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:

(1) 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