9. The endocrine pancreas/ alpha cell function, beta cell function Flashcards
Pancreas develops as an out growth of the ____ _____
Closely associated with the _________ of the gall bladder.
Ducts join before emptying into the _______
Pancreas develops as an out growth of the gut tube.
Closely with the development of the gall bladder
Ducts join before emptying into the duodenum
Pancreas: exocrine and endocrine functions
Exocrine: PANCREATIC ACINI produce pancreatic amylase etc
Endocrine: ISLETS OF LANGERHANS produce hormones
What are the different cell types of the endocrine pancreas?
Various cell types within Islets of Langerhans (1869)
A (α;α2) cells - glucagon
B (β) cells - insulin
D (α1; γ; δ) cells - somatostatin
F cells - pancreatic polypeptide
Function of endocrine pancreas and which hormones are involved in each function?
Control of blood [glucose] in absorptive and post-absorptive states
(Insulin and glucagon)
Stimulate / inhibit digesEtive enzyme and HCO3- secreEon in GI tract (pancreatic peptide and somatostatin)
Location of different secretory cells in the islets of langerhans?
Beta in the centre
Alpha on the periphery
D and F throughout
Synthesis and processing of
Insulin in the B cells of islets of langerhans
During translation in the ER the the protein is cleaved before transciption is completed
Disulphide bonds form between the amino acid within the ER. This forms pro-insulin (c peptide + insulin)
Pre-insulin then sent to golgi
Converting enzymes cleave pro-insulin to form c peptide and precipitated zinc-insulin portions which are then packaged into secretory granules.
Contents: C peptide + insulin
Ready for secretion now
Factors regulating insulin release, excitatory?
Absorption of foo into GIT–>
Stimulatory:
- Alpha cell release of glucagon
- FFAs
- GIT hormones, incretins: GIP, GLT-1, CCF
- Certain Amino acids
- Increase blood glucose
- PS stimulation (Ach)
- Beta-adrenergic stimulation (Adr)
Factors regulating insulin release, inhibitory?
Absorption of foo into GIT--> Inhibitory: 1. Alpha adrenergic stimulation (NA) 2. D cell release of somatostatin 3. Insulin -ve feedback
Mechanisms of Insulin release from the pancreatic β cell
- Glucose enters the cell via a GLUT2 transporter, which mediates facilitated diffusion of glucose into the cell
- The increased glucose influx stimulates glucose metabolism, leading to an increased in [ATP]i
- The increased [ATP]i inhibits an ATP sensitive K+ channel
- Inhibition of this K+ channels causes Vm to become more positive (depolarisation)
- The depolarisation activates a voltage-gated Ca2+ channel in the plasma membrane
- The activation of this Ca2+ channel promotes Ca2+ influx and thus increased [Ca2+]i, which also evokes Ca2+ induced Ca2+ release
- The elevated [Ca2+]i leads to exocytosis and release into the blood of insulin contain within the secretory granules
NOTE: Other modulators of secretion act via the adenylyl cyclase-cAMP-protein kinase A pathways and the phospholipase C-phosphoinositide pathways
Physiological actions of Insulin released from beta cells
- INCREASED PROTEIN SYNTHESIS
@most tissues
Leads to growth and maintenance - INCREASED GLYCOGENESIS
@liver and muscle cells
Leads to increase glucose transport into muscle and adipose cells.
Consequently there is decreased blood glucose - INCREASED LIPOGENESIS
@liver and adipose tissue
Regulating factors of glucagon release from alpha cells on eating high protein meal?
Excitatory:
- GIT hormones
- Certain AAs
- Decrease blood glucose *****
- PS stimulation (Ach)
- Beta-adrenergic stimulation (Adr)
- alpha-adrenergic (NA)
Inhibitory:
- Beta cell release of insulin
- D cells release of somatostatin
Physiological actions of glucagon?
Release: From alpha cells
actions mainly in the LIVER
- CREASED LIPOGENESIS. INCREASE LIPOLYSIS
(Due to lack of insulin)
Leads to increased FFAs and increased glycerol - INCREASED GLYCOGENOLYSIS
So increased blood glucose - INCREASED GLUCONEOGENESIS
(Due to more cortisol)
Also increased blood glucose
Glucagon has no receptors in…
adipose tissue
Diabetes melltius results in..
