Diabetes pharmacotherapy and physiopathology

• Insulin


  Synthesised in beta cells of the Islets of Langerhans in the pancreas, synthesised as a single polypeptide called pro-insulin, hydrolysed at two points to form two chains linked by disulphide bridges, the "inactive" segment released by hydrolysis is termed the C-peptide
• Insulin


  • A chain - 21 amino acids
  • B chain - 30 amino acids
• Insulin half-life


  1. 10 minutes (large hepatic extraction)
• 1. peptide half-life


  20-50 minutes (more stable, better indicator of insulin secretion), very recent evidence suggests C-peptide may have some biological activity (possible effects on inflammation)
• 98 to 99% of the pancreas is exocrine pancreas, involved in the production of digestive enzymes
• 1 to 2% is endocrine pancreas responsible for the production of hormones
• The hormone producing cells are grouped together in Islets of Langerhans or pancreatic islets
• About 90% of the islet cells are beta cells, specialized in secreting insulin
• The remaining 10% of islet cells are alpha and delta cells producing glucagon, pancreatic polypeptide and somatostatin, respectively
• Insulin secretion


  1. Glucose enters beta cells via NID transporter and is metabolised

  2. ATP produced inactivates ATP-dependent hyperpolarising-K+ channel

  3. Depolarisation of the beta cells

  4. Calcium-dependent release of insulin
• NID (Non-Insulin Dependent) glucose transporter


  Transport really active when plasma Glucose>5.5 mM
• Other stimuli of insulin secretion

  • Parasympathetic vagal activity (cephalic phase)
  • Gastrointestinal hormones (gastrointestinal phase)
  • Glucagon (secreted by alpha pancreatic cells)
  • Some amino acids, particularly alanine, glycine, arginine, leucine
  • Glucagon-like peptides (GLP): potentiate glucose-induced insulin secretion (but do not stimulate insulin secretion by themselves)
• Insulin secretion is inhibited by

  • Sympathetic innervations (alpha2-adrenoceptor-dependent process, involved in stress response)
  • Somatostatin (secreted by delta pancreatic cells, paracrine modulation)
• Atypical neuroleptics or some tricyclic antidepressants can block muscarinic receptors of the M1/M3 family, which can cause side effects
• Plasma insulin levels over time

  1. Food is presented

  2. Food is ingested

  3. Cephalic phase

  4. GI phase

  5. Substrate phase (made of two phases) caused by metabolic fuel mainly glucose (first substrate phase generally absent in diabetes type II)
• Insulin receptor


  Like growth factor receptors, is a tyrosine kinase receptor, the cytosolic catalytic domain possesses intrinsic tyrosine phosphorylation activity, insulin receptor will then phosphorylate a series of intracellular proteins: the Insulin Receptor Substrate (IRS)
• GLUT4 translocation in muscle and adipose tissues


  1. Involves the movement to the cell surface of vesicles containing the glucose transport protein, GLUT4, responsible for bringing sugar into the cell

  2. Insulin receptor substrates form complexes with docking proteins, and promote GLUT4 translocation

  3. Exercise stimulates glucose transport by pathways that are independent of IRS
• Not all tissues are dependent on insulin for glucose entry (brain, liver, kidney...)
• When insulin receptor is no more activated, glucose transporter is internalised back in intracellular vesicles
• Effects of Insulin


  • Carbohydrate metabolism
  • Lipid and protein metabolism
  • Ion transport
  • DNA expression in various tissues (at high doses it can act as a growth factor)
• Overall effect of insulin

  Promotes fuel storage
• Enzymes induced by insulin

  Glycogen synthase, glucokinase, lipoprotein lipase (adipose tissue)
• Effects of insulin on the liver

  1. Stimulates glycogen synthesis (glycogenesis)

  2. Inhibits synthesis of new glucose (inhibits gluconeogenesis)

  3. Stimulates glycolysis (for the synthesis of fatty acids)

  4. Suppresses lipolysis and favours synthesis of fatty acid and cholesterol
• Effects of insulin on muscles

  1. Stimulates glucose uptake (translocation of GLUT-4)

  2. Stimulates amino acid uptake and protein synthesis

  3. Glucose will be used for glycolysis (20-50%) and synthesis of muscle glycogen (50-80%)
• Effects of insulin on adipose tissue

