ENDOCRINE SYSTEM (4) PANCREAS DR FATAI OLUYADI USMLEINCLINED.COM 1

ENDOCRINE PANCREAS ANATOMY USMLEINCLINED.COM 2

ISLETS OF LANGERHANS USMLEINCLINED.COM 3

ISLETS OF LANGERHANS HISTOLOGY USMLEINCLINED.COM 4

PANCREATIC HORMONES  INSULIN (β-cells)  GLUCAGON (α-cells)  SOMATOSTATIN (δ-cells) USMLEINCLINED.COM 5

REGULATION OF ISLET CELL HORMONES USMLEINCLINED.COM 6

INSULIN RELEASE USMLEINCLINED.COM 7

INSULIN SYNTHESIS  Synthesized and Released from the β-cells in the Islet of langerhans  Synthesized as Preproinsulin which is then cleaved to Proinsulin then stored in secretory granules.  Cleavage of Proinsulin yields Insulin and C-peptide which is then released into circulation via exocytosis.  C-peptide levels is used to differentiate between Insulinoma/Sulfonylurea use and Exogenous Insulin use (Absent C-peptide) USMLEINCLINED.COM 8

FUNCTIONS OF INSULIN Insulin works by binding to Insulin receptors intrinsic tyrosine kinase activity Functions include: Increased glucose transport into skeletal muscle and adipose (GLUT-4) Increased glycogen synthesis and storage Increased triglyceride synthesis Increased Na retention in the kidneys Increase protein synthesis in the msucles Increased cellular uptake of Pottassium and Amino acids Decreased glucagon release USMLEINCLINED.COM 9

GLUCAGON Synthesized and released from the α-cells of the Islets of langerhans in the pancreas Functions include: Glycogenolysis Gluconeogenesis Lipolysis and ketone production Secreted in response to hypoglycemia. Release is inhibited by Insulin, Hyperglycemia and somatostatin USMLEINCLINED.COM 10

SOMATOSTATIN Synthesized and released from the δ-cells of the Islets of Langerhans of the pancreas. Functions include: Decrease Insulin and glucagon release Decrease gastric and pancreatic exocrine secretions Decrease splanchnic blood flow Inhibits Growth hormone secretion *Octreotide is an analog of somatostatin used to treat Acromegaly, Insulinoma, Carcinoid syndrome and variceal bleeding. USMLEINCLINED.COM 11

DIABETES MELLITUS Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia. Diagnostic criteria for Diabetes Mellitus include the following: a fasting plasma glucose of 126 mg/dL or more classic symptoms of hyperglycemia plus a random plasma glucose of 200 mg/dL or more, or, a plasma glucose level of 200 mg/dL or more after an oral dose of 75 g of glucose (oral glucose tolerance test, OGTT) *Hemoglobin A1c reflects average blood glucose over a 3 month period and is a very useful tool in he diagnosis and management of Diabetes mellitus. USMLEINCLINED.COM 12

ETIOLOGY OF DIABETES MELLITUS  Autoimmune damage to the Beta cells of the Islets of Langerhans (Type 1)  Target tissue resistance to the effects of insulin (Type 2)  Maturity Onset Diabetes Mellitus of the young(A variant of Type 2 sometimes due to Glucokinase gene mutations)  Gestational diabetes mellitus (Increased Human Plancental Lactogen)  Hypercortisolism  Glucagonoma  Glucocorticoid therapy (Steroid Diabetes Mellitus)  Growth Hormone excess USMLEINCLINED.COM 13

DIABETES MELLITUS TYPE 1 Autoimmune destruction of Beta cells Presence of Anti-Glutamic acid decarboxylase antibodies Age of onset is usually less than 30 years Not associated with obesity Relatively weak genetic predisposition Associated with HLA-DR3 and HLA-DR4 Classic symptoms include Polyuria, Polydipsia, Polyphagia and weight loss (All symptoms here are more commonly found with type 1) *Always treated with Insulin therapy USMLEINCLINED.COM 14

DIABETES MELLITUS TYPE 2 Target tissue resistance to insulin (Adipose tissues and skeletal muscles) Progressive Pancreatic β-cell failure (β-cells get overwhelmed) Age of onset is usually older than 40 years Strong association with obesity Strong genetic predisposition Classic symptoms of polyphagia, polydipsia and weight loss not typically found Presence of Amyloid deposits in the Islets of Langerhans (IAPP) *Treated with Oral Hypoglycemics and sometimes Insulin USMLEINCLINED.COM 15

