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Definition
Chronic disorder of carbohydrate, fat, and protein metabolism. Characterized by hyperglycemia resulting from impaired carbohydrate (glucose) utilization resulting from a defective or deficient insulin secretory response. The chronic hyperglycemia is associated with dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.
Incidence
1-2%
of US adult population (13 million 5%) >50% in some native American groups 35,000 annual deaths in US alone Number 7 leading cause of death Type I (IDDM Insulin-dependent DM) 10 20% (Lifetime risk = 0.5%) Type II (NIDDM Non-insulin dependent DM) 80 90% (Lifetime risk = 5-7%)
Secondary
Chronic Pancreatitis
(most common)
Classification Primary DM
Clinical Onset TYPE I (IDDM) < 20 Years Normal weight Insulin Islet cell Abs Common 50% in twins HLA-D associated Autoimmunity Severe insulin def Insulitis early Beta cell depletion TYPE II (NIDDM) > 30 Years Obese Nl or Insulin No islet cell Abs Rare (HONK) 90-100% in twins No HLA association Insulin resistance Relative insulin def No insulitits Mild beta cell loss
Classification Secondary DM
secondary to pancreatic islet cell destruction
Chronic pancreatitis
Tumors (Pheochromocytoma, pituitary) Drugs (Corticosteroids, thiazides, others) Hemochromatosis Genetic diseases (lipodystrophy) Hyperglycemia
Hormone
Insulin Glucagon Somatostatin Panc Polypeptide Serotonin VIP
Alpha
Beta
Action
Glucose Glucose Glucose Glucose
Diabetic Syndrome
AAs Glycogen formation in liver and muscle Glucose conversion to triglycerides Nucleic acid synthesis Protein synthesis All act to decrease blood glucose levels
Insulin Release from -cells and prolonged with increased stimulation Insulin & C-peptide stored and released in secretory granules & released together Tyrosine kinase receptor modulates this activity phosphorylation
Insulin
is the only hormone that decreases blood glucose. Insulin travels to its target sites of liver, muscle, & fat cells. Glucose can enter these cells only with the aid of insulin. Insulin binds with a cellular receptor site to exert its effect.
Insulin
Insulin Action
Pathogenesis Type I DM
Severe lack of insulin caused by reduction in
Autoimmunity Insulitis Islet cell antibodies (T-cell mediated) Association with autoimmune endocrine diseases Enviromental factors Viral mimicry (mumps, coxsachie B), toxins, cows milk
Insulin Insulin
Primary Diabetes
Type I Diabetes (~15% - IDDM) Hyperglycemia Type II Diabetes (~85% - NIDDM) Blood Vessels Kidneys Eyes Nerves
Pathogenesis Type II DM
Genetic susceptibility 90% concordance in identical twin studies Link not yet identified Insulin resistance Metabolic Defects Deranged insulin secretion to meet needs Insulin resistance in peripheral tissues Decreased numbers of insulin receptors Post-receptor defects Obesity associated with insulin resistance/ insulin
is defined as a diminished biologic response (such as glucose transport) to insulin. Obesity is associated with hyperinsulinemia in the face of a normal or elevated blood glucose (the constellation of laboratory findings consistent with insulin resistance)
distribution, and duration of obesity NIDDM is up to 10 times more likely in an obese person with a diabetic parent than in an equally obese subject with a negative family history Morbidly obese not necessarily diabetic
Metabolic Derangements
Disordered metabolism
Carbohydrates
fuel is broken down Fats increased lipolysis of stored fat Protein catabolism increased
Polyuria, polydipsia, polyphagia triad
osmotic diuresis polyuria Loss of water polydipsia Poorly defined mechanism polyphagia
Hyperglycemic
Metabolic Derangements
Ketoacidosis
Stimulated
by increase in glucagon Excessive breakdown of fat triglycerides fatty acids ketone bodies (in liver) Ketone bodies normally metabolized in muscle Lack of insulin ketonemia and ketonuria
Coma
DKA
Pathogenesis of Complications
Non-enzymatic glycosylation Attachment to amino group of proteins Leads to AGEs (Advanced glycosylation end products) Accumulate on proteins in blood vessels & BMs Trapping of LDL/Cholesterol in vessels (atherosclerosis) Laboratory measurement glycosylated
