Pathology of endocrine pancreas By: Shifaa’ Alqa’qa’

major cell types: Beta ----- insulin Alpha ----- glucagon Delta ----- somatostatin PP (pancreatic polypeptide) cells ------ VIP

DIABETES MELLITUS Normal blood glucose levels ???? DM diagnosis: 1. A random blood glucose concentration of 200 mg/dL or higher, with classical signs and symptoms 2. A fasting glucose concentration of 126 mg/dL or higher on more than one occasion 3. An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate load (75 g of glucose).

HbA1C ?????????

Prediabetes : impaired glucose tolerance serum fasting glucose greater than 110 but less than 126 mg/dL OGTT values of greater than 140 but less than 200 mg/dL Risk for DM and cardiovascular disease

Classification: - Type 1 diabetes (T1D) ---- 10% - Type 2 diabetes (T2D) ---- 80% to 90% - monogenic and secondary causes

PATHOGENESIS Type 1 Diabetes Mellitus: - autoimmune disease ------ failure of self tolerance in T cells, autoantibodies Childhood------ puberty------ more than 90% of the beta cells have been destroyed Insulitis ----- early

genetic susceptibility ---- HLA-DR3, or DR4 class II MHC (ch6) CTLA4 and PTPN22 genes (excessive T cell activation) environmental factors--------- Infections ----- viruses (mumps, rubella, and coxsackie B (molecular mimicry)

Type 2 Diabetes Mellitus: complex multifactorial disease - Genetic factors: Diabetogenic genes - Environmental factors: sedentary life style, dietary habits insulin resistance --------------- beta cell hyperfunction and hyperinsulinemia in the early stages ---------------- beta cell dysfunction

Insulin Resistance: failure of target tissues to respond normally to insulin - decreased uptake of glucose in muscle, - reduced glycolysis and fatty acid oxidation in the liver, - an inability to suppress hepatic gluconeogenesis

Obesity and Insulin Resistance: metabolic syndrome ---- DM 2 - excess free fatty acids (FFAs)----Intracellular triglycerides (muscle, liver) - FFA ----- Inflammation ---- inflammasome -------proinflammatory cytokines ---- IL-1β ---- macrophages and other cells, adipokines (fat cells)

Beta Cell Dysfunction: - FFAs - pro-inflammatory cytokines from beta cells - recruitment of mononuclear cells (macrophages and T cells) into the islets cytokine production Amyloid replacement of islets ---- islet amyloid polypetide (IAPP)

Monogenic Forms of Diabetes monogenic forms of diabetes are uncommon examples of the diabetic phenotype occurring as a result of loss-of-function mutations within a single gene. maturity-onset diabetes of the young (MODY)

Complications of Diabetes The pathogenesis of the long-term complications of diabetes: 1. Formation of advanced glycation end products (AGEs): AGEs ---hyperglycemia---- glucose-derived precursors- amino groups of proteins. AGE-RAGE (receptor of AGE on inflammatory cells,endothelium, vascular smooth muscle )---- pro-inflammatory cytokines---- reactive oxygen species---- procoagulant activity-- proliferation of vascular smooth muscle cells and synthesis of extracellular matrix AGEs can directly cross-link extracellular matrix proteins---- enhancing protein deposition-----trap other plasma or interstitial proteins---- (LDL) accelerating atherosclerosis---------- (albumin) basement membrane thickening

Activation of protein kinase C: Intracellular hyperglycemia-----stimulate the de novo synthesis of DAG (diacylglycerol) ----activation of PKC---- production of proangiogenic molecules (VEGF) ----- neovascularization

Disturbances in polyol pathways: Hyperglycemia----- increase in intracellular glucose (nerves, lens, kidneys, blood vessels)----- aldose reductase----- sorbitol (polyol) ----- NADPH ------ fructose ---- reduction in GSH (antioxidant) ----- oxidative stress ----- diabetic neuropathy

complications appear approximately 15 to 20 years after the onset of hyperglycemia

macrovascular disease Basement membranes of small vessels (microangiopathy), Kidneys (diabetic nephropathy), retina (retinopathy), Nerves (neuropathy)

Pancreas: - Reduction in the number and size of islets - Leukocytic infiltration of the islets---- More in Type1 - Amyloid replacement of islets in long-standing type 2 diabetes - An increase in the number and size of islets ????

Diabetic Macrovascular Disease: accelerated atherosclerosis Myocardial infarction Gangrene of the lower extremities Hyaline arteriolosclerosis ????

Diabetic Microangiopathy: diffuse thickening of basement membranes leaky Diabetic nephropathy, Retinopathy neuropathy

Diabetic Nephropathy: glomerular lesions (thick BM)---- Diffuse mesangial sclerosis---- Nodular glomerulosclerosis ----- nephrotic syndrome (2) renal vascular lesions ---- Renal atherosclerosis and arteriolosclerosis---- macrovascular disease (3) pyelonephritis, including necrotizing papillitis (4) end-stage renal disease

Ocular Complications of Diabetes: Nonproliferative retinopathy (microangiopathy: hemorrhages, retinal exudates, microaneurysms, venous dilations, edema) - proliferative retinopathy (neovascularization--- Vitreous hemorrhages---organization----retinal detachment----blindness ) - Cataract formation, - glaucoma

Diabetic Neuropathy (microangiopathy) : peripheral, symmetric neuropathy of the lower extremities affecting both motor and sensory function autonomic neuropathy diabetic mononeuropathy (footdrop or wristdrop)

Clinical Features: type 1 diabetes: honeymoon period???? Infection ---- abrupt ----- polyuria (glycosuria) , polydipsia, polyphagia, and in severe cases, ketoacidosis (500 to 700 mg/dL, dehydration, lipase--- FFAs---oxidized by the liver to produce ketones---- metabolic acidosis ---- nausea, vomiting, respiratory difficulties weight loss and muscle weakness

Type 2 diabetes mellitus: older than 40 years and frequently are obese osmotic diuresis---- dehydration---- hyperosmolar nonketotic coma-----delays recognition of the seriousness of the situation until the onset of severe dehydration and coma.

Diabetic patients are plagued by an enhanced susceptibility to infections of the skin, as well as to tuberculosis, pneumonia, and pyelonephritis

PANCREATIC NEUROENDOCRINE TUMORS islet cell tumors Nonfunctional, Functional malignant benign

Insulinomas---- Mc attacks of hypoglycemia, below 50 mg/dL ( central nervous system manifestations as confusion, stupor, and loss of consciousness). They are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose

Gastrinomas: Zollinger-Ellison syndrome???? peptic ulceration diarrhea