Neuroendocrine Activation

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Insulin-induced hypoglycaemia was used to study pituitary function as early as the 1940s. The development of assays for adrenocorticotropic hormone (ACTH) and growth hormone (GH) allowed the direct measurement of pituitary function during hypoglycaemia in the 1960s, and many of the processes governing these changes were unravelled before elucidation of the counterregulatory system. The studies are comparable to those evaluating counterregulation, in that potential regulatory factors are blocked to measure the hormonal response to hypoglycaemia with and without the regulating factor.

Box 1.3 Neuroendocrine activation

Hypothalamus

t

Corticotrophic releasing hormone

t

Growth hormone releasing hormone

Anterior Pituitary

t

Adrenocorticotropic hormone

t

Beta endorphin

t

Growth hormone

t

Prolactin

Thyrotrophin

Gonadotrophins

Posterior pituitary

t

Vasopressin

t

Oxytocin

Pancreas

t

Glucagon

t

Pancreatic polypeptide

t

Insulin

Adrenal

t

Cortisol

t

Epinephrine (adrenaline)

t

Aldosterone

Others

t

Parathyroid hormone

t

Gastrin

t

Somatostatin (28)

Hypothalamus and anterior pituitary

ACTH, GH and prolactin concentrations increase during hypoglycaemia, but there is no change in thyrotrophin or gonadotrophin secretion. The secretion of these pituitary hormones is controlled by releasing factors which are produced in the median eminence of the hypothalamus, secreted into the hypophyseal portal vessels and then pass to the pituitary gland (Figure 1.7). The mechanisms regulating the releasing factors are incompletely understood, but may involve the ventromedial nucleus, one site where brain glucose sensors are situated (Fish et al, 1986).

Figure 1.7 Anatomy of the hypothalamus and pituitary gland

ACTH: Secretion is governed by release of corticotropin releasing hormone (CRH) from the hypothalamus; alpha adrenoceptors stimulate CRH release, and beta adrenoceptors have an inhibitory action. A variety of neurotransmitters control the release of CRH into the portal vessels, including serotonin and acetylcholine which are stimulatory and GABA which is inhibitory. The increase in ACTH causes cortisol to be secreted from the cortices of the adrenal glands.

Beta endorphins are derived from the same precursors as ACTH and are co-secreted with it. The role of endorphins in counterregulation is uncertain, but they may influence the secretion of the other pituitary hormones during hypoglycaemia.

GH: Growth hormone secretion is governed by two hypothalamic hormones: growth hormone releasing hormone (GHRH) which stimulates GH secretion, and somatostatin which is inhibitory. GHRH secretion is stimulated by dopamine, GABA, opiates and through alpha adrenoceptors, whereas it is inhibited by serotonin and beta adrenoceptors. A study in rats showed that bioassayable GH and GHRH are depleted in the pituitary and hypothalamus respectively after insulin-induced hypoglycaemia (Katz et al., 1967).

Prolactin: The mechanisms underlying its secretion are not established. Prolactin secretion is normally under the inhibitory control of dopamine, but evidence also exists for releasing factors being produced during hypoglycaemia. Prolactin does not contribute to counterregulation.

Posterior pituitary

Vasopressin and oxytocin both increase during hypoglycaemia (Fisher et al., 1987). Their secretion is under hormonal and neurotransmitter control in a similar way to the hypothalamic hormones. Vasopressin has glycolytic actions and oxytocin increases hepatic glucose output in dogs, but their contribution to glucose counterregulation is uncertain.

Pancreas

• Glucagon: The mechanisms of glucagon secretion during hypoglycaemia are still not fully understood. Although activation of the autonomic nervous system stimulates its release, this pathway has been shown to be less important in humans. A reduction in glucose concentrations may have a direct effect on the glucagon-secreting pancreatic alpha cells, or the reduced beta cell activity (reduced insulin secretion), which also occurs with low blood glucose, may release the tonic inhibition of glucagon secretion. However, such mechanisms would be disturbed in type 1 diabetes, where hypoglycaemia is normally associated with high plasma insulin levels and there is no direct effect of beta cell-derived insulin on the alpha cells.

• Somatostatin: This is thought of as a pancreatic hormone produced from D cells of the islets of Langerhans, but it is also secreted in other parts of the gastrointestinal tract. There are a number of structurally different polypeptides derived from prosomatostatin: the somatostatin-14 peptide is secreted from D cells, and somatostatin-28 from the gastrointestinal tract. The plasma concentration of somatostatin-28 increases during hypoglycaemia (Francis and Ensinck, 1987). The normal action of somatostatin is to inhibit the secretion both of insulin and glucagon, but somatostatin-28 inhibits insulin ten times more effectively than glucagon, and thus may have a role in counterregulation by suppressing insulin release.

• Pancreatic polypeptide: This peptide has no known role in counterregulation, but its release during hypoglycaemia is stimulated by cholinergic fibres through muscarinic receptors and is a useful marker of parasympathetic activity.

Adrenal and Renin-Angiotensin system

The processes governing the increase in cortisol during hypoglycaemia are discussed above. The rise in catecholamines, in particular epinephrine from the adrenal medulla, which occurs when blood glucose is lowered, is controlled by sympathetic fibres in the splanchnic nerve. The increase in renin, and therefore angiotensin and aldosterone, during hypoglycaemia is stimulated primarily by the intra-renal effects of increased catecholamines, mediated through beta adrenoceptors, although the increase in ACTH and hypokalaemia due to hypoglycaemia contributes (Trovati et al., 1988; Jungman et al., 1989). These changes do not have a significant role in counterregulation, although angiotensin II has glycolytic actions in vitro.

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