Endocrine Pancreas and Hormone Functions

Endocrine Pancreas

• The endocrine pancreas is the hormone-producing portion of the pancreas.
• It contains millions of islets (Islets of Langerhans) within the pancreatic tissue.
• Beta cells are the most abundant cell type in the islets. They produce and release insulin.
• Alpha cells are centrally located and produce and secrete glucagon.
• Delta cells produce somatostatin.
• Alpha/delta cells are located in the outer islets.

Pancreatic Islets

• Islets of Langerhans are clusters of endocrine cells in the pancreas.
• They are responsible for hormone secretion.
• Beta cells produce insulin.
• Alpha cells produce glucagon.
• Delta cells produce somatostatin.
• Pancreatic islets are important for blood glucose regulation.

Insulin

• Insulin is a protein hormone, primarily produced by beta cells.
• Insulin is synthesized as preproinsulin.
• It undergoes sequential processing: preproinsulin → proinsulin → insulin (and C-peptide).
• The processed insulin is packaged into secretory granules within the beta cells.
• Insulin and C-peptide are packaged into granules and released in response to stimuli.

Insulin Structure

• Insulin has an alpha chain and a beta chain.
• Disulfide bonds link the chains.
• C-peptide is a connecting peptide between the alpha and beta chains.
• These structures enable proper insulin function.

Insulin Release

• Insulin release is stimulated by glucose and amino acids in the blood.
• Glucose enters beta cells via GLUT-2.
• Glucokinase converts glucose to glucose-6-phosphate (G-6-P).
• ATP production closes K+ channels.
• Depolarization opens voltage-gated calcium channels.
• Calcium triggers exocytosis of insulin from granules.
• Glucose and amino acids directly regulate insulin output.
• Epinephrine inhibits insulin release through beta-2 and alpha-2 receptors.

Glucokinase

• Glucokinase is an enzyme involved in glucose metabolism.
• It is found in beta cells, liver, and pancreas.
• Its activity is increased by insulin.
• It is responsible for the initial step in glycolysis.
• High Km (rate varies with glucose) and High Vm (convert lots of glucose) mean the rate varies with glucose concentration but has a high capacity.

GLUT-2 Transporter

• GLUT-2 is a bidirectional glucose transporter.
• It is found in liver, kidney, and beta cells.
• In beta cells, glucose level regulates glucose in/out based on plasma level.
• In liver and kidney, it is involved in gluconeogenesis.

Insulin Receptor

• The insulin receptor is a tetramer composed of two alpha and two beta subunits.
• The alpha subunits are extracellular, and the beta subunits are transmembrane.
• Insulin binding activates tyrosine kinase activity in the receptor.
• IRS proteins (Insulin receptor substrates) mediate downstream effects.
• Insulin binding leads to tyrosine phosphorylation, and the receptor activates other pathways.

PIK3 Pathway

• Intracellular lipid kinases phosphorylate the 3'-hydroxyl group of phospholipids.
• These enzymes generate PIP3 from PIP2.
• This pathway triggers many intracellular processes, including the activation and translocation of GLUT-4 (glucose transporter 4) to the cell membrane.
• This GLUT-4 translocation enables increased glucose uptake by muscle and fat tissue.

GLUT-4 Transporter

• GLUT-4 is critical for glucose uptake in muscle and fat cells.
• Insulin stimulates the translocation of GLUT-4 from intracellular vesicles to the cell membrane.
• This process is triggered by the PIK3 pathway.
• Increased glucose uptake is crucial for energy metabolism.

RAS/MAP Kinase Pathway

• Insulin activates the RAS protein, which triggers various growth pathways.
• These pathways include MAP kinase (MEK) and mitogen-activated protein (MAP).
• These pathways primarily regulate cell growth and gene expression.

Insulin Dependent Organs

• Muscle and fat cells mostly depend on insulin for glucose uptake using GLUT-4 transporters.

