Endocrine pancreas and glucose control Flashcards
Describe normal blood glucose values
- Glucose is an important energy source
- The brain, in particular, is dependent on glucose for normal function
- Blood glucose levels are tightly controlled
- Normal blood glucose levels
- Fasting: 3.5-5.0 mmol/l
- Fed state: 4.0-7.0 mmol/l
Describe hypoglycaemia
- Blood sugar < 3.5 mmol/l
- Results in:
- Activation of sympathetic nervous system
- Sweating, palpitations, anxiety
- Brain dysfunction (neuroglycopenic symptoms)
- Parathesia (e.g., tingling of lips)
- Confusion
- Seizures
- Coma
- Activation of sympathetic nervous system
- Results in:
Describe hyperglycaemia
- BSL > 6.0 fasting, >8.0 fed
-
Acute:
- Glycosuria (BSL > renal threshold ~ 10mM)
- Polyuria/thirst/dehydration
- Blurred vision
- Impaired immune function
- Candidiasis, Bacterial infections
-
Chronic:
- End-organ damage
- Microvascular: eyes/kidneys/nerves
- Macrovascular: IHD/PVD/CVD
- End-organ damage
-
Acute:
Briefly describe blood glucose control in fasting state
- Gut-derived glucose
- Hepatic (and renal) glucose production (glycogenolysis and gluconeogenesis)
- Blood Glucose decreases
- Pancreatic islets
- Insulin secretion suppressed
- Glucagon secretion increased (enhances hepatic and renal)
- Insulin-responsive tissues (e.g., Skeletal muscle, Adipose tissue)
- Insulin-independent tissues (e.g., Brain)
- Pancreatic islets
Briefly describe blood glucose control in fed state
- Gut-derived glucose
- Hepatic (and renal) glucose production (glycogenolysis and gluconeogenesis)
- Blood Glucose decreases
- Pancreatic islets
- Insulin secretion increased (inhibits GNG and upregulates responsive tissues)
- Glucagon secretion suppressed
- Insulin-responsive tissues (e.g., Skeletal muscle, Adipose tissue)
- Insulin-independent tissues (e.g., Brain)
- Pancreatic islets
Discuss in details what occurs in fasting state
Glucose and FFA/TG Metabolism - Fasting (Insulin↓/Glucagon↑): pancreas suppresses insulin secretion, increases glucagon production. Hepatic glucose production is stimulated
- When insulin ↓ = ↓ glucose uptake into insulin-dependent tissues
(heart, skeletal muscle, adipose tissue) - Glycogenolysis: stored glycogen broken into glucose
- Lipolysis: TAGs broken into FFAs
- FAs converted to KBs in liver → heart/brain use KBs for energy
- Gluconeogenesis: in liver (and 10% from kidney) from lactate, AAs
and glycerol - T1DM: FA production and KB production accelerated to
pathological levels → diabetic ketoacidosis
Discuss in detail what occurs in fed state
Glucose and FFA/TG Metabolism - Fed (Insulin↑/Glucagon↓): pancreas results in increaed insulin secretion and glucagon suppresssion. Liver reduces glucose production
* Glucose-stimulated insulin secretion from pancreas
* Glucose taken to liver, heart, skeletal muscle and adipose
tissue
* Glycogenesis: glucose converted to glycogen for storage
* Glucose oxidised via glycolysis to provide energy (ATP)
* Glucose used preferentially to KBs and FFAs in the fed state
* Insulin switches off FFA production (lipolysis) from fat
* Glucose in the liver synthesises FAs and triglycerides → VLDL
export from liver providing energy for storage to tissues
* Lipoprotein lipase (LPL) in heart, skeletal muscle and
adipose tissue breaks down VLDL for use
* Lipids from the gut are stored chylomicrons and provide FAs to
tissues
Describe the anatomy and histology of the pancreas
Pancreas
- The pancreas is a retroperitoneal organ
- It lies posterior to the abdominal wall, and posterior to the stomach
- It sits anterior to the lumbar spine (L1-2)
Histology
- Acinar cells: extensive small, dense clusters of exocrine cells (produce pancreatic