Pathogenesis of Complications
Intracellular hyperglycemia with disturbances
of PolyolSorbitol Pathway
Hyperglycemia may increase intracellular glucose Hyperosmolarity results in water influx osmotic cell injury (cataracts) Damage to Schwann cells (demyelination of nerves) & retinal capillary pericytes (microaneurysms) ? sorbitol/fructose
Pathogenesis of Complications
Increased Intracellular Glucose - Polyol Pathways Non-Insulin Requiring Cells Nerves Fructose Lens Sorbitol Kidneys Blood Vessels Glucose Osmolality Ion Pump Impairment + Osmolality
Pathogenesis of Complications
Increased Intracellular Glucose - Polyol Pathways Non-Insulin Requiring Cells Schwann Cells Retinal Pericytes
Sorbitol Sorbitol
Lens
Fructose Sorbitol
Pathology - Atherosclerosis
75% under age of 40 have severe
atherosclerosis Complicated atherosclerosis ulceration, calcification, thrombosis ~50% with dyslipidemia, HDL Accelerated atherosclerosis
Platelet adhesiveness Thromboxane A2 Prostacyclins
Pathology Microangiopathy
BM thickening in capillaries of skin, skeletal muscle,
retina, glomeruli and renal medulla PAS+ thick BM Vessels become permeable to plasma proteins Secondary to AGEs Nephropathy, retinopathy, neuropathy Hypertension
Pathology Nephropathy
Microangiopathy leads to one or more of the
following: Diffuse or nodular diabetic glomerulosclerosis Renal arteriosclerosis & atherosclerosis Necrotizing renal papillitis
Pathology Nephropathy
Diffuse glomerulosclerosis less specific Nodular glomerulosclerosis more specific Insudative lesions accumulation of plasma proteins Fibrin cap between glomerular endothelium & GBM Capsular drop between parietal epithelial cell & Bowmans capsule Arteriolosclerosis both afferent & efferent arterioles
resulting in hypertension
Pathology - Retinopathy
Proliferative Retinopathy Non-Proliferative Cataracts Glaucoma
Ocular complications
Retinopathy 4th leading cause of blindness in US Non-proliferative retinal hemorrhages, exudates,
edema, venous dilatation, microangiopathy Proliferative neovascularization and fibrosis; blindness especially when it involves macula Cataracts, glaucoma Neovascularization of iris anterior chamber hemorrhage Mononeuropathy of cranial nerves diplopia
Pathology Neuropathy
Microangiopathy & Polyol Disturbances Peripheral Sensory & motor function of
Pathology Pancreatic
Reduction in size & number of islets (I > II) Increase size & number in newborns (GDM) Beta cell degranulation by EM (I) Fibrosis of islets (I & II) Amyloid replacement of islets (II > I) Lymphocytic infiltration Insulitis (II > I)
Infections
Mucormycosis of nasal sinuses
cavernous sinus thrombosis Staph, strept skin infections furuncles (boils), caruncles Candidiasis of vagina & oral cavity
Clinical
Type I (IDDM) 15% <20 y/o Normal Weight Insulin Islet Cell Abs Ketoacidosis Type II (NIDDM) 85% >30 y/o Obesity Nl/ Insulin No islet cell abs No ketoacidosis (HONK)
Diabetic Ketoacidosis
Insulin Fat Breakdown (Ketone Bodies) Ketoacids Acidosis
asymptomatic adult (>40y/o) Usually obese Unexplained weakness or weight loss May have polyphagia/polydipsia
Hypoglycemic Coma
Glucose < 60 tremor, tachycardia,
sweating, hunger Glucose < 40 intellectual and psychomotor impairment Glucose < 20 confusion, seizures, loss of consciousness
Classification of Diabetes Mellitus (1999) Fasting blood glucose 126 mg/dL on at least 2 occasions
Test should be performed after an 8-hour fast Normal fasting glucose < 110 mg/dL
polydipsia, polyphagia, unexplained weight loss with a casual blood glucose 200 mg/dL
Gestational diabetes screening 50-g glucose load If 1-hour 140 mg/dL then Complete 100-g 3-hour oral GTT Need 2 of 3 Fasting: 105, 1 hour: 190, 2 hour: 165, 3 hour: 145 mg/dL
HBA1C
HgB + Glucose Labile GHgB Pre-GHgB Amadori Reaction Stable GHB or HBA1C
Treatment
Effects of Insulin
Carbohydrate Uptake of Glucose by Cells Liver Glycogen Pyruvate Fat
Breakdown of Fat Formation of Fat FFA