;38:387-395.
Type 2 Diabetes:
A Progressive Disease
Normal
79,000,000
Type 2
Diabetes
25,800,000
Primary
prevention
Secondary
prevention
IFG/IGT
Complications
Disability
Death
Tertiary
prevention
14
Garber AJ, et al. Endocr Pract. 2008;14:933-46.
CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.
Summary: Hyperglycemia in
Type 2 Diabetes
• Hyperglycemia results from the
combination of
– Pancreatic -cell dysfunction, resulting in
impaired insulin secretion
– Increased hepatic glucose production due
to excessive glucagon
– Decreased peripheral glucose uptake due
to insulin resistance
15
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.