secretions) - Pancreatic duct: transports pancreatic exocrine cells to the ampulla of vater
- Islets of Langerhans: occasional larger clusters of lighter-staining cells
- Endocrine cells: produce glucagon, insulin and somatostatin
- Rich capillary network within islet - cords of cells separated by capillaries
- Round nuclei with salt-and-pepper chromatin and granular cytoplasm (hormones
stored in secretory granules) - 100-200μm diameter
- > 1 million islets per pancreas
- 4 cell types within islets (cannot be histologically distinguished without IHC)
- ß cells (60-80%): produce insulin
- α cells (~20%): produce glucagon
- Delta cells (10%): produce somatostatin (growth hormone inhibiting hormone)
- F cells (2%): produce pancreatic polypeptide (PP)
- Other very minor hormone production e.g. GLP1, gastrointestinal peptide
Discuss the functions of the pancreas
- Exocrine and endocrine
- Exocrine
- 97-98% of pancreatic mass
- Digestive enzymes and bicarbonate which pass via pancreatic duct to duodenum
- Endocrine
- 2-3% of pancreatic mass
- Hormones – insulin, glucagon, somatostatin secreted directly into the bloodstream
Discuss the islets
- In adult pancreas
- Endocrine pancreas: 2-3% of total mass
- Approximately 1 million islets
- 68% beta-cells (insulin) - stimulation bu nutritional status (glucose), incretin hormones and PSNS
- 20% alpha cells (glucagon) - stimulation by nutritional status (low glucose), high amino acids
- 10% delta cells (somatostatin) - stimulation : increased glucose
- 2% PP cells (pancreatic polypeptide)
Discuss insulin synthesis
- A chain: 21 AAs
- B chain: 30 AAs
- 2 disulphide bonds link A&B chains
- C-peptide (produced 1:1 ratio with mature insulin)
- Islet beta cell
- Produced by ß cells in membrane-bound granules
- Synthesised as pre-proinsulin → cleaved to pro-insulin (A and B chains disulphide linked)
- Pro-insulin → mature insulin + C-peptide
- C-peptide produced in 1:1 ratio with mature insulin - measured to indicate endogenous insulin
production - Many ER required for protein synthesis
- Many mitochondria - high energy use cell
Discuss steps of insulin secretion
- Glucose uptake
- Glucose metabolism
- Increase ATP/ADP ratio
- Closure of ATP-sensitive K+ channels
- Depolarisation of plasma membrane
- Opening of voltage-dependent Ca++ channels
- Influx Ca++
- Ca++ induced insulin vesicle exocytosis
Discuss modeulation of insuln secretion
- Augmented by:
- Other nutrients - FFA, amino acids
- Incretin hormones
- Glucagon-like peptide 1 (GLP-1)
- Glucose-dependent insulinotropic polypeptide (GIP)
- Parasympathetic NS
- Suppressed by:
- Sympathetic NS, adrenaline
- Somatostatin
Describe the phases of insulin secretion
Occurs in 2 stages
* Phase 1: insulin granules sitting on plasma membrane ready to go - readily releasable pool that is
released quickly (5-10 mins)
* Phase 2: takes time to recruit more granules to membrane (30-90 mins
What are the actions of insulin?
Insulin is an anabolic hormone:
- Glucose metabolism
- Stimulates glucose transport (skeletal muscle/heart/adipose tissue)
- Activates glycogen synthesis (skeletal muscle/liver)
- Suppresses endogenous glucose production (glycogenolysis and gluconeogenesis) (liver)
- Translocates GLUT4 to plasma membrane
- Protein metabolism
- Stimulates amino-acid transport
- Promotes protein synthesis (anabolism)
- Inhibits protein degradation
- Lipid metabolism
- Promotes lipogenesis (liver/adipose tissues)
- Suppresses lipolysis in adipose tissue
- Promotes hepatic VLDL triglyceride secretion
- Activates lipoprotein lipase (chylomicron and VLDL TG hydrolysis) allowing fat uptake into peripheral tissues (e.g., adipose tissue, skeletal muscle)
