Insulin and Diabetes Flashcards
What is diabetes?
Diabetes is a chronic health condition that affects how your body turns food into energy.
Glucose not correctly transported in muscles and adipose tissue.
Fat not correctly stored in adipose tissue.
How is insulin synthesised?
Synthesised in B-cells of the Islets of Langerhans in the pancreas.
Synthesised as a single polypeptide called pro-insulin
Hydrolysed at two points to form two chains, these are linked by disulphide bridges.
The “inactive” segment released by hydrolysis is termed the C-peptide.
How is insulin secreted?
Glucose is major stimulus to insulin secretion.
It enters the B cells via a non-insulin dependant transporter and is metabolised.
ATP is produced, this inactivates ATP-dependent hyperpolarising K+ channel. This channel becomes blocked so K+ can’t leave the cell. K+ accumulate at the cell membrane.
This leads to depolarisation of the B-cells.
Calcium-dependent channels release insulin.
What are some other stimuli of insulin secretion?
Parasympathetic vagal activity (cephalic phase of secretion of insulin, starts before meal ingestion-depends on muscarinic M3 receptors).
Gastrointestinal hormones (gastrointestinal phase of secretion, starts when food enters the stomach and duodenum).
Glucagon (secreted by the a pancreatic cells).
Some amino acids, particularly alanine, glycine, arginine, leucine.
Glucagon-like peptides (GLP): potentiate glucose-induced insulin secretion (but do not stimulate insulin secretion by themselves).
What inhibits insulin secretion?
Sympathetic innervations (a2-adrenoceptor-dependent process, involved in stress response). These receptors induce the hyperpolarisation of the insulin-secreting cells.
Somatostatin (secreted by D pancreatic cells, paracrine modulation). Most of these receptors produce a rise in intracellular calcium leading to the release of insulin.
How does glucose move into muscle cells and adipose tissue?
The process of GLUT4 translocation involves the movement to the cell surface of vesicles containing the glucose transport protein, GLUT4, responsible for bringing sugar into the cell.
Insulin receptor substrates form complexes with docking proteins, and promote GlUT4 translocation.
Exercise stimulates glucose transport by pathways that are independent of IRS.
Not all tissues are dependent on insulin for glucose entry (brain, liver, kidney…) when insulin receptor is no more activated, glucose transporter is internalised back in intracellular vesicles.
What does insulin do to glucose in the liver?
Insulin stimulates glycogen synthesis (glycogenesis).
Inhibits synthesis of new glucose (inhibits gluconeogenesis).
Stimulates glycolysis (for the synthesis of fatty acids).
Resulting effect: prevents glucose output from the liver.
Suppresses lipolysis and favours synthesis of fatty acid and cholesterol.
What does insulin do to glucose in the muscles?
Stimulates glucose uptake (translocation of GLUT-4).
Stimulates amino acid uptake and protein synthesis.
Glucose will be used for glycolysis and synthesis of muscle glycogen.
Resulting effect: promotes ATP production and fuel storage.
What does insulin do to glucose in adipose tissue?
Stimulates glucose uptake (translocation of GLUT-4), and is converted into glycerol-phosphate.
Promotes triglyceride storage.
Inhibits release of fatty acids and stimulates lipogenesis.
Activates adipose tissue lipoprotein lipase (hydrolyse triglycerides in chilomicrons and VLDL).
Stimulate fatty acid transport (translocation of FATP fatty acid transport protein).
Resulting effect: promotes deposition of circulating fat.
In summary:
Insulin exerts its effect by inducing Lipoprotein lipase (LPL) so that circulating triglycerides are hydrolyzed and free fatty acids can enter the adipocyte (through the FATP –fatty acid transport protein- which is also insulin-induced).
Inside the adipocyte, they will reform triglycerides (re-esterification).
Insulin is also required for the transport of glucose, which is needed for re-esterification of the triglycerides once inside the adipocyte (converted into glycerol phosphate).
What effects does insulin have on protein metabolism?
Promotes amino acid uptake and protein synthesis in a number of tissues (muscle).
Decreases protein catabolism in the liver.
What is gluconeogenesis?
Synthesis of new glucose (induced by adrenaline and glucagon, cortisol).
