Clinical Presentation of Type 2 Diabetes

1

2

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

3

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.

4

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

6

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

7

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

8

9

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

10

Müller WA, et al. N Engl J Med. 1970;283:109-115.

11

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

1

DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155.

12

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

13

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

14

15

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.