Diabetus Mellitus & Hypoglycemia

Diabetes Mellitus Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from: an absolute deficiency of insulin secretion or a reduction in the biologic effectiveness of insulin or both The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels

Classification In 1997, an international committee of diabetologists recommended a classification of diabetes that have been endorsed by the American Diabetes Association and the World Health Organization Type 1 diabetes B cell destruction, usually leading to absolute insulin deficiency Immune-mediated Idiopathic

Classification Type 2 diabetes Other specific types may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance Other specific types Genetic defects of B cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug- or chemical-induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes Gestational diabetes mellitus (GDM)

Type 1 Diabetes Mellitus This form of diabetes is immune-mediated in more than 90% of cases and idiopathic in less than 10% Diabetes mellitus type 1 occurs at any age but most commonly arises in children and young adults with a peak incidence before school age and again at around puberty Most patients with type 1 diabetes at diagnosis have circulating antibodies: islet cell antibody (ICA) Insulin autoantibody (IAA) antibody to glutamic acid decarboxylase (GAD) 65 localized within pancreatic beta cells and antibody to tyrosine phosphatases IA2

Genetics & Environmental Factors of Type 1 Diabetes Genetic influences are less marked in type 1 diabetes than in type 2 diabetes Only 30–40% of identical twins of type 1 diabetic patients develop the disease Type 1 diabetes is believed to result from an infectious or toxic environmental insult to genetically predisposed persons whose aggressive immune system destroys pancreatic β cells while overcoming the invasive agent Environmental factors that have been associated with altered pancreatic islet cell function include viruses (mumps, rubella) Toxic chemical agents such as hydrogen cyanide

Type 1 Diabetes Mellitus It is a catabolic disorder Circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic β cells fail to respond to all known insulinogenic stimuli In the absence of insulin, the three main target tissues of insulin (liver, muscle, and fat) fail to appropriately take up absorbed nutrients and continue to deliver glucose, amino acids, and fatty acids into the blood from storage depots alterations in fat metabolism lead to the production and accumulation of ketones

Type 2 Diabetes Individuals with insulin resistance who generally have relative rather than absolute insulin deficiency Accounts for 80–90% of cases of diabetes in the United States Patients are usually adults over age 40 with some degree of obesity They do not require insulin to survive, although over time their insulin secretory capacity tends to deteriorate, and many need insulin treatment to achieve optimal glucose control Ketosis seldom occurs suddenly, and if present, it is a consequence of severe stress from trauma or infection

The Pathophysiology of Type 2 Diabetes Islet Insulin deficiency Alpha cell produces excess glucagon Beta cell produces less insulin Pancreas The pathophysiology of hyperglycemia in type 2 diabetes involves three main defects: (1) insulin deficiency due to insufficient pancreatic insulin release; (2) excess hepatic glucose output; and (3) insulin resistance (decreased glucose uptake) in peripheral tissues (including muscle and fat) and the liver.1-3 Two pancreatic islet cell defects contribute to this pathology: Beta cells produce insulin, which facilitates glucose entry into tissues.4 In type 2 diabetes mellitus, a decline in functional beta-cell mass causes insulin deficiency, which in turn contributes to hyperglycemia.3-5 Alpha cells produce glucagon.6 Elevated glucagon levels promote increased hepatic glucose output.1 In type 2 diabetes mellitus, excess glucagon and diminished insulin secretion drive hepatic glucose output and contribute to hyperglycemia.1 Diminished insulin Excess glucagon Hyperglycemia Muscle and fat Excess glucose output Insulin resistance (decreased glucose uptake) Liver Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180; Rhodes CJ Science 2005;307:380–384. References Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483. Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther 2003;25(suppl B):B32–B46.  Powers AC. Diabetes mellitus. In: Kasper DL, Braunwald E, Fauci A et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180.  Del Prato S, Marchetti P. Targeting insulin resistance and β-cell dysfunction: The role of thiazolidinediones. Diabetes Technol Ther 2004;6:719–731. Rhodes CJ. Type 2 diabetes—a matter of β-cell life and death? Science 2005;307:380–384. Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, Massachusetts: Blackwell Publishing, 2004.

