Week 6

• Alpha cells make up 33-46% of the human islet cells and produce and secrete glucagon to elevate glucose levels in the blood.
• Excessive production of glucagon, as seen in glucagonoma (a rare tumor of the alpha cells), can cause up to 1000-fold overproduction of glucagon, leading to elevated blood glucose levels via gluconeogenesis and lipolysis and causing diabetes mellitus.
• Glucagon is a 29 amino acid peptide hormone synthesized from preproglucagon and processed by prohormone convertases 1 and 2.
• Glucagon increases blood glucose levels by triggering glycogen breakdown in the liver (glycogenolysis), activating glucose production pathways (gluconeogenesis), and promoting the breakdown of stored lipids (lipolysis) with glycerol used in gluconeogenesis and free fatty acids potentially converted into ketone bodies.
• Incretin is a hormone produced in the small intestine that stimulates insulin release, increases beta cell size and number, reduces appetite, and is reduced in diabetes.
• The pancreas has two major roles - exocrine (producing enzymes that digest food) and endocrine (controlling glucose levels in the body).

  The pancreas consists of lobules, acinar cells, ducts, and Islets of Langerhans.

  The Islets of Langerhans receive input from sympathetic adrenergic and parasympathetic cholinergic nerves.
• The Islets of Langerhans contain multiple cell types, including alpha cells (secreting glucagon), beta cells (secreting insulin), and delta cells (secreting somatostatin).
• Stimulation of insulin release includes high glucose levels, amino acids, gut hormones released post-prandially, low glucagon, acetylcholine, and beta1 adrenergic receptors.

  Inhibition of insulin release includes low glucose levels, somatostatin, intra-islet pancreatic and gastric factors, alpha2 adrenergic receptors, and higher adrenaline levels.
• Actions of insulin include fusion of vesicles and insertion of glucose transporters in the plasma membrane.

  Insulin facilitates glucose uptake through SGLUT1, which co-transports one molecule of glucose or galactose along with two sodium ions.
• GLUT-1: Expressed in many cells, transports glucose (high affinity) and galactose, not fructose.

  GLUT-2: Found in liver, pancreatic beta cells, small intestine, and kidney. Transports glucose, galactose, and fructose. Serves as a "glucose sensor" in pancreatic beta cells.

  GLUT-3: Found in the brain, placenta, and testes. Transports glucose (high affinity) and galactose, not fructose. Primary glucose transporter for neurons.
• SGLUT 1: found in Intestinal mucosa and kidney tubules and co-transports one molecule of glucose or galactose along with two sodium ions but not fructose.

  GLUT-4: Found in skeletal and cardiac muscle, and adipocytes. Insulin-responsive glucose transporter with high affinity for glucose.

  GLUT-5: Found in the small intestine and sperm. Transports fructose, but not glucose or galactose. Also present in the brain, kidney, adipocytes, and muscle.
• Insulin activates the enzyme hexokinase, which phosphorylates glucose and traps it in the cell.

  Insulin also activates enzymes involved in glycogen synthesis, including phosphofructokinase.
• Glycogen synthase inhibits the activity of glucose-6-phosphatase, resulting in insulin signaling the liver to store as much glucose as possible for later use.
• Multiple Daily Injections (MDI) with injection pens or Continuous Subcutaneous Insulin Infusion (Pump Therapy) are used for insulin replacement in type 1 diabetes.

  
  

  MDI involves the use of two different types of insulin: long-acting (insulin glargine, insulin detemir, insulin degludec) and rapid-acting (insulin aspart, insulin lispro, insulin glulisine).
• Insulin pump treatment involves wearing a device continuously, the size of a pager, powered by a battery, with a self-inserted subcutaneous catheter and a reservoir.
• Glucose homeostasis is critical for stabilizing glucose levels in plasma and maintaining glucose availability for the brain.
• Defects in insulin secretion or action can lead to dysregulation of glucose and the development of diabetes.

  
  

  Poorly managed diabetes can result in significant morbidity and mortality.
• The islets of Langerhans are scattered throughout the pancreas and consist of 2% of the volume of the gland.

  Humans have 1-2 million islets, and each is composed of alpha cells, which secrete glucagon; beta cells, which secrete insulin and delta cells, which secrete somatostatin.
• • Insulin is synthesized in pancreatic beta cells as single chain precursor (AKA preproinsulin) before removal of signal peptide (AKA proinsulin)
  • Proinsulin has three domains: N-terminal B chain, C-terminal A chain and Middle C-peptide
  • It also has 3 disulphide links cleaved by prohormone convertases 1 and 2
• insulin secretion

  1. Glucose enters beta cells through GLUT2
  2. Glucose metabolised to produce ATP
  3. ATP closes K channels (normally open)
  4. Membrane depolarisation leads to the opening of calcium channel
  5. Calcium influx leads to vesicle movement and release, leading to insulin secretion
• • During long-standing hyperglycemia in diabetics, glucose forms covalent bonds with proteins through a non-enzymatic reaction between free amino group of amino acid and carbonyl group of reducing sugars.
  • This process causes formation of advanced glycation end products (AGEs), which disrupt molecular conformation and alters protein function.
  • AGEs have crucial role in diabetes related cardiovascular and renal complications.
• • Binding of AGE to cell’s surface receptor causes activation of multiple signaling pathways inside cells and different responses of endothelial cells, smooth muscle cells, macrophages, and T cells.
  • Activation of nicotinamide adenine dinucleotide phosphate (NADPH) and the MAPK pathway in response to AGE interaction with cell surface receptors can induce reactive oxygen species (ROS) production and NFĸB activation, respectively.
  • ROS has pivotal roles in diabetes related cardiovascular and ophthalmological complications
• • Diabetic ketoacidosis (DKA) is a serious problem that can happen in people with diabetes if the body runs out of insulin.
  • When this happens, ketones build up in the body, which can be life-threatening if not found and treated quickly.
  • DKA mainly affects people with type 1 diabetes but can sometimes affect people with type 2 diabetes.
• Ketone bodies formation

  • There are three ketone bodies produced by the liver acetoacetate, betahydroxybutyrate, and acetone.
  • These compounds are used in healthy individuals to provide energy to the cells of the body when glucose is low or absent in the diet.
  • The liver, in order to keep supplying the brain with glucose, must convert amino acids, glycerol, pyruvate, and lactate into glucose.
  • This process is called gluconeogenesis and produces acetoacetate and beta-hydroxybutyrate.