Pancreas Hormones: Glucagon, Insulin & Diabetes

Learning Objectives for Pancreas - Part 2

• Understand the synthesis and secretion of glucagon hormone.
• Describe glucagon's physiological actions and its net effect on glucose metabolism.
• Understand glucose homeostasis involving insulin and counterregulatory hormones in target tissues.
• Define diabetes mellitus type I and II.
• Correlate diabetes mellitus clinical signs with the action mechanism of insulin in target tissues.
• List the main functions of pancreatic somatostatin and polypeptide.

Endocrine Pancreas: Islets of Langerhans

• Acini perform exocrine functions.
• Alpha cells secrete glucagon.
• Beta cells secrete insulin.
• Delta cells secrete somatostatin.
• F cells secrete pancreatic polypeptide.

Glucagon Hormone

• Glucagon is a polypeptide hormone produced by pancreatic alpha cells.
• Glucagon has an antagonistic relationship with insulin.
• Glucagon is synthesized from preprohormone to prohormone, and then to the hormone.
• Glucagon has a similar structure and function between species.
• The endogenous clearance half-life of glucagon is 5-7 minutes.

Glucagon: Synthesis and Secretion

• Glucagon synthesis and secretion is stimulated by decreased glucose concentration in the blood plasma.
• Glucagon secretion occurs when glucose levels decline below a hypoglycemia threshold, and this threshold differs between species.

Glucagon: Secretion Mechanism

• Glucose enters cells via the GLUT 1 transporter.
• Glucose is used to generate ATP.
• Low glucose results in low intracellular ATP.
• Low ATP levels cause ATP-sensitive potassium channels to close.
• Reduced potassium efflux changes the cell membrane voltage.
• Voltage-dependent Ca2+ channels open.
• Influx of Ca2+ triggers glucagon exocytosis.

Glucagon: Mechanism of Action

• The glucagon receptor is a GPCR (G protein-coupled receptor).
• Glucagon binds to the liver cell membrane receptor.
• The G-protein is activated.
• Adenylyl cyclase converts ATP to cAMP.
• cAMP activates PKA (protein kinase A).
• PKA phosphorylates several enzymes.

Glucagon: Actions

• The physiological actions of glucagon are opposite to those of insulin
• The main effect is centered in the liver and adipose tissue, which enhances the availability of glucose to other organs.
• Effects include decreased glycolysis, increased glycogenolysis and gluconeogenesis in glucose metabolism
• Effects include increased lipolysis TAG → FFA + Glycerol and ketogenesis in lipid metabolism
• Effects include increased ureagenesis and hepatic amino acid uptake in protein metabolism.

Glucose Homeostasis: Summary

• During the cephalic phase of digestion, when glucose levels are above 110 mg/dL, insulin is released.
• Carbohydrates become the primary energy source, and excess glucose is stored as glycogen and fat.
• When glucose levels fall below 60 mg/dL, glucagon and epinephrine are released.
• If reduced glucose intake persists, the body uses fatty acids as a primary energy source, except for the brain.
• Cortisol and GH release increases gluconeogenesis (glycerol, AA, lactate).

Insulin Counterregulatory Hormones

• These are hormones that oppose insulin's action to prevent hypoglycemia.
• Glucagon and epinephrine/norepinephrine have acute responses
• Cortisol and growth hormone (GH) have chronic responses.

Insulin Deficiency

• A lack or deficiency of insulin causes diabetes mellitus.
• Diabetes from the Greek = "Siphon - to pass through".
• Mellitus from Latin = "sweet."
• Insulin deficiency can be absolute (Type 1 diabetes) or relative (Type 2 diabetes).

Diabetes Mellitus Type I

• Characterized by permanent hypoinsulinemia.
• There is an absolute deficiency (no increase in endogenous insulin after stimulation).
• Patients are insulin-dependent to maintain control of glycemia and to avoid ketoacidosis.
• It is common in dogs (95% of cases).
• Risk factors include auto-immune disease, obesity, genetics, and pancreatitis.

Diabetes Mellitus: Hyperglycemia

• Insulin deficiency causes an increase in blood glucose.
• Insulin-dependent glucose uptake is compromised in tissues such as muscle and adipose tissue (GLUT 4).

Diabetes Mellitus: PPP

• Common findings in uncontrolled diabetic dogs with hyperglycemic state.
• The "PPP" symptoms include polyuria, polydipsia, and polyphagia (increased hunger).

Hyperglycemic State: PUPD and Glycosuria

• Insulin deficiency leads to increased blood glucose levels, causing hyperglycemia.
• When hyperglycemia surpasses the renal tubular threshold, glycosuria occurs.
• Glycosuria leads to osmotic diuresis, causing polyuria.
• Polyuria then triggers compensatory polydipsia.
• Renal tubular reabsorption thresholds for glucose (FYI):
  • Dogs: 180-200 mg/dL
  • Cats: 280-290 mg/dL (diabetic cats ≈ 200 mg/dL)
  • Horses: 160-180 mg/dL
  • Cattle: 100-140 mg/dL

Diabetes Mellitus: Weight Loss

• Protein catabolism increases, while protein synthesis is severely reduced.
• Lipolysis increases.

