Regulation of Insulin Secretion

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Chapter: Essential pharmacology : Insulin, Oral Hypoglycaemic Drugs and Glucagon

Under basal condition ~1U insulin is secreted per hour by human pancreas. Much larger quantity is secreted after every meal. Secretion of insulin from β cells is regulated by chemical, hormonal and neural mechanisms.


REGULATION OF INSULIN SECRETION

 

Under basal condition ~1U insulin is secreted per hour by human pancreas. Much larger quantity is secreted after every meal. Secretion of insulin from β cells is regulated by chemical, hormonal and neural mechanisms.

 

Chemical

 

The β cells have a glucose sensing mechanism dependent on entry of glucose into cells (through the aegis of a glucose transporter GLUT2) and its phosphorylation by glucokinase. Glucose entry and activation of the glucoceptor indirectly inhibits the ATP sensitive K+ channel resulting in partial depolarization of the β cells. This increases intracellular Ca2+ availability (due to increased influx, decreased efflux and release from intracellular stores) exocytotic release of insulin storing granules. Other nutrients that can evoke insulin release are—amino acids, fatty acids and ketone bodies, but glucose is the principal regulator and it stimulates synthesis of insulin as well. Glucose induces a brief pulse of insulin output within 2 min (first phase) followed by a delayed but more sustained second phase of insulin release.

 

Glucose and other nutrients are more effective in invoking insulin release when given orally than i.v. They generate chemical signals ‘incretins’ from the gut which act on β cells in the pancreas to cause anticipatory release of insulin. The incretins involved are glucagonlike peptide1 (GLP1), glucose-dependent insulinotropic polypeptide (GIP), vasoactive intestinal peptide (VIP), pancreozymin-cholecystokinin, etc.; but different incretin may mediate signal from different nutrient. Glucagon and some of these peptides enhance insulin release by increasing cAMP formation in the β cells.

 

Hormonal

 

A number of hormones, e.g. growth hormone, corticosteroids, thyroxine modify insulin release in response to glucose. PGE has been shown to inhibit insulin release. More important are the intra-islet paracrine interactions between the hormones produced by different types of islet cells. The β cells constitute the core of the islets and are the most abundant cell type. The α cells, comprising 25% of the islet cell mass, surround the core and secrete glucagon. The D cells (5–10%) elaborating somatostatin are interspersed between the α cells. There are some PP (or F) cells (pancreatic polypeptide containing) also.

 

·        Somatostatin inhibits release of both insulin and glucagon.

·        Glucagon evokes release of insulin as well as somatostatin.

·        Insulin inhibits glucagon secretion.

 

The three hormones released from closely situated cells influence each other’s secretion and appear to provide fine tuning of their output in response to metabolic needs (Fig. 19.2).

 


 

Neural

 

The islets are richly supplied by sympathetic and vagal nerves.

 

·  Adrenergic α2 receptor activation decreases insulin release (predominant) by inhibiting β cell adenylyl cyclase.

 

·       Adrenergic β2 stimulation increases insulin release (less prominent) by stimulating β cell adenylyl cyclase.

 

·   Cholinergic—muscarinic activation by ACh or vagal stimulation causes insulin secretion through IP3/DAGincreased intracellular Ca2+ in the β cells.

 

These neural influences appear to govern both basal as well as evoked insulin secretion, because the respective blocking agents have effects opposite to that mentioned above. The primary central site of regulation of insulin secretion is in the hypothalamus: stimulation of ventrolateral nuclei evokes insulin release, whereas stimulation of ventromedial nuclei has the opposite effect.

 

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