Diabetes Mellitus: Types and Mechanisms

• The pancreas has exocrine (acini and ducts) and endocrine (islets) components.

Origin and Distribution of Pancreatic Endocrine Cells

• Insulin is secreted by beta cells, while glucagon is secreted by alpha cells; both regulate energy metabolism and blood glucose levels.
• Delta cells secrete somatostatin, and F cells secrete pancreatic polypeptide (PP).
• PP cells have a unique pancreatic polypeptide with gastrointestinal effects like stimulating gastric and intestinal enzyme secretion and inhibiting intestinal motility.
• D1 cells produce vasoactive intestinal polypeptide (VIP), a hormone that induces glycogenolysis and hyperglycemia, stimulates gastrointestinal fluid secretion, and causes secretory diarrhea
• Enterochromaffin cells synthesize serotonin, the source of pancreatic tumors causing carcinoid syndrome.
• Immunoperoxidase staining shows dark reaction products for insulin in beta cells, glucagon in alpha cells, and somatostatin in delta cells.
• Electron micrographs show membrane-bound granules with a dense, rectangular core and distinct halo in beta cells.
• Alpha and delta cells also show granules with closely apportioned membranes; alpha-cell granules have a dense, round center.

Diabetes Mellitus

• Diabetes mellitus is a group of disorders characterized by hyperglycemia from defects in insulin secretion, insulin action, or both.
• Insulin increases the rate of glucose transport into certain body cells, providing energy.
• The regulatory and counterregulatory hormones that affect glucose uptake and metabolism include insulin and glucagon.
• Incretins, like glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are involved.
• GIP is secreted by enterochromaffin cells in the proximal small intestine.
• GLP-1 is secreted by cells in the distal ileum and colon.
• Glucagon exacerbates hyperglycemia in the absence of insulin by promoting glycogenolysis and lipolysis.
• Release of glucose from glycogenolysis and free fatty acids from lipolysis promotes ketone formation by the liver, resulting in ketogenesis.

Classification of Diabetes Mellitus

• Diabetes is classified into Type I, Type II, and other categories
• Other:

1. Genetic defect of beta-cell function
2. Genetic defects in insulin action
3. Exocrine pancreatic defects
4. Endocrinopathies
5. Infections
6. Drugs
7. Genetic syndromes associated with diabetes
8. Gestational diabetes mellitus

Type I Diabetes Mellitus (IDDM) Pathogenesis

• Type 1 diabetes involves a genetic predisposition (HLA-DR3 and DR4).
• Some predisposing events, like viral damage/antigen exposure, and autoimmune injury lead to insulin deficiency after years.
• Early stages of type I diabetes show circulating antibodies to pancreatic beta cells detectable by immunofluorescence.

Type II Diabetes Mellitus Pathogenesis

• Type II diabetes involves derangement of insulin secretion and amylin deposits in the islets.
• Insufficient insulin, delayed beta-cell response to glucose, resistance to insulin in peripheral tissues, decreased/defective receptors, and genetics is seen
• It involves post-receptor defects, multiple genetic defects, and environmental factors, but has no HLA linkage.

Type 2 Diabetes Mellitus

• Genetic predisposition and environmental factors cause insulin resistance.
• Compensatory beta-cell hyperplasia maintains normoglycemia.
• Beta-cell secretory dysfunction leads to impaired glucose tolerance and diabetes.
• Primary beta-cell failure can directly lead to type 2 diabetes without insulin resistance.

Long-Term Complications of Diabetes

• Development of long-term complications of diabetes may include various pathogenic pathways
• Formation of advanced glycation end products (AGEs) and release of cytokines and growth factors, such as TGF-beta and VEGF.
• Generation of reactive oxygen species (ROS) in endothelial cells, increased procoagulant activity, and enhanced proliferation of vascular smooth muscle cells.
• PKC activation stimulated by intracellular hyperglycemia, leading to increased VEGF, TGF-beta, and PAI-1, resulting in microangiopathy is seen
• Polyol pathway disturbances cause oxidative stress due to reduced GSH with sorbitol accumulation.
• Hyperglycemia induces glycolytic intermediates, like fructose-6-phosphate, that leads to cell damage and oxidative stress.
• AGEs are formed from nonenzymatic reactions between intracellular glucose-derived precursors and amino groups of intracellular and extracellular proteins, and bind to receptors (RAGE)
• Binding of AGEs to receptors causes deleterious effects, accelerating large vessel injury and microangiopathy.
• Activation of protein kinase C, stimulated by intracellular hyperglycemia, causes neovascularization, vasoconstriction, and deposition of basement membrane material.
• Intracellular hyperglycemia occurs in cells not requiring insulin, causing reduction in GSH, increasing susceptibility to oxidative stress

