L38 - Physiology of insulin&glucagon Flashcards
Pancreas blood supply?
Head = SMA + Pancreaticoduodenal artery
Neck, Body and Tail = Splenic artery
Define the 2 functional components of pancreas?
1) Exocrine = acinar cells secrete digestive enzymes into duodenum
2) Endocrine = islets of Langerhans for glucose homeostasis
Define the cell types in the islets of Langerhans in pancrease and their secretion?
Alpha(α) cells:
- 30-45% total islet cells
- Glucagon
Beta (β) cells
- 45-60%
- Insulin
Delta (δ)cells
- 3- 10%
- Somatostatin
Describe the feedback regulation of pancreatic hormone secretion?
Insulin activate B-cells + inhibit a-cells
Glucagon activate a-cells»_space; activate beta and delta cells too
Somatostatin inhibit alpha and beta cells
Precursors of insulin? Structure of mature insulin?
Preproinsulin: Signal peptide + A and B chains joined by C chain
Proinsulin = A and B chain joined by double SS bond, removed signal peptide
Mature Insulin = A and B chain only, removed C chain
Joined by 2 pairs of disulfide bonds + one intramolecular disulfide bond in A chain
Which peptide is measured to indicate normal synthesis of endogenous insulin?
C peptide
Equimolar amounts of C-peptide and insulin are stored in secretory granules in pancreatic Beta cells
Describe the mechanism of insulin release from B cells?
Unstimualted: ATP-sensitive K channel open, maintain resting membrane potential
High extracellular glucose
» Glucose diffuse through membrane transporter
» ATP production by TCA cycle and glycolysis
» Closure of ATP-sensitive K channels
» No K efflux, Depolarization opens V-gated Ca channels
» Increase cytosolic Ca concentration, Insulin granule exocytosis
Structure of insulin receptor?
2 Tyrosine kinase receptor:
α- subunit for ligand binding
β- subunit for protein kinase
Linked by disulfide bonds into a Tetramer (functionally dimeric protein complex)
Describe the activation of insulin receptor?
Insulin bind to a-subunit
» activate tyrosine kinase
» cause cross phosphorylation of B-subunit
» phosphorylation of insulin receptor substrate 1 (IRS-1)
» act as docking center for other downstream enzymes
Define the 2 intracellular pathways triggered by insulin receptor activation?
PI3K/AKT pathway = control metabolic effects: Antilipolysis, glucose uptake, glycogen and protein synthesis
Ras/ERK pathway = control cell growth and differentiation
Summarize the effects of insulin on peripheral tissue?
Muscle and adipose tissue:
- Increase insertion of GLUT-4 onto membrane = increase glu. intake
- Inhibit lipolysis
Muscle and liver:
- Stimulate glycogenesis by Glycogen synthase
Liver:
- Inhibit gluconeogenesis and glycogenolysis
- Increase Lipogenesis
Describe how the liver and adipocytes work together to process high plasma glucose?
Increase glycogenesis in liver first
> > if glucose level still too high
convert G 6-P to Fatty acid and transfer to adipocyte
Glucose at adipocyte form glycerol, combine with FA from liver
form Triglycerides
Structure and precursors of glucagon?
29 a.a.
Proglucagon»_space; proteolysis process»_space; mature glucagon
Describe the mechanism of glucagon secretion at low glucose level?
Low glucose level: self-fire:
- ATP-sensitive K channel remain open
- T-type Ca channel open»_space; depolarization trigger Na+ channel activation
- AP triggered»_space; Ca entry through N-type channels
- Induce glucagon granule exocytosis
Describe the mechanism of glucagon secretion at high glucose levels?
- Glucose enters a-cells and metabolized to ATP
- ATP causes ATP-sensitive K channel to close
- Inactivation of T-type Ca channels and Na channel
- No glucagon granule exocytosis
** Insulin blocks all channels: T-type Ca channel, Na channel and ATP-sensitive K channel **
Paracrine and intrinsic regulation of glucagon are mutually exclusive. T or F?
False
Isolated a-cells cannot respond properly without insulin effects
Summarize physiological effects of glucagon?
1) Liver: Activate cAMP/PKA pathway:
- Inactivate glycogen synthase > less glycogenesis
- Activate glycogen phosphorylase > glycogenolysis
- induces the expression of gluconeogenic genes»_space; gluconeogenesis
2) Adipose tissue: cAMP/PKA pathway:
- activates hormone- sensitive lipase (HSL)
» mobilize stored fats and stimulates lipolysis»_space; FA to liver for gluconeogenesis
What type of receptor is glucagon receptor?
GPCR
3 types of Diabetes mellitus?
Type 1 (Juvenile diabetes/ Insulin-dependent DM)
Type 2 (Non-insulin dependent DM = NIDDM)
Gestational diabetes
Cause of Type 1 DM?
Autoimmune destruction of B cells, inability to synthesize insulin
Cause of Type 2 DM?
Target tissue fail to respond to insulin due to defects in insulin signalling or Lipid-induced insulin resistance (overnutrition)
Mechanism of lipid-induced insulin resistance?
Obesity
> excessive fat in muscle, liver intracellular lipid
> converted to DAG to trigger PKC pathways
> Phosphorylate IRS-1 at serine residues
> Defect insulin signalling
Pathogenesis of gestational diabetes?
- Excessive glucose to fetus cause increased lipogenesis = obesity
- Fetal liver produces excess insulin = hypoglycemia after birth
List some causes of non-type 1 or 2 diabetes?
Acromegaly (excess grwoth hormone)
Cushing syndrome (excess cortisol)
Thyroitoxicosis (excess thyroid hormone - increase glucose absorption in gut)
Pheochromocytoma (increase Adrenaline/ NE)
Glucagonoma
List some symptoms of DM?
- Polyuria
- Unexplained weight loss
- Increased appetite, thirst (polydipsia)
- Fatigue
- Blurred vision, retinopathy
- Diabetic neuropathy
- Diabetic ketoacidosis
Explain how DM causes polyuria?
Increase glucose in glomerular filtrate = filtrate becomes hypo-osmolar (too much free water)
> decrease water reabsorption, increase urine volume
Explain how DM causes unexplained weight loss and increase appetite??
Cannot intake and utilize glucose after meal»_space; increase lipolysis and proteolysis for gluconeogenesis»_space; weight loss
Fail to utilize glucose»_space; increase appetite
Mechanism of diabetes- caused cataracts?
Glucose converted to Sorbitol in lens (by Aldose reductase)
Sorbitol not converted to fructose (lack of sorbitol dehydrogenase in lens)
Excess Sorbitol cause osmotic damage: increased fluid influx, depletion of NADPH
Symptoms and causes of insulin excess?
Insulinoma
Accidental / deliberate injection of excessive insulin
Hypoglycaemia =CNS effects: sedation, drowsiness, confusion
Autonomic discharge: palpitation, sweating, nervousness
Describe how DM leads to diabetic ketoacidosis?
Reduced glucose uptake into cells
> > Trigger glucogenesis and gluconeogenesis
> Increase fat breakdown causing high ketone levels
> > impair brain function, coma and death
List 5 hormones that increase the plasma glucose level?
Cortisol, growth hormone, catecholamines (adrenaline, noradrenaline), thyroid hormones, glucagon
Describe how DM can lead to hyperglycaemic coma?
Uncontrolled extracellular hyperglycaemia
> > severely hyperosmotic plasma with high solute concentration
> > Movement of water from cells into interstitium
> > Dehydration of brain cells and neurons
List some vascular complications of DM?
Atherosclerosis, Coronary artery disease, Stroke, Nephropathy, neuropathy, retinopathy