DIABETES MELLITUS SYMPTOMS Some features of Diabetes Mellitus include: Polydipsia Polyuria Polyphagia Weight loss Diabetic Ketoacidosis (Type 1) Hyperosmolar coma (Type 2) USMLEINCLINED.COM 16

ACUTE MANIFESTATIONS OF DIABETES MELLITUS USMLEINCLINED.COM 17

CHRONIC COMPLICATIONS OF DIABETES MELLITUS There are 2 main mechanism of tissue damage associated with chronic diabetes mellitus; Nonenzymatic glycation Osmotic damage USMLEINCLINED.COM 18

NONENZYMATIC GLYCATION Covalent bonding of protein or lipid molecule with a sugar molecule in the absence of any enzymes. Typically the complications via this mechanism are divided into: Microvascular – Diffuse thickening of basement membrane of blood vessels resulting in e.g retinopathy, nephropathy, arteriolosclerosis (Hypertension and chronic renal failure). Glaucoma and some neuropathies can also be seen. Macrovascular – Atherosclerostic plaque formation resulting in Coronary artery disease (MI, Angina), Peripheral vascular occlusive disease (Gangrene, Limb loss), Cerebrovascular disease (TIA, Stroke), Myocardial infarction is the most common cause of death among these complications. USMLEINCLINED.COM 19

OSMOTIC DAMAGE Sorbitol accumulation in tissues with aldose reductase and reduced sorbitol dehydrogenase. Presenting as: Neuropathy ( Motor, Sensory, Autonomic degeneration) Cataracts USMLEINCLINED.COM 20

DIABETIC KETOACIDOSIS Dangerous complication of diabetes mellitus more commonly seen with Diabetes Mellitus type 1. Increased insulin requirements due to stress (E.g Infections) Increase Glucagon activities (catabolism) leading to Increased ketogenesis from free fatty acids. Signs and symptoms include: Kussmaul respirations, Nausea/vomiting, abdominal pain, psychosis/delirium, dehydration, fruity breath odor (acetone) USMLEINCLINED.COM 21

DIABETIC KETOACIDOSIS Laboratory findings: Hyperglycemia (Usually above 400mg/dl) Increased H +, Decreased HCO 3 - (Increased anion gap metabolic acidosis) Increased blood ketone levels Leukocytosis Hyperkalemia (but depleted intracellular pottassium due to transcellular shift) Complications: Cerebral edema, Cardiac arrhythmias, heart failure, Mucormycosis from Rhizopus infection. USMLEINCLINED.COM 22

DIABETIC KETOACIDOSIS MANAGEMENT Intravenous fluids IV Insulin (Regular Insulin) Supplement to Pottassium Glucose if necessary to prevent hypoglycemia USMLEINCLINED.COM 23

MULTIPLE ENDOCRINE NEOPLASIA 1 Autosomal dominant inherited disease characterized by presence of tumors in the: Pituitary gland Parathyroid gland - Hypercalcemia Pancreas- The pancreatic tumors are usually Gastrinomas, Insulinoma, VIPomas or Glucagonomas Gastrinomas present as the Zollinger Ellison syndrome(Gastric and duodenal ulcers) VIPomas present as the WDHA syndrome characterized by (Watery diarrhea, Hypokalemia and Achlorhydria. USMLEINCLINED.COM 24

INSULINOMA Tumor of the Pancreatic Islets β-cells. Over production of Insulin > Hypoglycemia Whipple triad may be seen; Low blood glucose, Symptoms of hypoglycemia, resolution of symptoms after normalization of glucose. Increased C-peptide is associated with Insulin overproduction (Lack of C-peptide e.g in exogenous insulin use is an indication of the absence of an insulinoma) Treatment: Surgical resection is the preferred method of treatment *See Diaxozide USMLEINCLINED.COM 25

GLUCAGONOMA A Rare tumor of the of the pancreatic α-cells leading to overproduction of Glucagon. Features include: Dermatitis (Necrolytic migratory erythema) Secondary Diabetes Mellitus (Hyperglycemia) Deep venous thrombosis Depression Treatment: Surgical resection USMLEINCLINED.COM 26