Control of Blood Glucose & The Endocrine Pancreas

• Which glucose transport mechanism is insulin-independent?

  Facilitated diffusion via GLUT transporters (e.g. GLUT1, GLUT2, GLUT3) is insulin-independent.
• Which glucose transport mechanism is insulin-dependent?

  Facilitated diffusion via GLUT4 is insulin-dependent. Insulin stimulates the translocation of GLUT4 to the plasma membrane in muscle and adipose tissue.
• Where are SGLT transporters primarily found and what do they do?

  SGLT transporters are found in the small intestine (SGLT1) and renal proximal tubules (SGLT2).They use secondary active transport by coupling glucose transport with sodium (Na⁺) gradients.
• What drives glucose transport in SGLT proteins?

  The Na⁺/K⁺ ATPase pump maintains a low intracellular Na⁺ concentration, allowing Na⁺ to move into the cell with glucose against its concentration gradient.
• What is the function of GLUT transporters?

  GLUT transporters mediate facilitated diffusion of glucose down its concentration gradient, without energy use.
• What are the key GLUT transporters and where are they found?

  • GLUT1: All tissues, especially blood-brain barrier
  • GLUT2: Liver, pancreatic β-cells, kidney, small intestine (bidirectional transport)
  • GLUT3: Neurons
  • GLUT4: Skeletal muscle, adipose tissue (insulin-dependent)
  • GLUT5: Small intestine (mainly fructose transport)
• How does insulin promote glucose uptake in muscle and fat cells?

  Insulin binds to its receptor, triggering a signalling cascade that causes GLUT4-containing vesicles to fuse with the cell membrane, increasing glucose uptake.
• Why is GLUT2 important in pancreatic β-cells?

  GLUT2 allows glucose entry proportional to blood glucose levels, enabling β-cells to sense glucose and regulate insulin secretion accordingly.
• Which transporter is responsible for glucose reabsorption in the kidney?

  SGLT2 (in the proximal convoluted tubule) reabsorbs most of the filtered glucose; remaining glucose is reabsorbed by SGLT1 in the proximal straight tubule.
• What are the main cell types in the endocrine pancreas and their functions?

  The endocrine pancreas consists of Islets of Langerhans, which contain the following cell types:

  • Alpha cells: Secrete glucagon, which increases blood glucose levels by promoting glycogen breakdown in the liver and gluconeogenesis.
  • Beta cells: Secrete insulin, which decreases blood glucose levels by promoting glucose uptake into cells and glycogen storage in the liver.
  • Delta cells: Secrete somatostatin, which inhibits the secretion of both insulin and glucagon, acting as a regulator.
  • PP cells: Secrete pancreatic polypeptide, which regulates pancreatic secretion activities and appetite.
  • Epsilon cells: Secrete ghrelin, a hormone involved in appetite regulation and glucose metabolism.
• How does the parasympathetic nervous system influence insulin secretion?

  The parasympathetic nervous system plays a crucial role in stimulating insulin secretion during the fed state:

  • Activation of the vagus nerve triggers the release of acetylcholine, which binds to receptors on the beta cells of the pancreas.
  • This stimulation enhances the secretion of insulin from beta cells, facilitating the uptake of glucose into cells and lowering blood glucose levels.

  This response is particularly pronounced after eating, ensuring glucose is taken up and stored in tissues.
• How does glucagon raise blood glucose levels?

  Glucagon raises blood glucose levels primarily by acting on the liver to promote the following processes:

  1. Glycogenolysis: Glucagon stimulates the breakdown of glycogen (the stored form of glucose) into glucose, which is then released into the bloodstream.
  2. Gluconeogenesis: Glucagon promotes the synthesis of new glucose from non-carbohydrate sources like amino acids.
  3. Inhibition of glycogenesis: Glucagon prevents the formation of glycogen from glucose, ensuring glucose remains available in the bloodstream.

  These actions increase blood glucose levels, counteracting hypoglycemia.
• What is the role of somatostatin in the regulation of insulin and glucagon?

  Somatostatin, secreted by delta cells in the Islets of Langerhans, acts as a key regulator in balancing the secretion of insulin and glucagon:

  • Inhibits insulin secretion: Somatostatin reduces insulin secretion, preventing excessive insulin release when blood glucose levels are already low.
  • Inhibits glucagon secretion: Somatostatin also inhibits glucagon secretion to prevent the excessive release of glucose into the bloodstream when blood glucose levels are already elevated.

