Diabetes Mellitus and Pancreatic Endocrine Function

• The recommended reading is Robbins & Cotran pathologic basis of disease, chapter 24.

Objectives

• Identify and discuss different types of pancreatic endocrine cells and their function.
• Identify and discuss fundamental biochemical defects that characterize patients with diabetes.
• Identify and discuss the etiology and pathogenesis of diabetes.
• Identify and discuss the clinicopathologic features of diabetes mellitus.
• Identify and discuss the clinicopathologic features of pancreatic endocrine tumors.

Pancreatic Endocrine Cells

• Alpha cells secrete glucagon.
• Beta cells secrete insulin.
• Delta cells secrete somatostatin.
• D1 cells elaborate VIP (vasoactive intestinal peptide).
• Enterochromaffin cells synthesize serotonin.
• F cells secrete pancreatic polypeptide.

Metabolic Actions of Insulin

• Insulin has anabolic effects, promoting synthesis and growth.
• Insulin promotes glucose deposition into fat through lipogenesis (lipid synthesis).
• Insulin promotes glucose deposition into the liver through glycogen and lipid synthesis.
• Insulin promotes glucose deposition into muscle through glycogen and protein synthesis.
• Insulin has catabolic effects, which degrades glycogen, proteins, and lipids.
• In adipose tissue, catabolic effects lead to lipolysis, breaking down into fatty acids.
• In the liver, glycogenolysis increases glucose, and gluconeogenesis (glucose synthesis) occurs from amino acids.
• Conversion of fatty acids to ketone bodies is a part of insulin's catabolic effect in the liver.
• Initiated by food, GI Incretins increase GIP/GLP-1, which leads to an increased incretin effect .
• This incretin effect increases insulin and decreases glucagon to decrease gastric emptying and result in satiety.

Diabetes Mellitus

• A group of disorders characterized by hyperglycemia.
• Hyperglycemia is due to defects in insulin secretion, defects in insulin action, or both.
• Type I diabetes accounts for 5-10% of cases and involves autoimmune destruction of beta cells.
• Type II diabetes accounts for 90-95% of cases and involves peripheral resistance and insulin dysregulation.
• Diabetes may arise from genetic beta-cell or insulin action disorders, pancreatic destruction, endocrinopathies, infections, certain drugs, and various genetic syndromes.
• Maturity-onset diabetes of the young (MODY) is caused by mutations in factors like hepatocyte nuclear factor 4α (HNF4A) (MODY1) and glucokinase (GCK) (MODY2).
• Neonatal diabetes can be caused by activating mutations in KCNJ11 and ABCC8, encoding Kir6.2 and SUR1.
• Maternally inherited diabetes and deafness (MIDD) is due to mitochondrial DNA mutations (m.3243A→G).
• Genetic defects can also occur in insulin action, such as type A insulin resistance and lipoatrophic diabetes.
• Exocrine pancreatic defects, like chronic pancreatitis and cystic fibrosis, can cause diabetes.
• Endocrinopathies, such as Acromegaly and Cushing syndrome, can lead to Diabetes Mellitus.
• Infections such as Cytomegalovirus and Coxsackie B virus can also lead to Diabetes Mellitus.

Type 1 Diabetes Pathogenesis

• Mechanisms of beta-cell destruction involves major linkage to MHC class II genes, T-cell dysfunction, and predisposing environmental events like viral damage.
• Autoimmune Beta cell injury occurs, where there is an increased risk for type I diabetes, and autoimmune disturbance is present.
• First the stage is normoglycemic/presymptomatic, and <50% progress to DM in 5 years.
• Second the stage is dysglycemic/presymptomatic, and a loss of glucose tolerance occurs.
• The third stage the individual experiences insulin-lack (after years of elapse), and has progressed to a state of diabetes.

Type 2 Diabetes Pathogenesis

• Mechanisms of beta-cell dysfunction involves there is linkages to diabetogenic and obesity-related genes.
• There is individuals at risk for type II which is a major correlation with obesity.
• Adipokines are upregulated and free fatty acids (FFAs) are released.
• Promotes chronic inflammation in fat, inducing insulin resistance.
• Beta cells compensate by hypersecretion of insulin.
• This leads to Beta-cell failure and the individual progresses into diabetes.

Biochemical Basis of Diabetes Mellitus

• The biochemical basis of the diabetic classic clinical triad of P's is insulin deficiency and/or insulin resistance.
• A catabolic state is entered, where breakdowns of proteins, fat, and glycogen.
• This leads to hyperglycemia, which leads to volume depletion and osmotic diuresis.
• This causes polyphagia (increased hunger), polydipsia (increased thirst), and polyuria (increased urination).

Nonenzymatic Advanced Glycation End Products

• Nonenzymatic advanced glycation end products are accelerated by hyperglycemia.
• This involves glycated extracellular matrix proteins, leading to atherosclerosis and endothelial cell injury.
• There is excess BM material, reactive oxygen species, and procoagulant activity in the presence of glycated intracellular proteins.
• There is a proliferation of vascular smooth muscle cells, creating advanced glycation end products (AGE).

