Diabetes: Pathophysiology -- Type 2 Diabetes Lekshmi T. Nair, MD Division of Endocrinology, Diabetes and Metabolism

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 1TYPE 2 Other terms“Juvenile onset“ “Brittle DM” “Latent onset“ “Adult onset” “Maturity onset” Typical Age of Diagnosis < 30> 40 OnsetAbruptGradual KetosisCommonRare Body habitusUsually thin80% obese Twin concordance40-50%Almost 100% Insulin neededAlwaysVariable

Content: Diagnosis of diabetes mellitus Diabetes MellitusImpaired Fasting glucose ≥ 126mg/dL mg/dL 2 hr glucose ≥ 200mg/dL mg/dL A1c ≥ 6.5% % 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 Insulin Glucagon Neural Input Other hormone Insulin Glucagon Neural Input Other hormone

Content: Pathophysiology of diabetes mellitus Hepatic glucose production Peripheral glucose uptake/utilization Insulin Glucagon Neural Input Other hormone Insulin Glucagon Neural Input Other 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 production Peripheral insulin resistance Abnormal fat metabolism Diminished 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: Reproduced with permission from Elsevier  10 99 88 77 66 55 44 33 22 1 HOMA = homeostasis model assessment Content: Pathophysiology of diabetes mellitus Declining β-cell Function in T2DM β-cell Function (% of normal by HOMA) 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: Ludwig DS. JAMA. 2002;287: Content: Factors That Contribute to Progressive Nature of Type 2 Diabetes Insulin Resistance Glucose Toxicity (hyperglycemia)  -Cell Dysfunction “Lipotoxicity” (elevated FFA, TG) FFA = free fatty acids; TG = triglycerides.

Adapted from Ramlo-Halsted BA, et al. Prim Care. 1999;26: Reproduced with permission from Elsevier and the Council for the Advancement of Diabetes Research and Education (CADRE). Content: The Natural History of T2DM Decreasing Insulin Secretion in the Context of Insulin Resistance Leads to Increases in Blood Glucose and Diabetes Complications Impaired glucose tolerance Undiagnosed diabetes Known diabetes Macrovascular complications Microvascular complications Insulin resistance Postprandial glucose Fasting glucose β-cell function Insulin 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.

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