Endocrine Pancreas

• Pancreatic Islets


  The pancreas is a flattened organ located posterior and slightly inferior to the stomach, it can be classified as both endocrine and exocrine gland
• Pancreas


  • Organ (5 inches) consists of head, body & tail
  • Cells (99%) in acini produce digestive enzymes
  • Endocrine cells in pancreatic islets produce hormones
• Cell Organisation in Pancreas

  1. Exocrine acinar cells surround a small duct

  2. Endocrine cells secrete near a capillary
• Pancreatic Islets


  1. 2 million pancreatic islets per human pancreas (1-2% of weight)
• Cell Types in Pancreatic Islets

  • Alpha Cells (20%) produce glucagon
  • Beta Cells (70%) produce insulin and amylin
  • Delta Cells (5%) produce somatostatin
  • PP Cells produce pancreatic polypeptide
• Human pancreas contains 8 mg of insulin – secreted 0.5 – 1 mg per day
• Insulin rapidly destroyed by liver and kidney (t½ in circulation about 6 minutes)
• Regulation of Blood Glucose

  1. When blood glucose increases, pancreas secretes insulin to bring glucose back to normal levels

  2. Glucose enters b-cells via GLUT2 glucose transporter

  3. ATP synthesis increases

  4. ATP sensitive potassium channels close

  5. Insulin is released

  6. Insulin reduces blood glucose

  7. When blood glucose is low, pancreas secretes glucagon to maintain the levels constant, glucagon increases blood glucose
• Primary Targets for Insulin Action

  • Liver
  • Skeletal muscle
  • Adipose tissue
  • Pancreatic alpha cells (to inhibit glucagon release)
• Skeletal muscle and fat dependant on insulin for glucose uptake
• Insulin Promoting + Counter Regulatory Hormones

  • Glucogon Like Peptide 1 (GLP-1) and Glucose Dependant Insulinotropic Peptide (GIP), from GI tract, increase prandial insulin release (=Incretin effect)
  • Amylin inhibits hepatic gluconeogenesis
  • Glucagon, catecholamines, glucocorticoids & growth hormone oppose insulin action
• Regulation of glucagon and insulin secretion is via negative feedback mechanisms
• Low blood glucose stimulates release of glucagon
• High blood glucose stimulates secretion of insulin
• Insulin


  • Gene on chromosome 11 in humans
  • Human gene isolated and used to make human insulin from bacteria
  • Insulin contains 2 chains. A chain 21 amino acids and B chain 30 amino acids. Only one amino acid different between pig & man.
• Synthesis of Insulin


  1. Insulin synthesised in RER of ß islet cells as preproinsulin

  2. 23 amino acids removed to form proinsulin in RER

  3. In Golgi apparatus proinsulin packed into vesicles where it is cleaved into insulin & C peptide

  4. Released by exocytosis when high blood sugar present in blood.
• Insulin


  • Hormone of abundance (anabolic hormone)
  • Stimulated uptake of glucose in insulin-sensitive tissue like skeletal muscle and fat (via GLUT4 glucose transporter)
  • Stimulated glycogen synthesis
  • Stimulated lipid synthesis
  • Stimulated protein synthesis
  • Stimulated DNA/RNA synthesis
  • Stimulated glycolysis
• Amylin


  • 37 amino acid protein
  • Co-released with insulin
  • Actions in CNS
  • Inhibits glucagon release
  • Slows gastric emptying
  • Decreases food intake
  • Cleared by kidneys (t½ in circulation about 10 minutes)
• Glucagon


  • Fasting hormone & hormone of energy release (catabolic)
  • Secreted by α islet cells
  • 29 amino acid linear polypeptide
  • Synthesized as preproglucagon
  • Degraded by liver and kidneys (t½ in circulation about 6 minutes)
  • Increases glycogen breakdown in liver
  • Lipolytic action
  • Increases ketone body formation by liver
  • Increases gluconeogenesis in liver
• Diabetes


  • Diabetes insipidus (posterior pituitary disease)
  • Diabetes mellitus (pancreas disease)
• Diabetes Mellitus