  This feedback mechanism helps maintain stable blood glucose levels within a narrow range.
• What is the role of incretin hormones (e.g., GLP-1) in glucose metabolism?

  Incretin hormones, such as GLP-1 (glucagon-like peptide 1), play a significant role in glucose metabolism by enhancing insulin secretion:

  • GLP-1 is secreted by the intestinal L-cells in response to food intake, particularly carbohydrates.
  • It acts on beta cells in the pancreas to promote glucose-dependent insulin secretion, helping to lower blood glucose levels.
  • GLP-1 also inhibits glucagon release when blood glucose levels are elevated, further promoting glucose homeostasis.
  • Additionally, GLP-1 slows gastric emptying, which helps regulate the rate at which glucose enters the bloodstream after a meal.
• What are the primary receptors for insulin and glucagon in the body?

  • Insulin Receptor: The primary receptor for insulin is the insulin receptor (IR), which is a tyrosine kinase receptor located on the cell membrane of various tissues, including liver, muscle, and adipose tissue.
  • Glucagon Receptor: The primary receptor for glucagon is the glucagon receptor (GCGR), which is a G protein-coupled receptor (GPCR) found mainly in the liver.
• What is the mechanism of action of the insulin receptor?

  • The insulin receptor (IR) is a tyrosine kinase receptor that, when insulin binds to it, activates the receptor’s intracellular tyrosine kinase activity.
  • This leads to autophosphorylation of tyrosine residues on the receptor, which triggers a cascade of signaling pathways.
  • Key signaling pathways include the PI3K-AKT pathway, which promotes glucose uptake by increasing the number of GLUT4 transporters on the cell membrane in muscle and adipose tissue, and glycogen synthesis in the liver.
• What are the key effects of insulin binding to its receptor?

  • Increased glucose uptake into muscle and adipose tissue via GLUT4 transporters.
  • Increased glycogen synthesis in the liver.
  • Inhibition of gluconeogenesis and glycogen breakdown in the liver.
  • Fat storage promotion by enhancing lipogenesis and inhibiting lipolysis.
  • Protein synthesis in muscle cells.
• What is the mechanism of action of the glucagon receptor?

  • The glucagon receptor (GCGR) is a G protein-coupled receptor (GPCR).
  • When glucagon binds to the receptor, it activates the G protein, specifically the Gs protein, which in turn stimulates adenylyl cyclase to produce cyclic AMP (cAMP).
  • Increased cAMP activates protein kinase A (PKA), which initiates a cascade of reactions, leading to glycogen breakdown (glycogenolysis) and gluconeogenesis in the liver.
• What are the key effects of glucagon binding to its receptor?

  • Increased glucose production by the liver via glycogenolysis and gluconeogenesis.
  • Increased fatty acid oxidation by promoting lipolysis in adipose tissue.
  • Increased blood glucose levels to provide energy during fasting or stress.
•  Compare the actions of insulin and glucagon receptors

  • Insulin receptor (IR) promotes anabolism (building up of molecules), such as glucose uptake, glycogen synthesis, and fat storage.
  • Glucagon receptor (GCGR) promotes catabolism (breakdown of molecules), such as glycogen breakdown and glucose production, to raise blood glucose levels.
• How do insulin and glucagon interact in regulating blood glucose levels?

  • Insulin lowers blood glucose by promoting uptake into cells and storage as glycogen or fat.
  • Glucagon raises blood glucose by stimulating the liver to release glucose through glycogen breakdown and gluconeogenesis.
  • The balance between insulin and glucagon secretion ensures homeostasis in blood glucose levels, with insulin acting during fed states and glucagon acting during fasting states.
• What is Type 1 Diabetes Mellitus?

  An autoimmune disorder where the body's immune system attacks and destroys insulin-producing beta cells in the pancreas. This leads to little to no insulin production, resulting in elevated blood glucose levels (hyperglycemia). It is typically diagnosed in childhood or early adulthood.
• What are the key points in Type 1 Diabetes Mellitus?

  • Insulin deficiency
  • Autoimmune destruction of pancreatic beta cells
  • Onset typically in childhood or adolescence
  • Requires insulin therapy for management
• What is Type 2 Diabetes Mellitus?

  A metabolic disorder characterized by insulin resistance and eventual beta-cell dysfunction. In the early stages, the body produces insulin, but the cells become less responsive to it, leading to elevated blood glucose levels. Over time, the pancreas cannot produce enough insulin to overcome resistance.
• What are the key points in Type 2 Diabetes Mellitus?

