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Pathology of endocrine pancreas
By: Shifaa’ Alqa’qa’
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• major cell types:
Beta ----- insulin
Alpha ----- glucagon
Delta ----- somatostatin
PP (pancreatic polypeptide) cells ------ VIP
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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).
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• HbA1C ?????????
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• 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
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• Classification:
- Type 1 diabetes (T1D) ---- 10%
- Type 2 diabetes (T2D) ---- 80% to 90%
- monogenic and secondary causes
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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
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• 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)
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• 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
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• 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
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• 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)
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• 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)
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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)
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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
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• Activation of protein kinase C:
Intracellular hyperglycemia-----stimulate the de novo synthesis of DAG (diacylglycerol) ----activation of PKC---- production of proangiogenic
molecules (VEGF) ----- neovascularization
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• 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
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• complications appear approximately 15 to 20 years after the onset of hyperglycemia
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• macrovascular disease
• Basement membranes of small vessels (microangiopathy),
• Kidneys (diabetic nephropathy),
• retina (retinopathy),
• Nerves (neuropathy)
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• 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 ????
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• Diabetic Macrovascular Disease:
accelerated atherosclerosis
Myocardial infarction
Gangrene of the lower extremities
Hyaline arteriolosclerosis ????
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• Diabetic Microangiopathy:
diffuse thickening of basement membranes
leaky
Diabetic nephropathy,
Retinopathy
neuropathy
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• 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
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• 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
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• Diabetic Neuropathy (microangiopathy) :
- peripheral, symmetric neuropathy of the lower extremities affecting both motor and sensory function
- autonomic neuropathy
- diabetic mononeuropathy (footdrop or wristdrop)
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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
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• 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.
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• Diabetic patients are plagued by an enhanced susceptibility to infections of the skin, as well as to tuberculosis, pneumonia, and pyelonephritis
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PANCREATIC NEUROENDOCRINE TUMORS
• islet cell tumors
• Nonfunctional,
• Functional
• malignant
• benign
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• 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
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• Gastrinomas:
Zollinger-Ellison syndrome????
peptic ulceration
diarrhea