Diabetes Medication Mechanisms Quiz

Endocrine Pancreas, Diabetes Mellitus & Pharmacotherapeutics

• The pancreas is a flattened organ located posterior and slightly inferior to the stomach.
• It functions as both an endocrine and exocrine gland.
• Histologically, it consists of pancreatic islets (Islets of Langerhans) and acini (enzyme-producing exocrine cells).
• The pancreas is approximately 5 inches long and has a head, body, and tail.
• Endocrine cells within pancreatic islets produce hormones.
• Exocrine acinar cells surround a small duct.
• Endocrine cells (e.g alpha, beta, delta, F cells) secrete hormones near a capillary.
• Approximately 1 to 2 million pancreatic islets are present per human pancreas (making up 1-2% of its weight).
• The pancreas contains four types of endocrine cells.

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.
• The human pancreas contains 8 mg of insulin and secretes 0.5 to 1 mg daily.
• Insulin is rapidly destroyed by the liver and kidneys (t½ in circulation: ~6 minutes).

Regulation of Blood Glucose

• When blood glucose increases, the pancreas secretes insulin to lower blood glucose levels.
• Glucose enters beta cells via GLUT2 transporters.
• ATP production increases.
• ATP-sensitive potassium (KATP) channels close.
• Insulin is released.
• Insulin reduces blood glucose.
• When blood glucose is low, the pancreas secretes glucagon to maintain constant blood glucose levels.
• Glucagon increases blood glucose.
• Insulin and glucagon have opposing actions.

Primary Targets for Insulin Action

• Liver
• Skeletal muscle
• Adipose tissue
• Pancreatic alpha cells (to inhibit glucagon release)
• Skeletal muscle and fat cells are dependent on insulin for glucose uptake.

Insulin Promoting and Counter-Regulatory Hormones

• Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), from the GI tract, increase prandial insulin release ("incretin" effect).
• Amylin inhibits hepatic gluconeogenesis.
• Glucagon, catecholamines (e.g., noradrenaline, adrenaline), glucocorticoids (e.g., cortisol) and growth hormone oppose insulin action.

Insulin

• Isolated in 1921 by Banting and Best.
• Sequenced in 1955 by Sanger.
• Gene located on chromosome 11 in humans.
• Made from bacteria.
• Contains two chains: A chain (21 amino acids) and B chain (30 amino acids).
• Only one amino acid differs between pig and human insulin.

Insulin Synthesis

• Synthesized in the rough endoplasmic reticulum (RER) of beta islet cells as preproinsulin.
• 23 amino acids are removed to form proinsulin in the RER.
• In the Golgi apparatus, proinsulin is packaged into vesicles.
• Cleaved into insulin and C peptide within the vesicles.
• Released by exocytosis when blood glucose is high.

Insulin Actions

• Hormone of abundance (anabolic hormone).
• Actions via insulin receptor include:
  • Stimulated glucose uptake in insulin-sensitive tissues (e.g., 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 the central nervous system (CNS).
• Inhibits glucagon release.
• Slows gastric emptying.
• Decreases food intake.
• Cleared by kidneys (t½ in circulation about 10 minutes).

Glucagon

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

Glucose Transporters

• Various glucose transporters (GLUTs) are present.
• GLUT1-12 are in different tissues and perform different roles in glucose uptake and other processes.

Glucose Transport

• Insulin interacts with its receptor, vesicles move to surface and fuse with the plasma membrane.
• Increasing the number of glucose transporters in plasma membrane.
• When insulin levels drop, glucose transporters are removed from plasma membrane.

Pancreas Summary

• The endocrine pancreas mainly produces insulin and glucagon.
• Insulin and glucagon control blood glucose.
• A lack of insulin leads to diabetes mellitus (can be separated into type 1 and 2).
• Diabetes mellitus is treatable with diet, exogenous insulin, and additional hypoglycemic medications (in type 2 diabetes).