What is glycolysis?
Degradation of glucose into small products (induced by insulin) for ATP or fatty acid synthesis.
What is glycogenolysis?
Degradation of glycogen into glucose (glucagon, adrenaline).
What is glycogenesis?
Synthesis of glycogen from glucose (insulin, cortisol).
What is lipolysis?
Degradation of fatty acid (inhibited by insulin).
What is lipogenesis?
Synthesis of fatty acid and triglyceride (insulin)
What is somatostatin?
It is a pancreatic hormone that is synthesised by the D cells.
5 different somatostatin receptors, all are inhibitory receptors (inhibit cAMP production and hyperpolarise target cells).
Act primarily in a paracrine manner (1/2 life 3 min) to inhibit the secretion of both insulin and glucagon.
On the digestive system:
Decreases rate of nutrient absorption.
Inhibits GI hormones secretion (will reduce exocrine pancreatic secretion).
Suppresses gastric secretion.
Lowers the rate of gastric emptying, and reduces intestine contraction.
What is glucagon?
It is a pancreatic hormone that counteracts what insulin is doing.
It is synthesized first as proglucagon and processed to glucagon within alpha cells of the pancreatic islets.
Important role in maintaining normal concentrations of glucose in blood by potently increasing blood glucose levels.
Control over two pivotal metabolic pathways within the liver:
Stimulates breakdown of glycogen into glucose.
Stimulates gluconeogenesis.
Secretion is activated by low levels of glucose, high levels of some amino acids and exercise.
Secretion is inhibited by insulin and high levels of glucose.
What are incretins?
Incretins are gastro-intestinal hormones which regulates insulin secretion.
Glucagon-like peptide - gastrointestinal hormone, derived from the transcription product of the proglucagon gene.
Secreted by ileal L cells in response to the presence of nutrients in the GI tract.
Strongly potentiates glucose-mediated insulin secretion, and pro-insulin synthesis, stimulates regeneration of beta cells.
Potently inhibits glucagon secretion.
Rapidly degraded by peptidase, biological effect is limited by its very short half life (<2 min). High therapeutic value.
What is amylin?
It is co-secreted with insulin from the pancreatic beta cells in response to a rise in blood glucose.
Attenuates blood sugar fluctuation, and improves overall glycaemic control.
In Type 2 diabetes, certain forms of amylin may aggregate into fibrils and may induce damages to the beta cell and ultimately may restrain release and peripheral actions of insulin.
In summary:
Reduces postprandial glucagon secretion.
Regulates gastric emptying of food into the small intestine.
May suppress intake of food by causing the central nervous system to signal satiety.
What are pancreatic polypeptides?
Synthesized in the F-cells of the Islets of Langerhans.
Released into the plasma following the ingestion of food.
Inhibits the stimulation of gastric and pancreatic exocrine secretions.
What is type 1 diabetes?
Insulin dependent diabetes mellitus (IDDM).
Onset is common in childhood.
Causes:
Likely a viral infection that triggers an autoimmune disease which destroys islets.
Genetic defect in the synthesis of insulin (rare).
Genetic predisposition: moderate.
Insulin therapy is essential to prevent ketoacidosis.
What is type 2 diabetes?
Non-insulin dependent diabetes mellitus.
More common than Type 1.
Less prone to ketoacidosis (if well controlled), but other metabolic complications can be very serious .
Insulin is sometimes needed but not essential to survival.
Genetic predisposition: high.
Subdivided into obese and non-obese.
Causes:
Reduction in insulin secretion.
Insulin resistance (may be lack of receptors).
What are the symptoms of diabetes?
The 3 P’s:
Polyuria - constantly need to urinate.
Polydypsia - constantly thirsty.
Polyphagia - state of starvation.
Tissue damage:
Increased protein glycosylation.
Conversion of glucose to sorbitol by aldose reductase.
Abnormalities in protein metabolism - muscle wasting/asthenia.
Abnormalities in lipid metabolism - hypertriglyceridaemia, eventually ketosis and acidosis.
Resulting effects:
Vascular complications, accelerated atheroma, increased thickness in small blood vessels, increased capillary fragility which causes lack of blood supply to retina, kidneys, extremities and other tissue damages.
