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Diabetus Mellitus & Hypoglycemia. Dr. M. Alzaharna (2014) Diabetes Mellitus Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting.

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Presentation on theme: "Diabetus Mellitus & Hypoglycemia. Dr. M. Alzaharna (2014) Diabetes Mellitus Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting."— Presentation transcript:

1 Diabetus Mellitus & Hypoglycemia

2 Dr. M. Alzaharna (2014) 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 2

3 Dr. M. Alzaharna (2014) 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 1)Type 1 diabetes – B cell destruction, usually leading to absolute insulin deficiency Immune-mediated Idiopathic 3

4 Dr. M. Alzaharna (2014) Classification 2)Type 2 diabetes – may range from predominantly insulin resistance with relative insulin deficiency – to a predominantly secretory defect with insulin resistance 3)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 4)Gestational diabetes mellitus (GDM) 4

5 Dr. M. Alzaharna (2014) 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 5

6 Dr. M. Alzaharna (2014) 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 6

7 Dr. M. Alzaharna (2014) 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 7

8 Dr. M. Alzaharna (2014) 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 8

9 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. The Pathophysiology of Type 2 Diabetes Hyperglycemia Liver Insulin deficiency Excess glucose output Insulin resistance (decreased glucose uptake) Pancreas Muscle and fat Excess glucagon Islet Diminished insulin Alpha cell produces excess glucagon Beta cell produces less insulin

10 Dr. M. Alzaharna (2014) 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 10

11 Dr. M. Alzaharna (2014) 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 11

12 Dr. M. Alzaharna (2014) 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 12

13 Dr. M. Alzaharna (2014) 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 13

14 Dr. M. Alzaharna (2014) 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 14

15 Dr. M. Alzaharna (2014) 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

16 Dr. M. Alzaharna (2014) Signs and symptoms of DM Polydipsia (excessive thirst), Polyphagia (increased food intake), Polyuria (excessive urine production), Rapid weight loss, Hyperventilation, Mental confusion,

17 Dr. M. Alzaharna (2014) 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

18 Dr. M. Alzaharna (2014) 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

19 Dr. M. Alzaharna (2014) Laboratory tests Glucose Glycosylated Hemoglobulin (HbA1c) Ketone Bodies Serum osmolality Electrolytes Microalbuminuria

20 Dr. M. Alzaharna (2014) 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

21 Dr. M. Alzaharna (2014) Categories Of Fasting Plasma Glucose (FPG) Normal fasting glucoseFPG <100 mg/dL (<5.6 mmol/L) Impaired fasting glucoseFPG mg/dL ( mmol/L) Provisional diabetes diagnosis FPG ≥ 126 mg/dL (≤7.0 mmol/L) * * Must be confirmed

22 Dr. M. Alzaharna (2014) Glycated Hemoglobin (HbA1c) HbA 1c Value (%)Mean Capillary Blood Glucose Levels (mg/dL) Correlations of HbA 1c Levels with Average of Capillary Glucose Measurements (Preprandial, Postprandial, and Bedtime) in the Previous 3 Months

23 Dr. M. Alzaharna (2014) 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 23

24 Treatment of Diabetes Mellitus Sulfonylureas Meglitinides Injected Insulin Liver Plasma glucose Glitazones GI tract  -Glucosidase Inhibitors + Pancreas Metformin Muscle/Fat – (–)(+) (–) (+) (–) (+) Carbohydrate Absorption Glucose Production Insulin Secretion Glucose Uptake Insulin Secretion

25 HYPOGLYCEMIC DISORDERS 25

26 Dr. M. Alzaharna (2014) 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

27 Dr. M. Alzaharna (2014) 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 27

28 Dr. M. Alzaharna (2014) 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


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