Summary of present-day knowledge
We know today that the pancreatic islets are innervated by parasympathetic, sympathetic, and sensory nerves. The parasympathetic nerves stimulate insulin and glucagon secretion whereas sympathetic nerves inhibit insulin secretion and stimulate glucagon secretion; the net influence of the sensory nerves is not yet clearly established. We also know that besides the classical neurotransmitters, noradrenaline and acetylcholine, the islet autonomic nerves also release neuropeptides which can also influence insulin and glucagon secretion. PACAP, VIP, and GRP are released from parasympathetic nerves and can stimulate both insulin and glucagon secretion. Galanin and NPY are released from islet sympathetic nerves, can inhibit insulin secretion and stimulate glucagon secretion. CGRP and substance P can be released from islet sensory nerves with mixed effects on insulin and glucagon secretion. Several important questions remain to be answered to fully understand the role of the autonomic nerves in general, and their neuropeptides in particular, in the control of islet Function.
Questions for future research
What are the physiologic roles of the islet autonomic nerves?
Although we know the effects on islet hormone secretion of activating autonomic nerves, there is less known about the physiologic conditions that activate these nerves and therefore their physiologic role. It is known that islet parasympathetic nerves are activated in anticipation of meals and early during the ingestive phase of a meal. Thus, they likely contribute to the release of insulin at this very early stage, the so-called cephalic phase of insulin secretion. There is also evidence for a parasympathetic contribution to insulin secretion even after glucose absorption. The contribution of autonomic nerves to meal-induced insulin secretion has been verified in an interventional study in healthy humans in which subjects were served a test meal together with an intravenous infusion of trimethaphan. This substance interrupts ganglionic transmission and therefore simulates autonomic denervation, at least to the extent possible in humans. The study showed that the early (10min) increase in insulin was reduced by trimethaphan .
Thus, the likely physiologic role of islet parasympathetic nerves is to initiate and amplify the early insulin response to meals.
It is also known that pancreatic sympathetic nerves are activated during hypoglycemia. Since activation of these nerves stimulates glucagon secretion, it is likely that they contribute to glucagon counterregulation during hypoglycemia. This contribution was demonstrated in humans by inducing complete ganglionic blockade by trimethaphan during a hyperinsulinemic hypoglycemic clamp. It was found that the glucagon response was severely suppressed, which suggests that autonomic activation makes a major contribution to the glucagon response to hypoglycemia . This autonomic stimulation of glucagon secretion is likely amplified by the direct action of low glucose to stimulate glucagon secretion from the α cells by releasing the α cell from the inhibitory effect the β cell has on it. In addition to these two relatively clear examples of autonomic contributions to islet hormone responses, there are likely others that have not been as carefully defined. In particular, the potential contribution of the sensory nerves needs to be examined in more detail.
What is the contribution of neuropeptides?
The classical autonomic neurotransmitters (acetylcholine for parasympathetic nerves and noradrenaline for sympathetic nerves) mimic many of the effects seen by direct activation of the niterves. However, the neuropeptides may also contribute to the effect of nerve activation, and Table 9.1 shows the criteria needed for acceptance of a neuropeptide as a physiologic neurotransmitter involved in the control of islet function. In Table 9.2 and Table 9.3, these criteria have been applied for the neuropeptides known to be present in parasympathetic and sympathetic nerves, respectively. Although some neuropeptides meet all these criteria, others need more study, particularly in humans. More generally, there is need for further study of the detailed regulation of small vesicles release (which contain the classical neurotransmitters) versus large dense core vesicles release (which contain the neuropeptides). In particular, do dissociated release mechanisms exist for these two types of vesicles and, if so, are they relevant for the regulation of islet hormone secretion?
Insulin resistance is a common feature of type 2 diabetes. Under normal circumstances, a compensatory increase in insulin secretion occurs thereby ensuring the maintenance of normal glucose tolerance. If this β-cell adaptation is insufficient for the degree of insulin resistance, glucose intolerance and eventually type 2 diabetes develop. Several signals may mediate the appropriate increase of insulin release, including circulating glucose and lipids. However, mediation by parasympathetic nerves may also contribute. First, people with insulin resistance have increased circulating levels of pancreatic polypeptide (PP) [59,60], which is a marker for the parasympathetic nerve activity. Second, the hyperinsulinemia of obese rats and mice is reduced after vagotomy  and the hyperinsulinemia induced by experimental insulin resistance in humans is reduced by ganglionic blockade . Such studies provide proof of principle that the parasympathetic input to the islet is activated in states of insulin resistance and could, therefore, help prevent the failing insulin secretion in type 2 diabetes. However, further studies are needed to determine the contribution of defects in this parasympathetic pathway to the development of glucose intolerance and type 2 diabetes.
Is islet neurotransmission a therapeutic target for type 2 diabetes?
Due to the potent effects of the autonomic neurotransmitters on insulin secretion, it has been suggested that targeting their neurotransmitter receptors may be a potential therapy for type 2 diabetes. This has been of particular interest in relation to the parasympathetic receptors, since their activation increases insulin secretion. For example, activation of the M3 receptors  as well as of the PACAP [62,63], VPAC1 [64,65], and VPAC2 receptors  induces insulin secretion. A drawback is, however, that both PACAP and VIP also stimulate glucagon secretion, which would be predicted to aggravate hyperglycemia in type 2 diabetes; therefore this approach has not yet been approved for preclinical trials in humans.
Since the sympathetic neurotransmitters inhibit insulin secretion, interrupting their signals may be a therapeutic target, as has been suggested for α2-adrenoceptors . Finally, the islet sensory nerves have also been proposed as a target for therapy, since sensory deafferentation improves diabetes in ZDF rats . Again, both approaches need to be explored in more detail in preclinical human studies.
The author expresses his sincere gratitude to Dr. Gerald J Taborsky, Jr., Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, WA, USA, for very constructive criticism in the preparation of this chapter and continuous long-term discussions. The work by the author has been supported by grants from the Swedish Research Council (Grant No. 6834); the Faculty of Medicine, Lund University and Region Skåne.