  1. Stimulates glucose uptake (translocation of GLUT-4) and metabolism into glycerol-phosphate

  2. Promotes triglyceride storage

  3. Inhibits release of fatty acids and stimulates lipogenesis

  4. Activates adipose tissue lipoprotein lipase (hydrolyse triglycerides in chylomicrons and VLDL)

  5. Stimulate fatty acid transport (translocation of FATP - fatty acid transport protein)
• Insulin exerts its effect by inducing Lipoprotein lipase (LPL) so that circulating triglycerides are hydrolyzed and free fatty acids can enter the adipocyte (through the FATP –fatty acid transport protein- which is also insulin-induced)
• Inside the adipocyte, the free fatty acids will reform triglycerides (re-esterification)
• Insulin is also required for the transport of glucose, which is needed for re-esterification of the triglycerides once inside the adipocyte (converted into glycerol phosphate)
• Effects of insulin on protein metabolism


  • Promotes amino acid uptake and protein synthesis in a number of tissues (muscle)
  • Decreases protein catabolism in the liver
• Insulin can also stimulate cell proliferation and contribute to body growth
• Ingestion of 120 kcal of glucose (2 slices of white bread)

  1. 80% of glucose used by non hepatic organs immediately (muscle uptake)

  2. 20% glucose entered the liver through GLUT2

  3. 80% of it is stored as glycogen (20 kcal)

  4. 20% of it converted into pyruvate taken up into mitochondria to make ATP via tricarboxylic acid or TCA cycle, of more limited capacity

  5. Unused metabolites leave mitochondria under the form of citrate to make up fatty acid, only 1-2% of all glucose intake converted to TG
• Ingestion of 120 kcal of sucrose (1 large glass of fizzy drink), similar in calories to 2 slices of bread


  1. Produces 60 kcal glucose/ 60 kcal fructose

  2. 12 kcal glucose and nearly 60 kcal fructose reach the liver

  3. Liver has to cope with 72 kcal of sugar to metabolise (only 24 kcal if only glucose were absorbed!)

  4. In addition fructose does not stimulate insulin secretion (conversion of fructose to glycogen more difficult, some drinks are enriched in fructose-)
• 100% of ingested fructose ends up in the liver, 20% of ingested glucose ends up in the liver
• Fructolysis


  Degradation of fructose into small products, became a more important pathway, excessive production of fatty acids and VLDL secretion can result
• Metabolic pathways


  • Gluconeogenesis: synthesis of new glucose (induced by adrenaline and glucagon, cortisol)
  • Glycolysis: degradation of glucose into small products (induced by insulin) for ATP or fatty acid synthesis
  • Glycogenolysis: degradation of glycogen into glucose (glucagon, adrenaline)
• Glucose metabolism


  1. Glycolysis: degradation of glucose into small products (induced by insulin) for ATP or fatty acid synthesis

  2. Gluconeogenesis: synthesis of new glucose (induced by adrenaline and glucagon, cortisol)

  3. Glycogenolysis: degradation of glycogen into glucose (glucagon, adrenaline)

  4. Glycogenesis: synthesis of glycogen from glucose (insulin, cortisol)

  5. Lipolysis: degradation of fatty acid (inhibited by insulin. Promoted by cortisol, adrenaline, GH)

  6. Lipogenesis: synthesis of fatty acid and triglyceride (insulin)
• Fructolysis


  Degradation of fructose into small products
• Excessive production of fatty acids and VLDL secretion

  Can result from fructolysis
• Somatostatin


  14 or 28 AA peptides, synthesised by the D cells. Acts through inhibitory receptors (inhibit cAMP production and hyperpolarise target cells) primarily in a paracrine manner (1/2 life 3 min) to inhibit the secretion of both insulin and glucagon. On the digestive system: overall effect decreases rate of nutrient absorption, inhibits GI hormones secretion, suppresses gastric secretion, lowers the rate of gastric emptying, and reduces intestine contraction.
• Glucagon


  29-amino acid peptide, synthesized first as proglucagon and processed to glucagon within alpha cells of the pancreatic islets. Important role in maintaining normal concentrations of glucose in blood by potently increasing blood glucose levels. Control over two pivotal metabolic pathways within the liver: Stimulate breakdown of glycogen into glucose, Stimulate gluconeogenesis. Secretion activated by: Low levels of glucose, high levels of some amino-acids (may protect from hypoglycaemia if a meal contains disproportionate level of protein), exercise. Secretion inhibited by: Insulin, high levels of glucose.