7.3 The pancreas, insulin and glucagon

The pancreas

• The pancreas is a long, flattened glandular organ located posterior to the stomach in the abdominal cavity. It is roughly triangular in shape and has a head, a body and a tail.

• Its serves both endocrine and exocrine functions, producing digestive enzymes that are released into the small intestine to aid in digestion and hormones, including insulin and glucagon, which regulate blood sugar levels

• The exocrine portion consists of acinar cells that secrete digestive enzymes into ducts, while the endocrine portion consists of clusters of cells known as the islets of Langerhans, which include alpha cells that produce glucagon and beta cells that produce insulin.

Pancreatic endocrine cells

• Alpha cells: Pancreatic cells that produce glucagon, to increase blood sugar levels

• Beta cells: Pancreatic cells that produce insulin, to decrease blood sugar levels

• Delta cells: Pancreatic cells that produce somatostatin, a hormone involved in inhibiting the release of other hormones, such as insulin and glucagon

• Pancreatic polypeptide cells: Pancreatic cells that produce pancreatic polypeptide, a hormone involved in regulating appetite and digestion

Insulin and glucagon

• Insulin is a hormone produced by beta cells in the pancreas that plays a crucial role in lowering blood sugar levels by promoting the uptake of glucose into cells for energy storage and utilisation

• It also stimulates the conversion of glucose into glycogen for storage in the liver and muscles, thus decreasing blood sugar levels.

• Glucagon, produced by alpha cells in the pancreas, acts in opposition to insulin by increasing blood sugar levels through the breakdown of glycogen into glucose in the liver and stimulating the release of glucose into the bloodstream.

• These hormones work together to maintain blood glucose homeostasis in the body.

Stimulation of insulin production

• Glucose stimulates insulin secretion through a process known as glucose-stimulated insulin secretion (GSIS)

• When blood glucose levels rise, glucose molecules are transported into pancreatic beta cells via glucose transporters

• Inside the beta cells, glucose undergoes metabolism through glycolysis, leading to an increase in intracellular ATP levels

• This rise in ATP levels triggers the closure of ATP-sensitive potassium channels (KATP channels), depolarising the cell membrane and leading to the opening of voltage-gated calcium channels

• The influx of calcium ions triggers the exocytosis of insulin-containing vesicles, releasing insulin into the bloodstream, thus promoting the uptake and storage of glucose by cells throughout the body

Glucose transporters

• Glucose transporter proteins, or GLUTs, are integral membrane proteins responsible for transporting glucose across cell membrane.

• GLUT-1: Facilitates the transport of glucose across the plasma membranes of most cells

• GLUT-2: Principal transporter for transfer of glucose between liver and blood, and for renal glucose reabsorption

• GLUT-3: Main transporter of glucose into neurons

• GLUT-4: Skeletal muscle and adipose tissue. (it is the only one regulated by insulin)

Summary of insulin actions

• Carbohydrates

  1. Facilitates glucose uptake and utilisation (most cells)

  2. Stimulates glycogenesis and inhibits glycogenolysis (liver and muscles)

  3. Increases conversion of glucose to fatty acids (and ultimately triglycerides) in adipose cells

  4. Inhibits gluconeogenesis (decreasing availability of amino acids and inhibiting hepatic enzymes)

• Fats

  1. Increases fatty acid uptake into adipose

  2. Increases fatty acids synthesis from glucose in adipose

  3. Decreases lipolysis in adipose

• Protein

  1. Promotes the active transport of amino acids into muscle

  2. Increases protein synthesis

Glucagon actions

• Decreases the synthesis of glycogen and promotes the breakdown of stored glycogen within the liver

• Maintains hepatic output of glucose by stimulating gluconeogenesis

• Inhibits hepatic protein synthesis and promotes hepatic protein degradation

• Promotes fat breakdown and inhibits triglyceride synthesis in adipose tissue

• Enhances ketogenesis (ketone production) in the liver, which results in increased blood levels of fatty acids and ketones

Blood glucose regulation

• Blood glucose regulation involves a complex interplay of hormones and organs to maintain homeostasis, primarily through the actions of insulin and glucagon that work to lower and raise blood glucose levels, respectively.

• The pancreas releases insulin, when blood glucose rises which promotes the uptake of glucose by cells, storage of excess glucose in the liver and muscles as glycogen, and the conversion of glucose to fat

• The pancreas releases glucagon, when blood glucose drops, triggering the breakdown of glycogen in the liver to release glucose into the bloodstream, and promoting gluconeogenesis (the synthesis of glucose from non-carbohydrate sources

• Glycogenesis: The synthesis fo glycogen from glucose molecules for storage, primarily occurring in the liver and muscles

• Glycogenolysis: The breakdown of glycogen into glucose molecules to increase blood glucose levels, especially during periods of fasting or energy demand

• Gluconeogenesis: The synthesis of glucose from non-carbohydrate precursors, such as amino acids, glycerol, or lactate, primarily occurring in the liver and kidneys to maintain blood glucose levels during fasting or low carbohydrate intake

Diabetes mellitus

• Type I diabetes (10% of all diabetes mellitus cases)

  • It is the result of destruction of beta cells as a auto-immune response. Leading to the absence of insulin secretion

  • The absence of insulin leads to a chronic fasted state characterised by symptoms such as ketoacidosis, glucosuria, polyuria and polydipsia.

  • If left untreated, type 1 diabetes can progress to severe complications, including coma and death

• Type II diabetes (90% of all diabetes mellitus cases)

  • It is characterised by the gradual, progressive development of insulin resistance, often due to receptor downregulation and attenuation of meal-induced insulin secretion

  • More common in older and overweight individuals, this condition often correlates with a sedentary lifestyle and poor dietary habits, making lifestyle changes a crucial aspect of management.

Complications of Diabetes mellitus

• Complications of diabetes include cadiovascular diseases such as heart attacks and strokes due to damage to blood vessels, kidney disease leading to kidney failure, and neuropathy causing nerve damage, often resulting in peripheral neuropathy, which can lead to foot ulcers and amputation

• Additionally, diabetes increases the risk of vision problems, including diabetic retinopathy, which can lead to blindness if left untreated.

• Microvascular and macrovascular damage:

  • Increased risk for heart attack, stroke, nephropathy and end-stage kidney disease, retinopathy and blindness, ischemia and gangrene of limbs

  • Increased risk for hypertension. Elevated blood pressure often associated with diabetes, exacerbating cardiovascular risk

  • Increased risk for atherosclerosis. Build-up of plague in arteries, a common complication of diabetes leading to narrowed and hardened arteries

• Peripheral neuropathies and autonomic nervous system (ANS) dysfunction

  • Impaired reflexes can occur as a result of peripheral nerve damage, leading to decreased sensation and coordination, further complicating the diabetic condition.

  • Incontinence may also develop due to damage to the nerves controlling bladder function, significantly impacting the quality of life for those with diabetes.

  • Distal sensory neuropathy can lead to a loss of feeling in the toes and feet, increasing the risk of injuries and infections that may go unnoticed.

  • Gastroenteropathy is another complication that can arise from diabetes, affecting the digestive system and leading to symptoms such as nausea, vomiting, and altered bowel function.