  • Polyuria (increase urine volume)
  • Polydipsia (increase drinking)
  • Polyphagia (increased appetite)
  • Hyperglycaemia (raised blood sugar)
  • Glycosuria (glucose in urine)
  • Ketosis (ketone bodies in blood & urine)
  • Acidosis (excess acid in blood)
  • Rapid weight loss
  • Weakness, dowsiness, fatigue
  • Skin & visual problems
  • Coma
  • Due to absolute (type 1) or relative (type 2) lack of insulin
• Test for Diabetes Mellitus

  • Urine glucose stick test – if positive do further tests
  • Random plasma glucose > 11.1 mM
  • Fasting plasma glucose > 7 mM, if between 6.1-6.9 mM, impaired fasting glucose
  • Oral glucose tolerance test (OGTT) – 2h after 75g oral glucose load, if > 11.1 mM diabetic, if between 7.8-11 mM, impaired glucose
  • HbA1c > 6.5%
• Monitoring Diabetes


  • Measure blood glucose levels before meals either via hospital lab or blood glucose meter (immediate level). Urine glucose rarely used.
  • Measure glycated haemoglobin HbA1C indication average over about 8-12 weeks (normal <6%)
  • Plasma fructosamine (glycation of plasma proteins) shorter time than HbA1C (approx. 2-3 weeks)
  • Other tests for kidney damage, ketosis, serum lipids etc. may be used.
• Causes of Diabetes Mellitus


  • Autoimmune – destruction of B cells (Type 1 DM often)
  • Excess insulin "antagonists" e.g. growth hormone
  • Insulin receptor problems / insulin resistance (Type 2 DM often)
  • Defective insulin release (Type 2 DM often)
  • Abnormal insulin produced
  • Drug & chemical damage
  • Pancreatitis
  • Problems with glucose transport
• Diabetes Mellitus Short Term


  • Ketosis + acidosis (particularly uncontrolled Type 1 DM)
  • Hyperglycaemia
  • Iatrogenic hypoglycaemia
  • Infections
  • Poor wound healing
• Diabetes Mellitus Long Term


  • Retinopathy & cataracts
  • Neuropathy
  • Nephropathy
  • Circulatory problems including diabetic foot & atherosclerosis
  • Due to various causes such as: hyperglycaemia, high blood pressure, oxidative stress, glycation, sorbitol, protein kinase C activation, poor circulation & inflammation
• Therapy


  • Type 1 – Treat with exogenous insulin and diet control
  • Type 2 – Treat with dietary therapy especially if overweight, drug therapy + diet control, exogenous insulin + diet control
• Anti Diabetic Agents


  • Exogenous insulin preparations - e.g. REGULAR INSULIN, INSULIN LISPRO, INSULIN GLARGINE
  • Inhibitors of glucose absorption ("starch blockers") - -glucosidase inhibitors, e.g. ACARBOSE
  • Enhancers of glucose excretion - gliflozins e.g. DAPAGLIFLOZIN
  • Insulin secretagogues - sulfonylureas e.g. TOLBUTAMIDE + meglitinides (glinides) e.g. REPAGLINIDE
  • Analogues of amylin - e.g. PRAMLINTIDE
  • Glucagon-like peptide 1 (GLP-1), "incretin"-based therapy - GLP-1 agonists** e.g. EXENATIDE, inhibitors of dipeptidyl peptidase-4 (DPP-4)* e.g. SITAGLIPTIN
  • Insulin sensitisers - thiazolidinediones (TZDs) (aka glitazones) e.g. PIOGLITAZONE, biguanides e.g. METFORMIN
• Insulin Therapy


  • Indicated in Type 1 DM + Type 2 DM insufficiently responsive to diet and oral hypoglycaemic agents
  • Administered by subcutaneous injection
  • Typically, basal preparation to provide constant, low-level, background insulin throughout day/night + prandial bolus preparation before meals
  • Regimen (e.g. insulin preparation, dose, frequency) personalised and adjusted for e.g. patient's activity, meals, blood glycaemia
• Sulphonylureas