Insulin Independent Organs

• Brain and red blood cells (RBCs) use GLUT-1 for glucose uptake.
• These cells don't rely on insulin to absorb glucose.

Insulin Effects

• Insulin promotes glycogen synthesis, inhibiting gluconeogenesis.
• It also stimulates fatty acid synthesis and protein synthesis.
• Insulin regulates the activity of enzymes involved in these processes.

Hormone Sensitive Lipase

• Hormone-sensitive lipase removes fatty acids from triacylglycerols in adipocytes.
• Its activity is inhibited by insulin and activated by glucagon and epinephrine.

Glucagon

• Glucagon is a single polypeptide chain protein hormone synthesized from alpha cells.
• Glucagon opposes the effects of insulin.
• Primarily released in response to low plasma glucose levels.
• It stimulates glycogen breakdown in the liver, increasing blood glucose levels.

Glucagon Receptor

• Glucagon receptors are predominantly found in the liver.
• Glucagon binding activates adenylyl cyclase, increasing cAMP levels.
• This process activates protein kinase A (PKA), triggering downstream effects.
• Many activated processes including glycogen breakdown increase plasma glucose.

Hypoglycemia

• Hypoglycemia is a condition of low blood sugar.
• Treatment for unconscious patients includes IV dextrose or intramuscular glucagon.

Beta Blocker Overdose

• Glucagon is the drug of choice to treat beta-blocker overdose.
• Glucagon activates adenylyl cyclase, potentially raising cAMP, and myocyte calcium, aiding in treatment.

Insulinoma

• Insulinoma is a rare pancreatic islet cell tumor.
• It results in fasting hypoglycemia due to elevated insulin levels.
• Key features include neuroglycopenic symptoms (confusion), and sympathetic activation (palpitations).
• Diagnosis relies on fasting insulin levels.

Fasting Hypoglycemia

• This condition involves low blood glucose levels during periods of fasting.
• Differential diagnosis includes exogenous insulin use or oral hypoglycemics (sulfonylureas).

Glucagonoma

• Glucagonoma is a rare pancreatic tumor.
• It is characterized by excess glucagon secretion.
• Symptoms often include glucose intolerance, diabetes, and a distinctive rash (necrolytic migratory erythema).
• Somatostatin analogs are used in treatment.

MEN Syndromes

• MEN syndromes are rare inherited disorders.
• These disorders are associated with numerous endocrine tumors(e.g. pituitary, parathyroid).
• MEN type 1 typically features tumors in these three glands.
• Mutations of MEN1 tumor suppressor gene cause MEN type 1.

Diabetes

• Diabetes mellitus is a chronic disorder with elevated blood glucose levels.
• It's caused by insufficient insulin production or insufficient response to insulin (insulin resistance).

Diabetes Symptoms

• Symptoms may be absent or develop late (silent killer).
• Classic symptoms include polyuria (frequent urination), polydipsia (increased thirst), and increased blood glucose levels.

Diabetes Terminology

• Diabetes mellitus (sweet): a common disorder causing high blood glucose.
• Diabetes insipidus (lacking flavor): a rare disorder characterized by low ADH levels.

Diabetes Diagnosis

• Diagnosis involves blood glucose level measurements.
• Normal fasting blood glucose is below 100 mg/dL; pre-diabetes is 100-125 mg/dL, and diabetes is above 126 mg/dL.
• HbA1c measures average blood glucose over the past three months.

Hemoglobin A1C

• Hemoglobin A1c (HbA1c) measures glycated hemoglobin.
• It reflects average blood glucose levels during the past three months.
• Higher HbA1c values indicate poor blood sugar control.

Glucose Tolerance Test

• In a glucose tolerance test, an oral glucose solution is given, and blood glucose levels are repeatedly measured afterward.
• Elevated glucose levels indicate potential diabetes, especially gestational diabetes (during pregnancy).

Type 1 Diabetes

• Type 1 diabetes is an autoimmune disorder.
• It's a T-cell mediated destruction of pancreatic beta cells.
• It is associated with specific HLA types (DR3 and DR4), and autoantibodies are common.
• Early manifestations involve symptomatic hyperglycemia.