The Pathophysiology of Type 2 Diabetes Tissue insensitivity to insulin has been noted in most patients with type 2 disease irrespective of weight and has been attributed to several interrelated factors These include a genetic factor, which is aggravated in time by further enhancers of insulin resistance such as: aging a sedentary lifestyle, and abdominal visceral obesity

The Pathophysiology of Type 2 Diabetes In addition, there is an accompanying deficiency in the response of pancreatic β cells to glucose due to deposition of intraislet amyloid with aging Type 2 diabetes frequently goes undiagnosed for many years, because the hyperglycemia develops quite gradually and is generally asymptomatic initially These patients are at increased risk of developing macrovascular and microvascular complications

Insulin Resistance in Type 2 Diabetes Insulin resistance can be broadly defined as a decrease in tissue responsiveness to insulin Clinically it can be assessed directly by: measuring the ability of a fixed dose of insulin to promote total body glucose disposal It can be assessed indirectly by measuring fasting insulin levels An increase in insulin levels with normal plasma glucose indicates insulin resistance

Insulin Resistance in Type 2 Diabetes As adiposity increases, especially abdominal fat deposits, total body insulin sensitivity decreases Adipose tissue only removes a small fraction of plasma glucose Therefore, the increased adipose fat stores impact total body insulin sensitivity through effects on other tissues, especially muscle and liver, causing them to decrease insulin-stimulated glucose disposal The exact means by which fat storage in adipocytes affects the insulin sensitivity of other cells remains uncertain

Possible Mechanisms of Insulin Resistance Abnormalities of insulin receptors in concentration, affinity, or both affect insulin action Target tissues regulate the number of insulin receptors on the cell by increased intracellular degradation Conditions associated with high insulin levels and lowered insulin binding to the receptor include: obesity, high intake of carbohydrates, and chronic exogenous over insulinization Conditions associated with low insulin levels and increased insulin binding include exercise and fasting The insulin receptor itself is probably not the major determinant of insulin sensitivity Clinically relevant insulin resistance most commonly results from defects in postreceptor intracellular signaling pathways

Gestational diabetes mellitus Glucose intolerance that is induced by pregnancy Caused by metabolic and hormonal changes related to the pregnancy Glucose tolerance usually returns to normal after delivery An increased risk for development of diabetes in later years

Signs and symptoms of DM Polydipsia (excessive thirst), Polyphagia (increased food intake), Polyuria (excessive urine production), Rapid weight loss, Hyperventilation, Mental confusion,

Ketoacidosis The individual with type 1 diabetes has a higher tendency to produce ketones (Beta-hydroxybutyrate, Acetoacetate, Acetone) Absence of insulin and with increased glucagon leads to gluconeogenesis and lipolysis The liver thus produces large amounts of ketone bodies, which are moderately strong acids The result is severe acidosis the decrease in pH impairs tissue function, most importantly in the central nervous system In the absence of cellular glucose, fatty acids are oxidized for production of energy. Ketones are by-products of excessive beta-oxidation of fatty acids

Hyperosmolar Nonketonic States Type 2: have very little ketone production, but have a greater tendency to develop hyperosmolar nonketonic states This disorder is caused by elevated blood sugar levels and is usually brought on by a coexisting condition, such as an illness or infection The condition is characterized by hyperglycemia, hyperosmolarity, and dehydration without significant ketoacidosis It can be a life-threatening emergency hyperosmolar nonketonic states is one of two serious metabolic derangements that occurs in patients with diabetes mellitus and can be a life-threatening emergency.