Diabetes Mellitus: Effects on Adipocytes

• Without insulin, there is no translocation of GLUT 4, so the cell cannot uptake glucose, and it is "starving".

Diabetes Mellitus: Weight Loss

• Insulin deficiency causes lipolysis of stored fat, releasing FFA + glycerol.
• Hormone-Sensitive-Lipase (HSL) is strongly activated by glucagon.
• Hydrolysis of triglycerides releases large amounts of FFAs and glycerol into the blood.
• FFAs are used as a source of energy in the absence of glucose, except in the brain.
• Ketone bodies synthesis increases, which can lead to ketoacidosis.
• Excess FFA is converted into phospholipids and cholesterol in the liver.
• Triglycerides will form in the liver at the same time, which can lead to non-alcoholic fatty liver disease.
• Lipidemia (an increase in blood lipids) is expected in diabetic patients.

Diabetes Mellitus: What Is Happening?

• Insulin deficiency (absolute or relative) results in compromised glucose transport for muscle and adipose tissue
• Glucagon increases.
• Hyperglycemia results.
• Hepatic gluconeogenesis increases.
• Amino acids and glycerol are released into the blood.
• Protein and fat catabolism occurs.

Diabetes Mellitus: Main Clinical Signs Summary

• Insulin deficiency causes an increase in blood glucose levels -> hyperglycemia.
• Hyperglycemia exceeds the renal tubular threshold, resulting in glycosuria.
• Glycosuria leads to osmotic diuresis > polyuria.
• Polyuria leads to compensatory polydipsia
• The glucose cannot enter the satiety center -> poliphagia
• Weight loss will also occur

Diabetes Mellitus: Cataracts

• It is the most common long-term complication, mostly in dogs.
• Altered osmotic relationship in the lens induced by accumulation of sorbitol and galactitol.
• Aldose reductase reduces glucose → which produces alcohols in the lens.
• Alcohols are potent hydrophilic agents that cause water influx (osmosis) into the lens.
• Fiber swelling and rupture causes opacity.

Diabetes Mellitus Type II

• It's characterized by insulin resistance.
• The RTK pathway becomes less responsive to insulin due to disruptions at different levels.
• Muscle and adipose tissue can't easily take up glucose from the blood, and the liver has impaired biochemical pathways.
• The pancreas makes more insulin to help glucose enter the cells as a result.
• Relative deficiency (beta cell dysfunction)
  • Impaired insulin action in the liver, muscle, and adipose tissue along with beta cell failure (system is overworked).
• It's common in cats (80% of the cases).
• Obesity (metabolic syndrome) and islet amyloidosis are big risk factors.

Islets of Langerhans Amyloidosis

• For diabetes to develop, there must be beta cell dysfunction.
• A healthy beta cell can adapt to obesity and insulin resistance by increasing insulin secretion.
• Amylin (or Islet Amyloid Polypeptide – IAPP) is a polypeptide produced and secreted by beta cells, which increases satiety, decreases gastric emptying, and reduces glucagon production.
• Insulin resistance leads to increased insulin secretion, which in turn stimulates greater amylin secretion.
• Excess amylin can aggregate and form amyloid deposits, contributing to amyloid accumulation in tissues.
• Amylin deposition is toxic to beta cells and leads to beta cell dysfunction.

Diabetes Mellitus Type II

• Clinical remission can occur depending on beta cell dysfunction.
• Irreversible damage: Amyloidosis
• Reversible damage: Glucotoxicity
• Obesity (3.9 X more risk) decreases islet function and leads to amyloidosis/gluctotoxicity.
• Decreased production of insulin from Beta cell also leads to beta cell failure
• Amyloidosis together with or with Reduction action on liver, muscle and fat tissue also result in relative deficiency and absolute deficiency.

Diabetic Neuropathy: Chronic Complication

• Hyperglycemia can lead to nerve injury specifically on Schawnn cells and axons of myelinated fibers and microvascular abnormalities
• Pathogenesis is not completely understood but studies show it is scarce in cats
• Clinical signs can vary from very mild to severe:
  • Limb weakness
  • Difficulty to jump
  • Base narrow gait
  • Ataxia
  • Muscle atrophy in pelvic limbs
  • Plantigrade posture
  • Postural reaction deficits
  • Decreased tendon reflexes
  • Irritability when feet are touched

Pancreatic Somatostatin: Paracrine Regulator

• Produced by delta cells and functions similarly to other protein hormones
• Has Inhibitory actions
• Inhibits secretion of all endocrine cell types of the lslet of Langerhans
• Inhibits the release of glucagon and insulin
• Regulates exocrine and endocrine pancreas
  • Decreases motility and secretory activity of GI tract

Pancreatic Polypeptide

• Produced by F or PP cells.
• Secretion is stimulated by GI hormones, vagal stimulation, and protein ingestion.
• lnhibition occurs through somatostatin
• Has effect on GI tract
  • Decrease gut motility and gastric emptying
  • Inhibit secretion of pancreatic digestive enzymes and the contraction of the gall bladder.