Type 1 Diabetes Features

• Mostly a childhood disorder, often presenting in children or young adults.
• Characterized by unimpaired glucose uptake (insulin).
• Common presentation includes symptomatic hyperglycemia. This can lead to DKA (diabetic ketoacidosis).

Diabetic Ketoacidosis (DKA)

• DKA is a serious complication of diabetes.
• DKA is typically precipitated by infection or trauma, or if insulin therapy is missed.
• It's more common in type 1 diabetes due to insulin deficiency.
• DKA often features high blood glucose levels, and the body breaks down fat to produce ketone bodies.
• DKA features abdominal pain, nausea, vomiting, and fruity breath (from ketones).

Diabetic Ketoacidosis (DKA) - Clinical Presentation

• Common symptoms of DKA include abdominal pain and nausea/vomiting, dehydration, hyperkalemia, elevated plasma and urine levels of glucose and ketones.
• Symptoms may also include Kussmaul breathing (deep labored breathing), and fruity breath odor.
• This is characterized by low insulin and high epinephrine.

Diabetic Ketoacidosis (DKA) - Pathophysiology

• Low insulin and high epinephrine cause high fatty acid utilization.
• Oxaloacetate levels are depleted, leading to TCA cycle stalls.
• Excess acetyl-CoA formation triggers ketone production.
• High ketone levels lead to metabolic acidosis.

Hypophosphatemia

• Acidosis shifts phosphate to extracellular fluid, causing decreased intracellular phosphate.
• A loss of ATP and muscle weakness are potential complications.

Diabetic Ketoacidosis (DKA) - Clinical Presentation

• DKA may present with arrhythmias (hyperkalemia), cerebral edema, and other complications involving the central nervous system.

Mucormycosis

• Mucormycosis is a fungal infection.
• It mainly starts in the sinuses and spreads to adjacent tissues.
• It's a classic complication associated with high glucose and ketoacidosis conditions (e.g., DKA).

Type 2 Diabetes

• Type 2 diabetes is primarily characterized by insulin resistance.
• Muscle, adipose tissue, and liver cells have decreased responsiveness to insulin.
• This leads to hyperglycemia.
• The pancreas initially compensates by producing more insulin. However, eventual pancreatic failure can lead to reduced insulin secretion.

Type 2 Diabetes - Risk Factors

• Obesity is the primary risk factor.
• Intra-abdominal fat is a greater risk compared to subcutaneous fat.
• Additional factors are a family history of type 2 diabetes, and a genetic predisposition.

Type 2 Diabetes - Insulin Resistance Mechanism

• Insulin resistance's precise cause is unknown.
• Several factors suggest insulin receptor abnormalities, and excess fatty acids.
• These factors may affect the serine-threonine kinases in the insulin receptor pathway.
• TNF-alpha (tumor necrosis factor alpha), produced by adipocytes, can contribute.

Type 2 Diabetes - Histology

• Amyloid deposits, composed primarily of amylin, are a characteristic feature found in pancreatic islets.
• Amylin is secreted by pancreatic beta cells.

Hyperglycemic Hyperosmolar Syndrome (HHS)

• HHS is a serious diabetic complication.
• HHS is primarily observed in patients with type 2 diabetes.
• It's characterized by extremely high blood glucose levels, severe dehydration, in the absence or low levels of ketone bodies.

Hyperglycemic Hyperosmolar Syndrome (HHS) - Features

• Unlike DKA, HHS generally doesn't have significant ketoacidosis.
• It includes dehydration, excessive glucose in the urine (due to high sugar), and altered mental status, ultimately potentially leading to coma.
• Treatment includes close monitoring of hydration and electrolytes, in addition to insulin administration.

Acanthosis Nigricans

• Acanthosis nigricans is characterized by hyperpigmented (dark) plaques of skin in areas of skin folds (e.g., groin, neck).
• It is commonly associated with insulin resistance and in some patients, obesity, diabetes, or specific malignancies.

