W6 Hormones of Pancreas Flashcards
Hormones of the Pancreas:
Exocrine & Ductal system (98%)
Islets of Langerhans: (<2%)
Alpha cells (glucagon)
Beta cells (insulin)
Delta cells (somatostatin)
PP cells ( pancreatic polypeptide)
Structure of Insulin:
- Synthesised in pancreatic islets of Langerhans by β (beta) cells
- mw ~ 5800 Daltons
- A-Chain: 21 aa
- B-Chain: 30 aa
- Disulphide Bridges: 3
Insulin (biosynthesis)
Initially starts as..?
What does insulin crystallise and bind to?
- Initially as proinsulin (human, 86aa)
- C-peptide (Chain-C) is packaged with insulin in the secretory granules (1:1); C-peptide has no biological activity (?!) but is possibly an ideal surrogate*!
Enzymatic process
* proconvertase 1 (PC1)- cleaves at 32, 33
* proconvertase 2 (PC2)- cleaves at 65, 66
* carboxypeptidase H (CPH) – removes 31,32
Insulin is then crystalised with Zinc and stored in secretory granules until stimuli for release (predominately glucose)
(2 Zn 2+: 6 insulin crystalloid core
Nutrient regulation of insulin secretion
Food is swallowed then is absorbed into the..
GI tract: Nutrients (Carbs, fats, proteins)
Then is absorbed into the…
Blood: glucose, free fatty acids, and amino acids (broken down into these)
Pancreatic islets of Langerhans
B cells- stimulated by glucose and these nutrients, secrete insulin in response
α- cell
δ- cell
PP
Nutrients like glucose, free fatty acids, and amino acids serve as fuel stimuli for insulin release, promoting insulin granule exocytosis from the pancreatic beta cells.
Glucose-induced insulin release
At HIGH plasma glucose levels : (>5mmol/L)
1) Increased glucose levels in the
circulation lead to increased glucose uptake into pancreatic beta cells through GLUT2, a glucose transporter.
2) Increased intracellular glucose then leads to increased production of ATP and an
increase in the ATP/ADP ratio
3) The increased ATP/ADP ratio leads
to the closing of the potassium channel and depolarisation of the cell
(4); and cell depolarisation opens a calcium channel and raises intracellular calcium levels
(5); calcium facilitates the docking and
the fusion of the insulin granules at the plasma membrane and exocytosis of insulin (6)
Paracrine regulation of insulin secretion
- Glucagon from alpha cells stimulates insulin release
- Somatostatin from delta cells inhibits insulin release
Neural regulation of insulin secretion
- Parasympathetic (muscarinic receptors) innervation of beta cells stimulates insulin secretion, whereas sympathetic branches (adrenoceptors) inhibit insulin release
GI-Hormonal regulation of insulin secretion
Following the nutrient intake, enteroendocrine cells
within the intestinal lining release incretin
hormones, namely GIP (glucose-dependent
insulinotropic polypeptide secreted by K cells) and
GLP-1 (glucagon-like peptide-1 secreted by L cells),
into the bloodstream.
* Incretin stimulates/potentiates nutrient-mediated
insulin synthesis and secretion
Bi-phasic insulin secretion
- Insulin is released in two phases.
- The first, a rapid release phase, represents
preformed proinsulin, which is rapidly
depleted. - The second phase represents new insulin
synthesis, showing glucose stimulates insulin synthesis as well
Insulin, Function (anabolic hormone)
- Build energy reserves (Glycogen, Fat and Protein)
- Promote growth & development
- Cellular uptake of K+ (Na+-K+ ATPase pump)
Insulin elicits its action by binding and
activating the Tyrosine Kinase Receptor (also known as Receptor Tyrosine Kinase) (a catalytic receptor, recollect year 1 pharmacology lecture)
Glucagon
Glucagon is a peptide hormone (29 AA) synthesised and released by alpha cells in pancreatic islets of Langerhans
Release:
* Low blood glucose (<3.5 mmol/L) stimulates the glucagon release
* Both parasympathetic and sympathetic innervation stimulates glucagon release
* High blood glucose, insulin, GLP-1 and somatostatin inhibit the glucagon release
Action (Catabolic hormone):
Glucagon opposes insulin action and increases blood glucose level
* Stimulate hepatic glycogenolysis
* Stimulate hepatic gluconeogenesis
* Stimulate lipolysis
Glucose homeostasis
Insulin (anabolic) - reduce blood glucose
Glucagon (catabolic) - increase blood glucose
Adrenaline: Raise blood sugar to meet energy emergencies (“fight or flight”)
Growth hormone: Raise blood sugar to promote growth
Cortisol: Raise blood sugar to the mobilisation of energy to manage metabolic stress
Diabetes Diagnosis:
Signs & symptoms:
- Glucosuria
- Polydipsia
- Polyuria
- Thirst
- Tiredness
- Blurred vision,
- weight loss (unexpected),
- & recurrent infections
Symptoms may be mild or absent
(asymptomatic)
two glucose tests with
values > “normal”
Persistent Hyperglycaemia:
Plasma glucose levels:
* fasting > 7.0 mmol/L,
* random > 11.1 mmol/L
(OR)
HbA1c levels (level of glycosylated
haemoglobin)
* 20 – 42 mmol/mol; 4-6%
(OR)
OGTT: Plasma glucose concentration
> 11.1 mmol/L
Diabetes Mellitus
A chronic metabolic disorder characterised by high blood sugar levels (hyperglycaemia)
due to either insufficient insulin production, resistance to insulin’s action, or both
Type 1 Diabetes (5-15%)
* autoimmune condition where the immune system attacks and destroys insulin-producing beta cells in the
pancreas, leading to little to null insulin production.
* Insulin replacement therapy is essential.
Type 2 Diabetes (80-90%)
* combination of insulin resistance (cells don’t respond effectively to insulin) and reduced insulin production.
* Linked to lifestyle factors like obesity and physical inactivity.
* Managed through lifestyle changes, oral medications, and sometimes insulin.
Gestational Diabetes (2-5%)
* Develops during pregnancy when hormonal changes can lead to insulin resistance.
* It usually resolves after childbirth but increases the risk of type 2 diabetes later in life.
