Endocrine Pancreas PDF

## Endocrine Pancreas ### I Basic Principles - Composed of clusters of cells termed islets of Langerhans. - A single islet consists of multiple cell types, each producing one type of hormone. - Insulin is secreted by beta cells, which lie in the center of the islets. - Major anabolic hormone;...

## Endocrine Pancreas ### I Basic Principles - Composed of clusters of cells termed islets of Langerhans. - A single islet consists of multiple cell types, each producing one type of hormone. - Insulin is secreted by beta cells, which lie in the center of the islets. - Major anabolic hormone; upregulates insulin-dependent glucose transporter protein (GLUT4) on skeletal muscle and adipose tissue (glucose uptake by GLUT4 decreases serum glucose). - Increased glucose uptake by tissues leads to increased glycogen synthesis, protein synthesis, and lipogenesis. - Glucagon is secreted by alpha cells; it opposes insulin in order to increase blood glucose levels (e.g., in states of fasting) via glycogenolysis and lipolysis. ### II Type 1 Diabetes Mellitus - Insulin deficiency leading to a metabolic disorder characterized by hyperglycemia. - Due to autoimmune destruction of beta cells by T lymphocytes. - Characterized by inflammation of islets. - Associated with HLA-DR3 and HLA-DR4. - Autoantibodies against insulin are often present (sign of damage) and may be seen years before clinical disease develops. - Manifests in childhood with clinical features of insulin deficiency. - High serum glucose - Lack of insulin leads to decreased glucose uptake by fat and skeletal muscle. - Weight loss, low muscle mass, and polyphagia - Unopposed glucagon leads to gluconeogenesis, glycogenolysis and lipolysis, which further exacerbates hyperglycemia. - Polyuria, polydipsia, and glycosuria - Hyperglycemia exceeds renal ability to resorb glucose; excess filtered glucose leads to osmotic diuresis. - Treatment involves lifelong insulin. - Risk for diabetic ketoacidosis. - Characterized by excessive serum ketones. - Often arises with stress (e.g., infection); epinephrine stimulates glucagon secretion increasing lipolysis (along with gluconeogenesis and glycogenolysis). - Increased lipolysis leads to increased free fatty acids (FFAs). - Liver converts FFAs to ketone bodies (β-hydroxybutyric acid and acetoacetic acid). - Results in hyperglycemia (> 300 mg/dL), anion gap metabolic acidosis, and hyperkalemia. - Presents with Kussmaul respirations, dehydration, nausea, vomiting, mental status changes, and fruity smelling breath (due to acetone). - Treatment is fluids (corrects dehydration from polyuria), insulin, and replacement of electrolytes (e.g., potassium). ### III Type 2 Diabetes Mellitus - End-organ insulin resistance leading to a metabolic disorder characterized by hyperglycemia. - Most common type of diabetes (90% of cases); affects 5-10% of the US population. - Incidence is rising. - Arises in middle-aged, obese adults. - Obesity leads to decreased numbers of insulin receptors. - Strong genetic predisposition exists. - Insulin levels are increased early in disease, but later, insulin deficiency develops due to beta cell exhaustion; histology reveals amyloid deposition in the islets. - Clinical features include polyuria, polydipsia, and hyperglycemia, but disease is often clinically silent. - Diagnosis is made by measuring glucose levels (normal is 70-120 mg/dL). - Random glucose > 200 mg/dL. - Fasting glucose > 126 mg/dL. - Glucose tolerance test with a serum glucose level > 200 mg/dL two hours after glucose loading. - Treatment involves weight loss (diet and exercise) initially; may require drug therapy to counter insulin resistance (e.g., sulfonylureas or metformin) or exogenous insulin after exhaustion of beta cells. - Risk for hyperosmolar non-ketotic coma. - High glucose (> 500 mg/dL) leads to life-threatening diuresis with hypotension and coma. - Ketones are absent due to small amounts of circulating insulin. ### IV Long-Term Consequences of Diabetes - Nonenzymatic glycosylation (NEG) of vascular basement membranes. - NEG of large- and medium-sized vessels leads to atherosclerosis and its resultant complications. - Cardiovascular disease is the leading cause of death among diabetics. - Peripheral vascular disease in diabetics is the leading cause of nontraumatic amputations. - NEG of small vessels (arterioles) leads to hyaline arteriolosclerosis. - Involvement of renal arterioles leads to glomerulosclerosis, resulting in small, scarred kidneys with a granular surface. - Preferential involvement of efferent arterioles leads to glomerular hyperfiltration injury with microalbuminuria that eventually progresses to nephrotic syndrome; characterized by Kimmelstiel-Wilson nodules in glomeruli. - NEG of hemoglobin produces glycated hemoglobin (HbA1c), a marker of glycemic control. - Osmotic damage. - Glucose freely enters into Schwann cells (which myelinate peripheral nerves), pericytes of retinal blood vessels, and the lens. - Aldose reductase converts glucose to sorbitol, resulting in osmotic damage. - Leads to peripheral neuropathy, impotence, blindness, and cataracts; diabetes is the leading cause of blindness in the developed world. ### V Pancreatic Endocrine Neoplasms - Tumors of islet cells; account for < 5% of pancreatic neoplasms. - Often a component of MEN 1 along with parathyroid hyperplasia and pituitary adenomas. - Insulinomas present as episodic hypoglycemia with mental status changes that are relieved by administration of glucose. - Diagnosed by ↓ serum glucose levels (usually < 50 mg/dL), ↑ insulin, and ↑ C-peptide. - Gastrinomas present as treatment-resistant peptic ulcers (Zollinger-Ellison syndrome); ulcers may be multiple and can extend into the jejunum. - Somatostatinomas present as achlorhydria (due to inhibition of gastrin) and cholelithiasis with steatorrhea (due to inhibition of cholecystokinin). - VIPomas secrete excessive vasoactive intestinal peptide leading to watery diarrhea, hypokalemia, and achlorhydria.