Insulin deficiency OR insulin insensitivity (90% of cases)
Consequences of the hyperglycaemia in diabetes mellitus?
- Glucosuria - tubular fluid exceeds renal threshold for re-absorption
- Polyuria - osmotic diuresis due to glucose in tubular fluid
- Polydipsia - due to dehydration increasing angiotensin II levels which acts as dipsogen on thirst centres in brain
- Increased blood amino acids - due to increased protein catabolism
- Increased blood FFA and glycerol - due to increased lipolysis in adipose tissue
- Keto-acidosis - due to incomplete oxidation of fatty acids and ketogenic amino acids
Parameters of hyperglycaemia
Blood glucose above 10mM or 180 mg%
Excess of this leads to glucose in urine
Mechanism of the ketonuria seen in DM?
FFA/ketoacidic amino acids –> Acetyl CoA –> Beta-OH butyrate –> Actetone–> Increase in plasma ketones –> Ketonaemia –> Ketonuria
Due to incomplete oxidations of the fatty acids and ketoacidic amino acids
Glucose tolerance test
slide 11 (echo)
In Type 1 DM was is the:
- Pathophysiology?
- Treatment?
Type 1 = Insulin-dependent Diabetes mellitus (IDDM/juvenile-onet DM)
Pathophysiology:
Destruction of pancreatic beta cell (auto-immune disease after viral attack especially Coxsackie B virus)
Treatment:
Insulin administration via intramuscular injections of short and long-acting formulations of recombinant insulin)
+
Restricted carbohydrate diet
In Type 2 DM was is the:
- Pathophysiology?
- Treatment?
Type 2 DM= Non-insulin dependent diabetes mellitus (NIDDM/ maturity onset DM)
Pathophysiology:
- Capacity of beta cell to produce insulin decreased
- Decreased number and affinity of insulin receptors
- -> Reduced insulin responsiveness
Treatment:
-Restricted diet
-Sulphonyl ureas (increased beta cell response to glucose
-Biguanides (simulate glucose intake in muscles
(If uncontrolled, insulin injection)
Acute effects of DM, insulin deficiency —>
Insulin deficiency:
- Increased hepatic glucose output
- Decrease glucose uptake by cells
- Decrease triglyceride synthesis
- Increase lipolysis
- Decreased amino acid uptake by cells
- Increased protein degradation
DM long term pathologies
- INCREASED FAT MOBILISATION
- -> Increase plasma FFA/TG/Cholesterol - INCREASED BLOOD GLUCOSE
- -> Glycation and glycoxidation of proteins and lipo-proteins (esp LDL)
Both lead to modification of extracellular structural proteins in arteries and arterioles. (deposition of fats in arterial walls)
- -> Damage / loss of vascular endothelium (loss of NO release)
- -> Loss of capillary compliance
What are the consequences of loss of arterial compliance in long term DM?
- Diabetic atheroschleriosis
- Hypertension
Both leads to CV disease:
- Angina
- Cardiac arrhythmias
- Renal disease
Thymus develops from which pharyngeal pouch?
3rd then…
Migrates inferiorly to the superior mediastinum and loses connection with the pharynx
Where do lymphoid thymocytes come from?
Bone marrow, they invade and colonise the gland
Function of thymus
- Thymus controls the development and “education” of T lymphocytes
- Secretes several hormones that promote the maturation of different cells of the immune system
How does the increase in hepatic glucose output in DM lead to death acutely?
- -> Hyperglycaemia
- -> Glucosuria
- -> Osmotic diuresis
- -> Polyuria
- -> Dehydration
- -> Decreased in blood volume
- -> Peripheral circulatory failure
- -> Renal failure
- -> DEATH
Dehydration results in…
- polydipsia
- Cell shrinking
- -> Nervous system malfunction
- -> Low cerebral blood flow
- -> DEATH
What is the consequence of decreases triglycerides synthesis and increased lipolysis in DM?
- –> Increased blood free fatty acids
- -> Alternate energy course
- -> Ketosis
- -> Metabolic acidosis –> Increased vent
- -> Diabetic coma
- -> Death
What is the consequence of decreased amino acid uptake by cells in DM?
- -> Increased blood amino acid
- -> Increased gluconeogenesis
- -> Potentiation of hyperglycaemia
- -> Increased hepatic glucose output
- -> etc etc