Diabetic Complications

• Chronic hyperglycemia leads to various complications affecting multiple organs and systems.
• Key complications include cardiac disease, renal failure, neuropathy, and blindness.
• Non-enzymatic glycation and sorbitol accumulation are two key underlying mechanisms in diabetic complications.

Non-enzymatic Glycation

• Non-enzymatic glycation is the process by which glucose binds to proteins.
• The process doesn't require enzymes; it's driven by high glucose levels.
• This leads to cross-linking of proteins, forming advanced glycosylation end products (AGEs).
• AGEs contribute to various diabetic complications.

Atherosclerosis (Diabetic Macroangiopathy)

• AGEs in large vessels contribute to atherosclerosis.
• This process can lead to narrowing of arteries (e.g., coronary arteries, peripheral arteries).
• Common consequences include coronary artery disease (CAD), stroke, and peripheral vascular disease (PVD).

Diabetic Kidney Disease (Diabetic Microangiopathy)

• AGEs damage glomeruli and arterioles in the kidneys.
• This process leads to end-stage kidney disease in many diabetics.

Renal Arterioles (Hyaline Arteriosclerosis)

• Hyaline arteriosclerosis involves thickening of afferent and efferent arterioles in the kidneys, a common finding in diabetic kidney dysfunction.
• This also occurs in cases of hypertension.
• Thickening results from AGE formation and crosslinking of collagen.

Proteinuria in Diabetics

• Routine screening for albumin in the urine is used in diabetic patients to identify early kidney disease.
• Presence of protein in urine indicates damage to the kidney.
• ACE inhibitors help slow kidney dysfunction progression.

Glomerular Basement Membranes

• AGEs cause diffuse thickening of the glomerular basement membranes.
• The thickening leads to decreased kidney function and associated complications, eventually glomerulosclerosis.

Glomerulosclerosis

• Diffuse glomerulosclerosis involves protein deposits on glomeruli capillary loops, contributing to cell proliferation and decreased kidney function.
• Severe cases can lead to nephrotic syndrome.
• Nodular glomerulosclerosis is a specific type characterized by nodule formation in the periphery of glomeruli.

Kimmelstiel-Wilson Nodules

• Kimmelstiel-Wilson nodules are a characteristic finding of nodular glomerulosclerosis of diabetes.

Sorbitol Accumulation (Polyol Pathway)

• The polyol pathway involves the conversion of glucose into sorbitol then fructose.
• This pathway is important for diabetes.
• Sorbitol accumulation results from chronic hyperglycemia, causing osmotic damage to cells, including those in the lens (causing cataracts) and nerves (causing neuropathy).

Diabetic Retinopathy

• Diabetic retinopathy affects the blood vessels in the retina.
• Complications include microaneurysms, hemorrhages, leakage, exudates, and changes in pericytes.
• Severe retinopathy can lead to vision loss.

Type 1 vs Type 2 Diabetes - Comparison

• Type 1 diabetes involves a loss of insulin production, while type 2 diabetes features insulin resistance.
• Treatment and risk factors differ in each type.

Insulin

• Many types of insulin exist targeting various needs, differing in onset, peak, and duration of action.

Insulin Analogs

• Various modified insulin structures exist.
• Insulin analogs are used for different treatment approaches (e.g., faster or longer duration).

Hypoglycemia

• Hypoglycemia is a serious side effect of insulin therapy.
• The side effect concerns low blood sugar leading to symptoms like tremors, anxiety, sweating, and even coma.

Weight Gain

• Weight gain is a common side effect associated with insulin therapy.
• This is due to insulin's promotion of fatty acid and protein synthesis.

This quiz covers the structure and function of the endocrine pancreas, focusing on the Islets of Langerhans and their hormone-producing cells. It includes details about insulin, glucagon, and somatostatin, as well as their roles in glucose regulation.