Pathological Abnormalities Associated with Diabetes Mellitus

• Organ and tissue injuries include small vessels, arteries and arterioles, pancreas, kidneys, eyes, nervous system, skin, and leukocytes.
• Vascular abnormalities cause ischemic necrosis and tissue infarction.
• Basement membranes of small vessels thicken
• Amorphous hyalinization of renal arteriolar walls is caused partly by extravasation of plasma proteins through injured endothelium and increased deposition of basement membrane matrix
• Pancreatic abnormalities include reduction in size and number of islets, beta-cell degranulation, and autoimmune insulitis (IDDM).
• Hyaline (amyloid-like/amylin) replacement of islets is seen in long-standing NIDDM.
• Kidney pathologies are:

1. Diffuse glomerulosclerosis
2. Nodular glomerulosclerosis
3. Exudative lesions involving caps a fibrin cap, or a capsular drop

• Additionally there will be renal vascular lesions, pyelonephritis & necrotizing papillitis, Glycogen accumulation, and Fatty change.
• Eye issues will be Retinopathy, Cataracts, and Glaucoma
• Nervous system issues will be neuronal degradation, peripheral nerve issues (neuropathy), and brain issues (infarcts or hemorrhages)
• Skin related issues include lesions (necrobiosis lipoidica, erythema nodosum), infections (opportunistic), and xanthomas

Leukocyte Abnormalities

• Decreased Chemotaxis
• Decreased bactericidal activity

Causes of Death

• Myocardial infarction (most common, from early atherosclerosis)
• Renal failure
• Stroke
• Ischemic heart disease
• Infection
• Ketoacidosis and severe volume depletion which leads to coma
• Absolute insulin deficiency leads to a catabolic state causing Ketoacidosis and severe volume depletion; which can lead to coma and eventual death

Pancreatic Endocrine Neoplasms

• Insulinoma
• Gastrinoma
• VIPoma (Verner-Morrison syndrome)
• Glucagonoma
• Carcinoid
• MEN
• Spontaneous hypoglycemia occurs
• Glucose administration may lead to promp relief

Insulinoma

• Benign or in rare occasions Malignant mass or hyperplasia in that proliferates with abundant amyloid deposition

Gastrinoma (Zollinger-Ellison Syndrome)

• High levels of gastrin are observed in the blood
• Secretin challenge test may be helpful in the differential diagnosis.
• Gastrin-producing tumors are locally invasive or have already metastasized at the time of diagnosis in over half the diagnosed cases

VIPoma (pancreatic cholera - WDHA)

• Watery diarrhea is observed
• Hypokalemia, achlorhydria, and acidosis
• The disease may be invasive

Glucagonoma

• Severe hyperglycemia
• Spreading erythematous skin eruption
• Migratory necrotizing epidermolytic erythema
• Malignant and causes weight loss and anemia

NE or CARCINOID TUMORS

• The tumors may low malig potential but are active → atypical carcinoid syndrome
• Common hormones are

1. 5-OH tryptophan
2. 5-OH tryptamine (serotonin): urinary 5-HIAA
3. histamine: urinary tele-methylimidazoleacetic acid (MelmAA).

Tumors by intestine

• Tumors of the small intestine are usually malignant & active: 5-OH tryptamine (serotonin)
• Tumors of the appenix are common, usually inactive & benign
• Tumors of the large intestine are usually inactive & low malignant potential

CARCINOID SYNDROME

• cutaneous flushing
• cyanosis
• diarrhea with watery stools
• broncho constrictive episodes - asthma
• hypotension
• tachycardia – palpitations
• Cardiac murmurs: tricuspid & pulmonic stenosis

Explore the classifications, causes, and hormonal influences of Diabetes Mellitus. Understand Type I diabetes, glucagon's role, and immunological evidence. Learn about Type II diabetes, insulin resistance, and the impact of PKC activation.