Diabetes: Pathophysiology -- Type 2 Diabetes

Lekshmi T. Nair, MDDivision of Endocrinology, Diabetes and

MetabolismEmail: lekshmi.nair@osumc.edu

Learning Objectives

Discuss

• the pathophysiology of type 2 diabetes

Describe

• indications and procedures for screening and diagnosis of type 2 diabetes

Identify

• the typical clinical characteristics of type 2 diabetes and how to distinguish from Type 1 diabetes.

Describe

• causes of insulin resistance.

Describe

• other specific types of diabetes including LADA (Latent Autoimmune Diabetes of Adulthood)

Recognize

• the clinical characteristics of Hyperosmolar Hyperglycemic State (HHS)/Hyperosmolar Hyperglycemic Non-Ketotic State (HHNK)

Content: Background -- Epidemiology of Diabetes(US data released 1/26/2011)

Incidence: 1.9 million adults diagnosed with DM in 2010

Prevalence: Affects 25.8 million children and adults

Prevalence by race varies

DM carries significant morbidity, mortality and health care costs

Content: Classification of Diabetes - 1

Content: Classification of Diabetes - 2

Type 1 diabetes mellitus (T1DM) Type 2 diabetes mellitus (T2DM) Other types of diabetes mellitus: DM is a secondary

process or consequence of primary pathology Gestational diabetes mellitus (GDM) Latent Autoimmune Diabetes of Adulthood (LADA) Monogenic forms of Diabetes Mellitus (MODY)

Content: Clinical Characteristics of T1DM vs T2DM

TYPE 1 TYPE 2

Other terms “Juvenile onset““Brittle DM”“Latent onset“

“Adult onset”“Maturity onset”

Typical Age of Diagnosis

< 30 > 40

Onset Abrupt Gradual

Ketosis Common Rare

Body habitus Usually thin 80% obese

Twin concordance 40-50% Almost 100%

Insulin needed Always Variable

Content: Diagnosis of diabetes mellitus

Diabetes Mellitus Impaired

Fasting glucose ≥ 126mg/dL 100-125 mg/dL

2 hr glucose ≥ 200mg/dL

140-199 mg/dL

A1c ≥ 6.5% 5.7-6.4%

Random glucose ≥ 200mg/dL with symptoms

Source: American Diabetes Association, 2011.

Content: Screening for diabetes mellitus

• ADA recommendations:• All individuals > 45 years every 3 years• Earlier if overweight (BMI >25) and with additional risk

factor that is correlated with increased incidence of diabetes.

Source: American Diabetes Association, 2011.

Content: Pathophysiology of diabetes mellitus

Normal glucose homeostasis relies on a delicate balance between glucose production and utilization.

Hepatic glucose production

Peripheral glucose uptake/utilization

InsulinGlucagon

Neural InputOther hormone

Content: Pathophysiology of diabetes mellitus

Hepatic glucose production

Peripheral glucose uptake/utilization

InsulinGlucagonNeural InputOther hormone

Fasting glucose

Postprandial glucose

Multiple Defects in the Setting of Type 2 Diabetes

Content: Pathophysiology of diabetes mellitus

Reduced insulin secretion

Increased/inappropriate hepatic glucose productionPeripheral

insulin resistance Abnormal fat

metabolismDiminished incretin

secretion Diminished amylin secretion

Progressive Hyperglycemia

Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25. UKPDS Group. Diabetes. 1995;44:1249-1258. Reproduced with permission from Elsevier.

0

20

40

60

80

100

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6

HOMA = homeostasis model assessment

Content: Pathophysiology of diabetes mellitusDeclining β-cell Function in T2DM

β-c

ell

Fu

nct

ion

(% o

f n

orm

al b

y H

OM

A)

Years

Time of Diagnosis

Pancreatic function = 50% of normal at time

of diagnosis

?Decreasing β-cell function possibly for many years prior to diagnosis

Content: Type 2 Diabetes – Insulin resistance + Impaired Insulin secretion

Genetics. Adiposity.Insulin

signaling defects.

Reduced glucose

utilization.

Kahn SE. J Clin Endocrinol Metab. 2001;86:4047-4058.Ludwig DS. JAMA. 2002;287:2414-2423.

Content: Factors That Contribute to Progressive Nature of Type 2 Diabetes

InsulinResistance

Glucose Toxicity(hyperglycemia)

-CellDysfunction

“Lipotoxicity”(elevated FFA, TG)

FFA = free fatty acids; TG = triglycerides.

Adapted from Ramlo-Halsted BA, et al. Prim Care. 1999;26:771-789. Reproduced with permission from Elsevier and the Council for the Advancement of Diabetes Research and Education (CADRE).

Content: The Natural History of T2DMDecreasing Insulin Secretion in the Context of Insulin Resistance Leads to

Increases in Blood Glucose and Diabetes Complications

Impairedglucose tolerance

Undiagnoseddiabetes Known diabetes

Macrovascular complicationsMicrovascular complications

Insulin resistance

Postprandial glucose

Fasting glucose

β-cell functionInsulin secretion

Time

Content: Complications in Type 2 Diabetes Mellitus

Acute complications HHNK

Chronic Complications Macrovascular Microvascular

Content: Hyperosmolar Hyperglycemic Non-Ketotic State (HHNK)

Important features:

Little or no ketoacid accumulation.

Typically very elevated plasma glucose.

The plasma osmolality is elevated.

Dehydration is present.

Neurologic abnormalities are frequently present.

Content: Common precipitating factors in HHNK Pneumonia Urinary tract infection      Alcohol and drug abuse Silent myocardial infarction Stroke Pancreatitis Trauma Drugs (e.g. steroids and higher dose thiazide diuretics) Hot weather and insufficient water intake in elderly

patients

Glycosuria

Dehydration HYPEROSMOLARITY

Content: What happens in HHNK?

Content: HHNK treatment

Stabilize hemodynamically Electrolyte correction. Correct glucose gradually. (IV fluids + IV insulin)

Summary

Pathophysiology of T2DM involves both insulin resistance and secretion defects.

Age and risk factors help determine who should be screened for T2DM.

Screening for T2DM may involve a glucose tolerance test and/or hemoglobin A1C and ADA described goals.

T1DM and T2DM typically vary in clinical characteristics but it is important to consider exceptions and other types of diabetes.

HHNK results from progressive hyperglycemia and dehydration leading to hyperosmolar state.

Pathophysiology of Type2 Diabetes Quiz

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Questions? Contact me at:

lekshmi.nair@osumc.edu

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