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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #39: Normal Beta-cell Function Part 4 of 6

Aug 30, 2016

Beta-Cell response to hormones and the nervous system

As already mentioned insulin is the only hormone with a blood glucose lowering effect, while many other hormones (glucagon, cortisol, adrenaline) exert a hyperglycemic action.The changes in glucose levels elicited by these hormones obviously will be detected by the β cell, which will respond by enhancing insulin secretion. Yet, all these hormones, as well as others and the nervous system exert a coordinated direct effect on the β cell resulting in an integrated and sophisticated control network.

The typical example is the intra-islet networking encompassing the entangled interaction between α, β, and δ cells [100]. Glucagon released from the α cell has a stimulatory effect on insulin secretion by the β cell, an effect that is commonly used to test residual endogenous insulin secretion in vivo [101].

The latter requires, however, pharmacologic doses of glucagon (1mg), while the small increase in circulating insulin levels observed with glucagon infusion is more likely the result of the hyperglycemic effect of the hormone. Insulin secretion, in turn, exerts an inhibitory effect on glucagon secretion, whereas somatostatin, released from δ cells, suppresses secretion of both insulin and glucagon [102], and therefore, is believed to integrate pancreatic islet hormonal effect. More recently an interaction between somatostatin and ghrelin has been reported in regulating insulin release [103]. On top of the direct effect on the β cell, resulting in suppression of both basal and stimulated insulin secretion, somatostatin may exert an effect on insulin secretion also through modulation of a number of gastrointestinal hormones, for instance by inhibiting, with different potency, the release of gastrointestinal hormones [104]

The effects of GLP-1 and GIP on insulin secretion have already been mentioned but other gastrointestinal hormones may contribute to modulating insulin secretion. For instance, animal studies have indicated that ghrelin can counteract the insulinotropic effect of GLP-1 [105]. An even greater inhibitory effect has been claimed to be exerted by obestatin [106] though variable and divergent effects may be elicited by different levels of the hormone [107]. Leptin, secreted by the adipocyte, interacts with receptors located on the β cell where it causes reduced insulin gene expression and inhibits insulin secretion by a KATP channel dependent and independent pathway [108].

Contra-insular hormones such as catecholamines [109], cortisol [110], and growth hormone via the effects of IGF-1 [111] mainly exert a suppressive effect on insulin secretion, which may not be readily appreciated because of the concomitant induction of insulin resistance.

More complex appears to be the role of the nervous system. Claude Bernard first suggested the involvement of the nervous system in the regulation of insulin secretion. His hypothesis was then supported by the discovery by Langerhans that pancreatic islets were indeed highly innervated. Subsequently it was found that parasympathetic, sympathetic, and sensory nerve endings are present that can affect insulin and the β-cell function through the release of a number of neurotransmitters [112]. These include catecholamine and acetylcholine as well as neurotransmitters such as the vasoactive intestinal polypeptide (VIP), pituitary adenylcyclase activating polypeptide (PACAP), the gastrin-releasing polypeptide (GRP), galanin, neuropeptide Y, and the calcitonin gene-related polypeptide (CGRP). The response of the β cell to nerve stimulation is the result of the balance between the stimulatory effects of the parasympathetic nerve endings and the inhibitory one of the sympathetic nerves. However, much of the information is derived from animal studies, whereas investigation into the innervation of the human islet is limited [113–115]. Acetylcholine and noradrenaline are locally released to act on cholinergic and adrenergic receptors. Acetylcholine stimulates insulin by enhancing Ca2+ release from intracellular depots, while activation of α2-adrenergic receptors suppresses glucose-mediated insulin release [116] via hyperpolarization of the β-cell membrane thus contributing to rapid adaptation of insulin secretion under conditions of hypoglycemia. On the contrary a stimulation of insulin secretion is elicited by activation of β2-adrenergic receptors.

A potential role in the neuronal regulation of the activity of pancreatic islet cells appears to be exerted also by sensory fibers, including fibers containing neuropeptides GGRP and substance P, since pancreatic sensory denervation has been proposed to contribute to defective insulin secretion in Zucker diabetic animals [117].

To make the picture even more complex is the observation that a number of neurotransmitters (i.e., galanin, melatonin, melacortin, orexin, vasopressin, and so on) may also contribute to modulate β-cell function [118]. Also in this case, however, much of the information has been obtained with in vitro studies using murine islet models, while a careful profile of the human islet is still far from available. Moreover, the evaluation of the physiologic role of innervation of the pancreatic human islet poses a number of interpretation issues as stimulation or inhibition of the parasympathetic and sympathetic branches of the autonomic nervous systemelicits an array of responses (metabolic changes, regional blood flow, release of multiple neurotransmitters and neuropeptides) that can ultimately result in a direct effect on the β cell. By using more selective pharmacologic agents such as tyramine, a negative effect of sympathetic activation on insulin secretion induced by i.v. arginine has been confirmed in human subjects [119].

The islet innervation may play a main role in humans by mediating the cephalic phase of insulin secretion, that is, the rapid increase in insulin secretion occurring in the first couple of minutes upon initiation of the stimulus [120]. Thus, pharmacologic denervation (parasympathetic and sympathetic inhibition by trimetaphan) results in the abolition of the cephalic phase of insulin secretion, without affecting early GLP-1 and GIP secretion [121].

More recent observations suggest that the autonomic nerves may also play a role in the synchronization of the islet ensuring simultaneous and harmonic response of the islets as a unit [122].

Pulsatile secretion of insulin

Insulin secretion is a very dynamic process.This characteristic is even more appreciated if the typical pulsatile secretion of the hormone is taken into consideration. Insulin oscillates with a slow ultradian periodicity (∼140 min) and a high frequency periodicity [123]. Pulse intervals have been recently calculated in a more reliable manner and shown to occur with a periodicity of 4–6 min in humans [124]. These oscillations suggest the pancreatic islet has a pacemaker function. This efficient pulsatile secretion requires formidable coordination of the secretory activity of the β cell dispersed through the 1 million pancreatic islets scattered in the 25-cm long human pancreas.

This coordination process is believed to require the integrated action of intra-islet nerves, metabolites, and hormones [125]. Recent studies have shown that oscillation of intracellular calcium is synchronized with β-cell metabolism [126]. Many factors affecting insulin secretion also impact on pulsatility of insulin secretion. Both sulfonylureas and GLP-1 can enhance in vivo pulsatility [127]. Although oscillatory insulin secretion may have a role in modulating insulin action, particularly at the level of the liver, it has also been proposed recently that this pattern may have a major effect at the level of the β cell by preventing desensitization of the insulin signaling pathway that contributes to regulation of β-cell mass [128]. Pulsatility, indeed, leads to periods of low autocrine stimulation enabling the cell to set with the background concentration of circulating insulin and other growth factors.The pulse release is believed to improve release control and enhance the action of the hormone. Studies performed in normal as well as diabetic individuals have shown that less insulin is required to maintain euglycemia with pulsatile versus continuous insulin administration [129].


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