Normal glucose physiology

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Normal homeostatic mechanisms maintain blood glucose levels within a narrow range of 3.5-6.5 mmol/l
Insulin is produced in and secreted by the beta cells in the islets of Langerhans in the pancreas.

Islet of Langerhans: (Paul Langerhans; 1847-1888)
Make up 2% of mass of adult pancreas; approx. 1 million islets; 4 distinct cells types – alpha (~20%; secretes glucagon); beta (~75%; secretes insulin); delta (~1-8%; secretes somatostatin); pancreatic polypeptide (~1-2%; secretes pancreatic polypeptide)
Innervated with peptidergic and autonomic fibres; sympathetic fibres  insulin release; parasympathetic fibres  inhibit insulin and increase glucagen secretion

Discovered in 1921 (by Banting & Best)
Peptide hormone that consists of two amino acid chains (the ‘A’ or acidic chain and the ‘B’ or basic chain) with 51 amino acids linked by two disulfide bridges (differs from pig insulin by one amino acid)
synthesised in endoplasmic reticulum of beta cell; proinsulin in pancreatic beta cell is cleaved to insulin and a connecting peptide; secretory granules from the beta cell contains equal amount of insulin and c-peptide (c-peptide levels can be used to measure amount of endogenous insulin production, as commercial insulin preparations do not have c-peptide)
main stimulus for release is glucose, but release can also be triggered by amino acids, fatty acids and ketone bodies. Activation of beta2-adrenergic receptors in pancreas also stimulate release of insulin whereas stimulation of the alpha-adrenergic receptors in pancreas inhibit insulin release
secretion of insulin is closely tied to blood glucose levels
basal (background) secretion of insulin is continuous (accounts for about 50% of all insulin secretion)
effects of insulin are anabolic  conservation of energy, promotes cell growth
suppresses gluconeogenesis and promotes glycogenolysis
promotes peripheral uptake of glucose – especially in skeletal muscle cells
encourages storage (as muscle glycogen)
promotes lipogenesis and suppresses lipolysis
two phases of insulin action are seem in humans – rapid and transient spike in insulin secretion in response to glucose entering system (first phase; lasts only a few minutes) and a gradual prolonged period of insulin release (second phase); first phase is absent in type 2 diabetes

Glucose levels are lowered via effects of insulin primarily through suppressing liver glucose production and stimulating glucose disposal.

Insulin receptors:
The receptors for insulin are found on most mammalian cells – action of insulin is mediated through these receptors.
- Receptor is a glycoprotein with two extracellular subunits and two subunits that cross the cell wall.
- When insulin binds to receptor  tyrosine kinase enzyme becomes active  postreceptor events triggered.
Impaired action of insulin can result from defects in the receptors or defects in post-receptor events.

GLUT Transporters:
- Glucose transported into cells by specialised transporters (GLUT’s)
- Several types of GLUT’s

Deficiency of insulin:
• catabolic effects (breakdown of complex molecules)  contribute to signs and symptoms of diabetes
• glycogen  glucose; proteins  amino acids; fats  glycerin and free fatty acids
• promote hyperglycaemia by increasing glycogenolysis and glycogenesis and a reduction in glucose utilisation

Counter-regulatory hormones:
The metabolic actions of insulin can be antagonised by:
• glucagon (peptide hormone released from alpha cells of pancreas; in response to low blood glucose levels – release also stimulated by certain amino acids, catecholamines and glucocorticoids, as well as autonomic nervous system; acts to stimulate liver for increased glucose production (gluconeogenesis) and breakdown of glycogen (glycogenolysis); secretion is suppressed by high blood glucose levels and insulin)
• catecholamines (increase glycogenolysis)
• growth hormone (reduce glucose uptake into cells)
• glucocorticoids (steroid hormone; increases gluconeogenesis in liver; reduce amount of glucose taken up by muscle)

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