Long-term Diabetes

• Decreased insulin leads to lipolysis and DAG synthesis, activating PKC and recruiting/activating VEGF and TGF-β, leading to deposition of BM and microangiopathy.
• Intracellular hyperglycemia in cells not requiring insulin causes decreased GSH and increased ROS with sorbitol accumulation, potentially leading to cataracts and neuropathy also referred to as Neuronal Oxidant Injury.

Summary of Diabetic Complications:

• Pancreatic islets exhibit insulitis vs amyloid.
• Vasculopathy includes myocardial infarction (MI), cerebrovascular accident (CVA), gangrene, and hemorrhage.
• Nephropathy is characterized by ischemic and nodular glomerulosclerosis (GS).
• Ocular complications include retinopathy, cataracts, and glaucoma.
• Neuropathy affects motor and sensory functions, including autonomic neuropathy.

Autoimmune Insulitis

• Autoimmune insulitis, a feature of IDDM (Type I Diabetes), is associated with circulating antibodies to pancreatic beta cells.

Diabetic Vascular Complications

• Macrovascular disease involves endothelial dysfunction, hyaline arteriolosclerosis, and accelerated atherosclerosis.
• Microangiopathy is associated with basement membrane thickening and vascular walls that are more leaky to plasma proteins.
• Atherosclerosis of the aorta, coronary and peripheral arteries, as well as hyalinization of renal arterioles can occur.
• Narrowing of vascular lumens can result in gangrene, myocardial infarction, stroke, and ischemic nephropathy.
• Diabetic microangiopathy is PKC/AGE-related.

Kidney Complications

• Diffuse mesangial sclerosis and nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) are virtually diagnostic of diabetes.
• Other possible kidney lesions include mesangiolysis, capillary microaneurysms, accumulations of hyaline material, fat lipophages in glomerulus, and glycogen deposits.
• Acute and chronic pyelonephritis can occur due to repeated episodes of ascending urinary tract infection.

Eye Lesions

• Nonproliferative retinopathy, the vessels have microaneurysms and small hemorrhages.
• Proliferative retinopathy rises due to hypoxia-induced VEGF expression and causes neovascularization, fibrosis, and thickened fibrotic detached retina.
• Cataracts and glaucoma are also eye lesions associated with Diabetes Mellitus.

Nervous System Complications

• Ischemia and polyol pathways have different mechanisms that result in the following compilations
• Myelin and neuronal degeneration occurs.
• Peripheral nerves experience innervation disturbances and peripheral neuropathy.
• Motor and sensory losses can occur in the peripheral nervous system.
• The brain can be ischemic/hemorrhagic, resulting in infarcts and hemorrhages.

Mechanisms of Nervous System Damage

• In the polyol pathway, increased cellular glucose is converted to sorbitol via aldose reductase.
• Sorbitol is then converted to fructose, requiring NADPH, which is also needed for glutathione reductase.
• Decreased GSH leads to increased ROS, causing neuronal oxidant injury.

Causes of Death in Diabetic Patients

• Myocardial infarction is the most common cause of death in diabetic patients.
• Other causes include renal failure, cerebrovascular accident (CVA), ischemic heart disease, infection, coma, lipolysis, and osmotic diuresis.

Neuroendocrine Pancreatic Neoplasms

• Insulinoma arises from beta cell tumors.
• Gastrinoma arises from cells in the gut or pancreas.
• Glucagonoma arises from alpha-cell tumors.
• VIPoma arises from D1 cell tumors (WDHA syndrome).
• Carcinoid arises from Enterochromaffin cell tumors (synthesize serotonin).
• MEN (Multiple Endocrine Neoplasia) affects the pancreas, adrenal medulla, thyroid medullary, and parathyroid tumors.

Insulinoma

• Insulinoma, typically benign, is characterized by Whipple's triad.
• Spontaneous hypoglycemia (less than 50 mg/dL).
• Confusion, stupor, and loss of consciousness.
• Prompt relief by glucose administration.
• Histologically shows that Insulinoma has amyloid presence

Gastrinoma

• Physiologic effects of gastrin includes increasing of acid seretion, increasing gastric mucosal blood flow, and stimulating gastric mucosal growth.
• Gastrinoma may arise in the duodenum, peripancreatic soft tissues, and pancreas leading to gastric hyperacidity, multiple peptic ulcers and diarreah.
• Pathologic effects cause zollinger-ellison Syndrome, in which there is high release of calcitonin, a marked hyperacidis, mucosal hypertrophy, release of insulin, steatorrhea, and hyper stimulation of water and electrolyte secretion.
• A secretin challenge test, which typically shows a paradoxical rise of gastrin secretion, can diagnose high gastrin levels caused by Gastrinoma.

Glucagonoma

• Glucagonoma is typically malignant.
• Glucagonoma can cause migratory epidermolytic erythema and hyperglycemia.

MEN (Multiple Endocrine Neoplasia)

• MEN I (Wermer syndrome) involves pancreatic adenomas (ZE syndrome) can occur which causes Parathyroid hyperplasia.
• MEN II A (Sipple syndrome) causes Pheochromocytoma, and Medullary thyroid CA
• MEN II B is the same as in IIA and causes ganglioneuromas and marfanoid.

Explore the complexities of diabetes mellitus, pancreatic endocrine function, and associated pathologies. Understand the roles of insulin, glucose metabolism, and the mechanisms leading to conditions like ketoacidosis. Investigate the features that distinguish benign from malignant pancreatic tumors.