Endocrine Pancreas Physiology

Overall

• Main role is regulation of glucose homeostasis

Glucagon

• Secreted by α cells (20% of cells, lie peripherally)
  • Responds primarily to serum glucose concentration, but in a reciprocal fashion
  • Glucose has a strong suppressive effect on glucagon secretion
• Polypeptide
• Increases BGL through catabolism, stimulation of
  • Glycogenolysis
  • Lipolysis
  • Gluconeogenesis
• Major counter regulatory hormone to insulin
• Considered a stress hormone because it increases metabolic fuel in the form of glucose during stress
• Excess glucagon can lead to hyperglycaemia
• Insufficient glucagon can lead to profound hypoglycaemia
• Dysfunctional secretion of glucagon may play a role in the elevation of BGL in diabetes

Insulin

• Anabolic hormone synthesized in β cells of islets (70% of cells, lie centrally)
• Promotes glucose transport into all cells
  • Except β cells, hepatocytes, and CNS
  • Increased glucose, fatty acid, and amino acid storage
• 56–amino acid polypeptide
• T1/2: 7-10 mins
• Synthesized as precursor proinsulin, in response to glucose
  • Cleaved into insulin and C peptide (equal amounts of each)
  • Insulin moved into secretory granules
    • Released via exocytosis directly into blood stream
• β cell highly sensitive to increases in glucose concentration
  • Immediately reacts with a short burst of stored insulin (4 to 6 minutes)
  • Followed by sustained secretion of insulin
• Requires active synthesis within the islet cell
• Primarily metabolized by the liver
• Brain cells and RBCs do not take up insulin
• Insulin binds to a specific insulin receptor
• Actively transported across cell membranes throughout the body
• Several classes of glucose transporters, with varying affinities for glucose
• Insulin resistance (in T2DM) can be the result of
  • Decreased numbers of receptors
  • or a decreased affinity of receptors for insulin
• Sulfonylureas stimulate insulin secretion, are used in T2DM insulin resistance

Other Influences on Glucose Metabolism

• Enteric hormones released from the proximal gastrointestinal tract also influence glucose homeostasis

• Reason why PO administered glucose has a greater effect on insulin secretion than an equivalent IV

• Incretins, act directly on the β cells to stimulate insulin release

  • Examples of Incretins: Gastric inhibitory polypeptide (GIP), Glucagon, Glucagon-like peptide-1 (GLP-1), Cholecystokinin (CCK), some amino acids, and free fatty acids

• Humoral inhibitors of insulin secretion include Somatostatin, Amylin, Leptin, and Pancreastatin

• Ghrelin (hormone produced by ghrelin cells)

  • Inhibits insulin release from the pancreas
  • Increases hepatic glucose production
  • Prevents glucose disposal in muscle and adipose tissues
  • Leads to hyperglycaemia and impaired glucose tolerance
  • In diet-induced obesity, ghrelin exacerbates hyperglycaemia
  • In starvation or severe calorie restriction, ghrelin increases blood glucose concentrations to maintain glucose homeostasis

• Leptin (produced in adipose cells)

  • Feedback mechanism signals to inhibit food intake and to regulate body weight
  • In response to adequate fat stores, leptin inhibits insulin secretion
  • In obese humans, leptin levels are increased, exacerbating hyperglycaemia
  • Leptin resistance is thought to exist in the obese state, with lack of inhibition of food intake
  • Insulin and glucagon secretion are also under neuronal control
  • Vagal (cholinergic) stimulation leads to the release of insulin
  • α-sympathetic stimulation strongly inhibits insulin release
  • β-sympathetic fibres stimulate it

Somatostatin

• 14–amino acid polypeptide secreted by δ (Delta) cells (5-10%, lie intermediate)
• Inhibits GI hormones
  • Insulin
  • Glucagon
  • Pancreatic Polypeptide
• Gastric, pancreatic, and biliary secretions
• Controversy as to whether endogenous somatostatin influences the secretion of other islet hormones directly
• Synthetic octapeptides mimic the pharmacologic action of somatostatin
• Have a longer T1/2 than endogenous somatostatin
• More potent inhibitors of growth hormone, glucagon, and insulin secretion
• Used to treat exocrine and endocrine disorders of the pancreas, including secretory diarrhoea, bowel fistulas, pancreatic fistulas, and endocrine hypersecretory syndromes

Pancreatic Polypeptide

• 36–amino acid polypeptide secreted by F cells (1-2%, lie peripherally)
  • From islets in HOP from ventral bud
• Belongs to YY/neuropeptide Y family.
• Causes loss of appetite and reduced food intake
• Inhibits exocrine pancreas & biliary emptying
• Physiologic role is unclear
• Clinical usefulness is limited to role as a marker for other endocrine tumours of the pancreas
• Secretion regulated by cholinergic innervation
• Surgical vagotomy ablates the increased PP response normally observed after meals
• In diabetes and normal aging, PP secretion is increased
• Absence of PP may play a role in diabetes observed after total pancreatectomy or after chronic atrophic pancreatitis

Vasoactive Intestinal Peptide (VIP)

• 28–amino acid
• Actions – stimulates cAMP
  • Stimulates GI epithelial secretion and absorption
  • Can cause voluminous watery diarrhoea
  • Promotes fluid and bicarbonate secretion from bile duct cholangiocytes
  • A potent relaxer of smooth muscle
    • Incl. LES and colon
  • Causes vasodilation
  • Increases the growth of certain adenocarcinomas
  • Stimulates insulin release
  • Important neurotransmitter
• Found throughout GI Tract
• And also in the respiratory tract
• Vasodilation and bronchodilation

Gastrin

• Produced by G cells
  • NB: NOT normally present in Pancreas islet cells
• Only present when have developed a tumor
• Located in the Gastrinoma triangle
• Stimulates gastric acid secretion
• Inhibited by Secretin

Gastrinoma Triangle

• 90% of gastrinomas found in this location
• Junction of the Cystic and Common Bile Duct
• Junction of the D2 and D3
• Junction of the Body and Neck of Pancreas

Other Hormones

• Serotonin
• MSH
• Chorionic gonadotropin
• Kinins