Diabetes

• Two diseases: diabetes insipidus (posterior pituitary disease) and diabetes mellitus (pancreas disease).
• Diabetes mellitus first described by Egyptians in 550 BC.
• Diabetes is Greek for siphon (or pass through).
• Mellitus was added meaning honey-sweet in 1700s
• Two major types of diabetes mellitus: Type 1 and Type 2.

Diabetes Mellitus (Signs & Symptoms)

• Polyuria (increased urine volume) & Polydipsia (increased drinking)
• Polyphagia (increased appetite)
• Hyperglycemia (raised blood sugar)
• Glycosuria (glucose in urine)
• Ketosis (ketone bodies in blood & urine)*
• Acidosis (excess acid in blood)
• Rapid weight loss*
• Weakness, drowsiness, fatigue.
• Skin problems,
• Visual problems
• Coma.

Criteria for Diagnosing Diabetes

• Diabetes symptoms plus:
  • A random venous plasma glucose concentration ≥ 11.1 mM or
  • A fasting plasma glucose ≥7 mM or
  • A 2-hour plasma glucose concentration ≥11.1 mM 2 hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT).
• In certain situations where HbA1c testing is appropriate, HbA1c of 48 mmol/mol (6.5%) is recommended as the cut-off point for diagnosing diabetes.

Causes of Diabetes Mellitus

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

Types of Diabetes Mellitus

• Type 1

  • Under 30 years of age.
  • Abrupt onset.
  • Rare.
  • Obesity is uncommon.
  • Polyuria is frequent.
  • Ketoacidosis may be present.
  • Endogenous insulin is negligible.
  • ẞ islet cells are few.
  • All need insulin therapy.
  • Hypoglycemic drugs are not used.
  • All need strict diet control.
  • 10% of diagnosed cases are type 1.
  • Uncommon family history -HLA associated.
  • Seasonal trends generally absent.
  • Β cell loss is possible due to (viral or chemical).
  • Vascular problems include microvascular.
  • The ratio of males to females are similar.

• Type 2

  • Over 40 years of age
  • Gradual onset
  • Common
  • Obesity is common.
  • Polyuria is less frequent.
  • Ketoacidosis less common.
  • Endogenous insulin is present.
  • β islet cells are present.
  • 20-30% need insulin therapy.
  • Hypoglycemic drugs can be used.
  • Diet control is important.
  • Family history may be a factor.
  • Seasonal trends generally not applicable.
  • Increased insulin resistance is an associated factor.
  • Possible causes are (viral or chemical) and insulin resistance.
  • Vascular problems include macrovascular.
  • Ratio of males to females tend to be less as compared to males.

Acute Complications of DM

• Diabetic ketoacidosis (particularly Type 1 DM)
• Hyperglycemia
• Hyperosmolar Hyperglycemic State (HHS) (associated with type 2 DM).
• Iatrogenic hypoglycemia

Chronic Complications of DM

• Retinopathy (eye problems)
• Neuropathy (nerve damage)
• Nephropathy (kidney problems)
• Heart attack & stroke (atherothrombotic problems)
• Diabetic foot (circulatory problems)
• Gum disease (infection & circulatory problems)
• Increased cancer risk (tumorigenesis problems)
• Sexual dysfunction (nervous & circulatory problems)

Diabetes Mellitus Therapy

• Type 1 DM: exogenous insulin + diet control
• Type 2 DM: possible therapies include dietary therapy, drug therapy, and exogenous insulin, or a combination.

Pharmacotherapeutic Management of Diabetes: Classes of Anti-Diabetic Agents

• Exogenous insulin preparations (e.g., regular insulin, lispro, glargine).
• Inhibitors of glucose absorption (“starch blockers”) (e.g., acarbose).
• Enhancers of glucose excretion (e.g., dapagliflozin).
• Insulin secretagogues (e.g., sulfonylureas, meglitinides).
• Glucagon-like peptide 1 (GLP-1), “incretin”-based therapy (e.g., GLP-1 agonists, DPP-4 inhibitors; incl. sitagliptin, saxagliptin, etc)
• Insulin sensitizers (thiazolidinediones, biguanides).

