Download - Clinical Presentation of Type 2 Diabetes
Clinical Presentation of Type 2 Diabetes
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Risk Factors for Prediabetes and Type 2 Diabetes
• 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
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
Insulin resistance
Insulin resistance
Abnormalβ-Cell
Function
Relative insulin
deficiency
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Gerich JE. Mayo Clin Proc. 2003;78:447-456.
Type 2 diabetes
Normalβ-Cell
FunctionCompensatory
hyperinsulinemiaNo
diabetes
Genes & environment
Genes & environment
Etiology of β-cell Dysfunction
Poitout V, Robertson RP. Endocrine Rev. 2008;29:351-366.
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Genetic predisposition
Lean phenotype Obese phenotype
IGT, IFG Elevated FFA
Oxidative stress and glucotoxicity
Cellular lipid synthesis and glucolipotoxicity
Progressive -cell failure and type 2 diabetes
Initial glucolipoadaptation (increased FFA usage)
Hyperglycemia
Glucolipotoxicity and glucotoxicity
5NGT=normal glucose tolerance; IGT=impaired glucose tolerance; EMBS=estimated metabolic body size.
Weyer C et al. J Clin Invest. 1999;104:787-794.
Progression to Type 2 Diabetes: “Falling Off the Curve”
0
100
20 0
300
400
500
0 1 2 3 4 5
Glucose disposal (insulin sensitivity)(mg/kg EMBS/min)
Acu
te in
sulin
resp
onse
(U
/mL)
DIA
IGT
NGT
Progressors
NGTNGT
NGT
Nonprogressors
Pathophysiology of T2DMOrgan System DefectMajor RolePancreatic beta cells Decreased insulin secretion
Muscle Inefficient glucose uptake
Liver Increased endogenous glucose secretion
Contributing RoleAdipose tissue Increased FFA production
Digestive tract Decreased incretin effect
Pancreatic alpha cells Increased glucagon secretion
Kidney Increased glucose reabsorption
Nervous system Neurotransmitter dysfunction
DeFronzo RA. Diabetes. 2009;58:773-795
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Natural History of 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
Fasting glucose
Type 2 diabetes
Years from diagnosis
0 5–10 –5 10 15
Prediabetes
Onset Diagnosis
Postprandial glucose
Macrovascular complicationsMicrovascular complications
Insulin resistanceInsulin secretion
-Cell functionIncretin effect
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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.
Type 2 Diabetes
-C
ell F
unct
ion
(%)
Years from Diagnosis
25 –
100 –
75 –
0 –
50 –
l-12
l-10
l-6
l-2
l0
l2
l6
l10
l14
Impaired Glucose
TolerancePostprandial
Hyperglycemia
UKPDS: -cell Loss Over Time
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Müller WA, et al. N Engl J Med. 1970;283:109-115.
Normal Glucose Homeostasis and Pre- and Postmeal Insulin and Glucagon Dynamics
Premeal Postmeal
Insulin Insulin
Glucagon
HGP
Glucagon
HGP
Just enough glucose to meet metabolic needs between meals
Modest postprandial increase with
prompt return to fasting levels
Glucose (mg %)
Glucagon (pg/mL)
Time (min)-60 0 60 120 180 240
Meal120906030
0
140130120110100
90
Insulin (µU/mL)
360330300270240
11080
Normal (n=11)
Premeal Postmeal
Insulin Insulin
Glucagon
HGP
Glucagon
HGP
FPG PPG
Hyperglycemia in Type 2 Diabetes Results from Abnormal Insulin and Glucagon Dynamics
Glucose (mg %)
Insulin (µU/mL)
Glucagon (pg/mL)
Time (min)-60 0 60 120 180 240
Meal120906030
0
140130120110100
90
360330300270
T2DM (n=12)Normal (n=11)
240
11080
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Müller WA, et al. N Engl J Med. 1970;283:109-115.
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Acute Insulin Response Is Reduced in Type 2 Diabetes
IRI=immunoreactive insulin.Pfeifer MA, et al. Am J Med. 1981;70:579-588.
Pla
sma
IRI
(µU
/ml)
Time (minutes)
20 g glucose infusion
2nd phase1st
-300
20
40
60
80
100
0 30 60 90 120
120 Normal (n=85)Type 2 diabetes (n=160)
Defective Insulin Action in T2DM
Leg
Glu
cose
Upt
ake
(mg/
kg le
g w
t per
min
)
Time (minutes)0
P<0.01
12
1801401006020
8
4
0
Tota
l Bod
y G
luco
se U
ptak
e (m
g/kg
• m
in)
T2DMNormal0
7
6
5
4
3
2
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DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155.
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DeFronzo RA, et al. Metabolism. 1989;38:387-395.
Elevated Fasting Glucose in Type 2 Diabetes Results From
Increased HGPB
asal
HG
P(m
g/kg
• m
in)
FPG (mg/dL)
2.0
2.5
3.0
3.5
4.0
100 200 300
r=0.85P<0.001
Control
T2DM
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Normal IFG/IGT Type 2 Diabetes
Complications
Disability Death
Secondaryprevention
79,000,000 25,800,000
Tertiaryprevention
Primaryprevention
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.
Type 2 Diabetes: A Progressive Disease
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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
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.