  • Insulin secretagogues, i.e. stimulate islet ß cells to release insulin (in glucose-independent manner)
  • e.g. tolbutamide, glibenclamide, glimepiride
  • Bind to SUR1 subunit on ATP-dependent potassium (KATP) channel, thus blocking channel leading to depolaristion and stimulating (glucose-independent) insulin release
  • Main side effects e.g.: raised insulin levels, hypoglycaemia (especially in elderly), weight gain, appetite stimulation, GI upset, skin rash, blood dyscrasias
• Meglitinides (Glinides)


  • Insulin secretagogues, i.e. stimulate islet ß cells to release insulin (in glucose-independent manner)
  • e.g. nateglinide, repaglinide
  • Similar site and mechanism of action as sulphonylureas, but more selective for ß cell KATP channels
  • Rapid onset and offset kinetics with short duration of action
  • Less potent than sulphonylureas
  • Reduce postprandial hyperglycaemia
  • Usually administered before main meal
  • Similar main side effect profile as for sulphonylureas, but lower risk of hypoglycaemia and weight gain
• Biguanides


  • Insulin sensitisers and inhibitors of hepatic glucose production
  • Activates adenosine 5'-monophosphate-activated protein kinase (AMPK)
  • Decrease glucose absorption from gut
  • Increase insulin receptor activity
  • e.g. metformin
  • No weight gain/some weight loss; reduces insulin levels and appetite; low risk of hypoglycaemia (monotherapy); reduces lipids and glucagon levels
  • Main side effects e.g.: GI upset, lactic acidosis, reduced vitamin B12 absorption
• Starch Blockers


  • Inhibit α-glucosidase enzymes in gut, blocking starch and sucrose breakdown and reducing/delaying glucose absorption from gut
  • E.g. acarbose, voglibose, miglitol
  • No weight gain
  • No hypoglycaemia
  • Reduces postprandial hyperglycaemia
  • Main side effects: GI upset, flatulence, aminotransferase elevation, raised triglycerides
  • Poorly tolerated, but tolerance can develop
• Thiazolidinediones / Glitazones


  • Insulin sensitisers
  • e.g. pioglitazone
  • Stimulate nuclear hormone receptor PPAR- (peroxisome proliferator activated receptor ), with predominant action in muscle
  • Reduce peripheral insulin resistance
  • Low risk of hypoglycaemia; reduces insulin levels, triglycerides and free fatty acids
  • Main side effects e.g.: weight gain, fluid retention, oedema, anaemia, GI upset, headache, fatigue, potential liver toxicity (need to monitor), heart failure, raised LDL cholesterol
• Gliptins


  • Inhibit dipeptidyl peptidase-4 (DPP-4) enzyme
  • "Incretin"-based therapy ("incretin" enhancers) - raise levels of GLP-1
  • e.g. sitagliptin, saxagliptin, vildagliptin, linagliptin
  • Enhance glucose-dependent insulin release, decrease glucagon release + hepatic glucose production, delay gastric emptying
  • Low risk of hypoglycaemia; no weight gain
  • Main side effects e.g.: upper respiratory tract infection, headache, GI upset, nasopharyngitis, raised creatinine levels
• GLP-1 Agonists


  • Analogues of GLP-1 (DPP-4 resistant)
  • "Incretin"-based therapy ("incretin" agonists) - mimics actions of GLP-1
  • e.g. exenatide, liraglutide, lixisenatide, albiglutide
  • Enhance glucose-dependent insulin release, decrease glucagon release + hepatic glucose production, delay gastric emptying
  • Appetite suppression; weight loss
  • Main side effects e.g.: GI disturbances, gastro-oesophageal reflux disease, hypoglycaemia, headache, dizziness
• Gliflozins


  • Sodium glucose-linked transporter-2 (SGLT-2) inhibitors
  • e.g. dapagliflozin, canagliflozin, empagliflozin
  • Prevent proximal tubular reabsorption of filtered glucose from renal filtrate
  • No hypoglycaemia; weight loss
  • Main side effects e.g.: polyuria, dehydration, aggravated glycosuria, genital yeast infection, urinary tract infection