Common Insulin Preparations

• Prandial bolus (short/rapid acting) - regular, lispro, aspart, glulisine
• Basal (intermediate/long acting)- NPH, glargine, detemir.

Insulin Therapy

• Indicated in type 1 and type 2 diabetes insufficiently responsive to diet.
• Administered by subcutaneous injection.

Sulphonylureas

• Insulin secretagogues.
• Examples include tolbutamide, glipizide, and glimepiride.
• Bind to SUR1 subunit to block ATP-dependent potassium channels and stimulate glucose-independent insulin release.
• Side effects: raised insulin levels, hypoglycemia (particularly in elderly), weight gain, appetite stimulation, GI upset, skin rash, and blood dyscrasias.

Meglitinides (Glinides)

• Insulin secretagogues.
• Example, repaglinide.
• Similar site and mechanism of action as sulphonylureas, but more selective for β cell KATP channels.
• Rapid onset and offset.
• Less potent than sulphonylureas.
• Reduce post-prandial hyperglycemia.
• Administered before main meals.
• Similar side effect profile to sulphonylureas but a lower risk of hypoglycemia and weight gain.

Biguanides (e.g. Metformin)

• Insulin sensitiser.
• Inhibitor of hepatic glucose output (predominant action in liver).
• Inhibits gluconeogenesis and glycogenolysis.
• Inhibitor of glucose absorption from gut
• Activates hepatic adenosine 5´-monophosphate (AMP)-activated protein kinase (AMPK)
• Increases insulin receptor activity and reduces insulin resistance
• Enhances insulin effects in target tissues (e.g. muscle, fat, liver).
• Increases insulin dependent glucose uptake (muscle and fat).

Starch Blockers (e.g. Acarbose)

• Inhibit α-glucosidase enzymes in gut.
• Prevent the breakdown of starch and sucrose into glucose in the gut.
• Reduce post-prandial hyperglycemia.
• Side effects: GI upset, flatulence, raised triglycerides, aminotransferase elevation.

Thiazolidinediones (TZDs/Glitazones) (e.g. Pioglitazone)

• Insulin sensitizers.
• Stimulate the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPAR-γ).
• Predominantly act in muscle.
• Reduce peripheral insulin resistance, reduce insulin levels, triglycerides, and free fatty acids.
• Potential side effects include weight gain, fluid retention (oedema), anaemia, GI upset, headache, fatigue, potential liver toxicity (needs monitoring).

DPP-4 Inhibitors (Gliptins)

• Inhibit dipeptidyl peptidase-4 (DPP-4) enzyme
• Incretin enhancers, to elevate GLP-1 level
• Enhance glucose-dependent insulin release, reduce glucagon release + hepatic glucose production, and delay gastric emptying.
• Lower risk of hypoglycemia (monotherapy).
• Main side effects include upper respiratory tract infection, headache, GI upset, nasopharyngitis, raised creatinine levels.

GLP-1 Agonists

• Analogues of GLP-1 (DPP-4 resistant)
• Mimic actions of GLP-1.
• Examples include exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide, tirzepatide.
• Enhance glucose-dependent insulin release, decrease glucagon release, and delay gastric emptying.
• Appetite suppression & weight loss.
• Side effects: include GI disturbances, gastroesophageal reflux disease, hypoglycemia, headache, dizziness

Gliflozins

• Sodium glucose-linked transporter-2 (SGLT-2) inhibitors.
• Prevent proximal tubular reabsorption of filtered glucose from renal filtrate.
• Examples include dapagliflozin, canagliflozin, empagliflozin, ertugliflozin.
• Low risk of hypoglycemia (monotherapy); weight loss.
• Side effects: include polyuria, dehydration, aggravated glycosuria, genital yeast infection, urinary tract infection, skin infection, diabetic ketoacidosis.