  • Insulin resistance (body cells do not respond to insulin effectively)
  • Often associated with obesity, physical inactivity, and genetic factors
  • Typically diagnosed in adults, but increasing in children due to lifestyle changes
  • Managed with lifestyle changes, oral medications, and sometimes insulin therapy
• What are the main differences between Type 1 and Type 2 Diabetes Mellitus?

  1. Cause:

  • T1DM: Autoimmune destruction of pancreatic beta cells.
  • T2DM: Insulin resistance followed by beta-cell dysfunction.

  1. Insulin Production:

  • T1DM: Little to no insulin production.
  • T2DM: Initially normal or increased insulin production, but ineffective due to resistance.

  1. Onset:

  • T1DM: Typically in childhood or early adulthood.
  • T2DM: Common in adulthood, with increasing cases in children due to lifestyle factors.

  1. Management:

  • T1DM: Insulin therapy is essential.
  • T2DM: Managed with lifestyle changes, medications, and sometimes insulin.
• What is the role of the endocrine pancreas in blood glucose regulation?

  The endocrine pancreas regulates blood glucose levels through the secretion of two main hormones: insulin and glucagon. Insulin lowers blood glucose by promoting its uptake into cells and storage as glycogen, while glucagon raises blood glucose by stimulating the liver to release stored glycogen.
• How do insulin and glucagon regulate blood glucose homeostasis?

  • Insulin: Produced by beta cells of the pancreas; lowers blood glucose by promoting cellular uptake and storage (as glycogen in the liver and muscle).
  • Glucagon: Produced by alpha cells of the pancreas; raises blood glucose by stimulating glycogen breakdown and gluconeogenesis in the liver.
  • Homeostasis: Insulin and glucagon work antagonistically to maintain blood glucose within a narrow physiological range (~4–7 mmol/L).
• What are the symptoms of Type 1 and Type 2 Diabetes Mellitus?

  • Common Symptoms of Both:
  • Polyuria (frequent urination)
  • Polydipsia (excessive thirst)
  • Polyphagia (excessive hunger)
  • Unexplained weight loss (more prominent in T1DM)
  • Type 1 Diabetes Symptoms:
  • Rapid onset of symptoms
  • Severe weight loss
  • Ketosis or diabetic ketoacidosis (DKA) may occur if untreated
  • Type 2 Diabetes Symptoms:
  • Gradual onset of symptoms
  • More commonly associated with obesity
  • May be asymptomatic in the early stages
• What is the incretin effect?

  The phenomenon where oral glucose intake causes a greater insulin response than intravenous glucose, even when blood glucose levels are the same. This is due to gut-derived hormones called incretins.
• Why does oral glucose lead to more insulin release than IV glucose?

  Because oral glucose stimulates the release of incretin hormones (like GLP-1 and GIP) from the gut, which enhance insulin secretion from pancreatic β-cells.
• What are the two main incretin hormones involved in the incretin effect?

  Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
• Where is GLP-1 secreted from and in response to what?

  GLP-1 is secreted from L-cells in the ileum and colon in response to nutrient ingestion, especially carbohydrates and fats.
• Where is GIP secreted from and in response to what?

  GIP is secreted from K-cells in the duodenum and jejunum in response to nutrient ingestion.
• What are the effects of GLP-1 on pancreatic function?

  GLP-1 stimulates insulin secretion, inhibits glucagon secretion, slows gastric emptying, and promotes satiety.
• What are the effects of GIP on pancreatic function?

  GIP primarily stimulates insulin secretion in a glucose-dependent manner; it has less effect on glucagon and gastric motility compared to GLP-1.
• How does glucose-dependency relate to incretin hormones?

  Both GLP-1 and GIP enhance insulin secretion only when blood glucose levels are elevated, preventing hypoglycaemia.
• What enzyme rapidly degrades incretin hormones and what is its clinical relevance?

  Dipeptidyl peptidase-4 (DPP-4) degrades incretins; DPP-4 inhibitors are used in diabetes treatment to prolong incretin activity and enhance insulin secretion.
• How is the incretin effect altered in Type 2 diabetes?

  In Type 2 diabetes, the incretin effect is reduced due to decreased secretion and/or reduced sensitivity to GLP-1 and GIP, contributing to impaired insulin secretion.