Laboratory tests Glucose Glycosylated Hemoglobulin (HbA1c) Ketone Bodies Serum osmolality Electrolytes Microalbuminuria

Criteria For Diagnosis Of DM 1. Random plasma glucose ≥ 200 mg/dL (≥11.1 mmol/L), + symptoms of diabetes 2. Fasting plasma glucose ≥ 126 mg/dL (≥7.0 mmol/L) 3. Two-h plasma glucose ≥ 200 mg/dL (≥11.1 mmol/L) during an OGTT Each of which must be confirmed on a subsequent day by any one of the three methods N.B. To convert mmol/l of glucose to mg/dl, multiply by 18

Categories Of Fasting Plasma Glucose (FPG) Normal fasting glucose FPG <100 mg/dL (<5.6 mmol/L) Impaired fasting glucose FPG 100-125 mg/dL (5.6-6.9 mmol/L) Provisional diabetes diagnosis FPG ≥ 126 mg/dL (≤7.0 mmol/L)* * Must be confirmed

Glycated Hemoglobin (HbA1c) Correlations of HbA1c Levels with Average of Capillary Glucose Measurements (Preprandial, Postprandial, and Bedtime) in the Previous 3 Months HbA1c Value (%) Mean Capillary Blood Glucose Levels (mg/dL) 5 97 6 126 7 154 8 183 9 212 10 240 11 269 12 298

Differential Diagnosis An attempt should be made to characterize the diabetes as type 1 or type 2 based on: the clinical features present and on whether ketonuria accompanies the glycosuria For the occasional patient, measurement of ICAs, including ICA 512, and GAD and insulin antibodies can help in distinguishing between type 1 and type 2 diabetes

Treatment of Diabetes Mellitus Plasma glucose -Glucosidase Inhibitors Glitazones Carbohydrate Absorption Glucose Uptake (–) (+) Glucose Production GI tract Muscle/Fat (+) Injected Insulin Metformin (–) Liver (–) Slide 4-5 Antihyperglycemic Agents: Major Sites of Action The abnormalities in blood glucose regulation that characterize type 2 diabetes mellitus are complex and involve defects in insulin secretion as well as insulin resistance. The complexity of the metabolic defects in this condition has led to the development of therapeutic agents that affect different targets along the metabolic pathways involved. Plasma glucose may be lowered via the stimulation of insulin secretion by the sulfonylureas or the meglitinides, as well as by the stimulation of glucose uptake by muscle and fat, or by the decrease in hepatic production of glucose mediated by metformin or insulin. Acarbose and miglitol may decrease plasma glucose by slowing absorption of glucose from the gastrointestinal tract; the thiazolidinediones lower plasma glucose by enhancing tissue uptake of glucose. – + Insulin Secretion Sulfonylureas Meglitinides Insulin Secretion (+) Pancreas

Hypoglycemic Disorders

Hypoglycemia Hypoglycaemia, means “low blood glucose” (< 70 mg/dl) It can arise from many causes, and can occur at any age If too low can be life threatening (< 30 mg/dl) Most effective on the CNS there is shaking and tremors, heart rate increases- dizziness, cold sweat, if not corrected can result in unconsciousness-coma and death Epinephrine act with glucagon to increase plasma glucose The plasma glucose concentration at which glucagon and other glycemic factors are released is between 65 and 70 mg/dL In addition cortisol and GH are also released

Hypoglycemia The most common forms of moderate and severe hypoglycaemia occur as a complication of treatment of diabetes with insulin or blood glucose-lowering medicines Risk increases with: Consuming too little carbohydrate Missing a meal or eating a meal later than the usual time Prolonged or unplanned physical activity

Fasting hypoglycemia Hypoglycemia that occurs after fasting is rare May occur as a response: to insulin-producing tumors of the pancreas (insulinomas) hepatic dysfunction, glucocorticoid deficiency, sepsis, or low glycogen stores Itypoglycaemia is sometimes seen in patients with septicaemia. It is thought to be a result of the release of cytokines, which may stimulate insulin secretion or have a direct effect on hepatic glucose production.