Brain Glucose Sensing And Neural Regulation Of Insulin And Glucagon Secretion Pdf

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Is the Brain a Key Player in Glucose Regulation and Development of Type 2 Diabetes?

Glucagon is a potent counterregulatory hormone that opposes the action of insulin in controlling glycemia. In this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo using Sur1KO mice lacking neuroendocrine-type K ATP channels and paired wild-type WT controls. Sur1KO mice fed ad libitum have normal glucagon levels and mobilize hepatic glycogen in response to exogenous glucagon but exhibit a blunted glucagon response to insulin-induced hypoglycemia.

WT islets increase glucagon secretion approximately fold when challenged with 0. Glibenclamide stimulated insulin secretion and reduced glucagon release in WT islets but was without effect on secretion from Sur1KO islets. In combination with insulin, glucagon determines the rate of gluconeogenesis and glycogenolysis in the liver and thus plays a key role in the counterregulatory response to hypoglycemia 1.

The inhibition of glucagon release after a meal is often blunted and contributes to postprandial hyperglycemia by accelerating glycogenolysis in type 2 diabetes 2. The stimulation of glucagon release by insulin-induced hypoglycemia during the counterregulatory response is impaired in type 1 diabetes and in advanced stages of type 2 diabetes 3 , 4. This reduced secretion predisposes individuals to repeated hypoglycemic episodes that may lead to coma or neurological injury 5.

Although all are potential regulators, the mechanism s by which falling blood glucose controls glucagon secretion is not well understood.

One school of thought holds that low glucose sensing in the brain, particularly neurons in the hypothalamus 18 , 19 , activates autonomic pathways that stimulate glucagon release 20 , implying intact innervation of pancreatic islets is required Recent studies provide evidence for intra-islet control, demonstrating that glucagon release is stimulated strongly by a combination of falling plasma glucose and insulin levels 22 — Here we evaluate the ability of mouse islets to secrete glucagon in response to a hypoglycemic challenge and use Sur1KO islets to establish a role for K ATP channels in the glucagon secretory response to hypoglycemia.

Sur1KO mice were generated by homologous recombination as described previously A 6-h fast was initiated between and h; experiments were done between and h.

Experiments with fed mice were done between and h. Data points were obtained from mice euthanized at the time points as indicated in the figure legends. Short-acting human insulin 0. Human glucagon 0. Insulin and glucagon were dissolved in 0. The final dimethyl sulfoxide concentration was 0. Pancreatic islets were isolated by intraductal injection of 1. Amino acids were included to simulate conditions in vivo ; antibiotics were included to prevent bacterial growth.

Islets were washed twice with KRB and preincubated at 37 C with gentle shaking. After 30 min, the medium was replaced with KRB containing 1. Aprotinin 5. Louis, MO. Determinations were done in duplicate for the number of different islet preparations indicated in the figure legends. The glucose concentration was raised to Samples were collected at the indicated time points, aprotinin was added, and the samples were handled as described above. Charles, MO.

Plasma insulin was measured in 5. Liver glycogen content was determined using the anthrone reaction 35 normalized to protein content determined using the BCA bicinchoninic acid assay Pierce Biotechnology, Inc. Values are expressed as micrograms glycogen per microgram protein. To compare their counterregulatory responses, insulin was administered to fed WT and Sur1KO animals to induce hypoglycemia. The initial blood glucose values were the same in both animals, but administration of insulin 0.

Blood glucose values returned to normal in the control animals within approximately 90 min, whereas the Sur1KO mice exhibited a slower rate of recovery Fig. Although their initial plasma values were equivalent, 15 min of hypoglycemia prompted a 2-fold increase in glucagon level in Sur1KO mice vs. Similar observations have been made in patients with persistent hyperinsulinism of infancy 36 and another Sur1KO mouse model The initial hepatic glycogen contents were the same in both animals, and insulin produced a comparable transient increase in glycogen content during the first 15 min, presumably as a consequence of increased insulin-dependent glucose uptake 37 or because of a greater hepatic glycogen cycling as a result of inhibition of glycogenolysis This transient increase was followed by a marked decline in glycogen content in both animals, although the rate of glycogen use was reduced in the Sur1KO animals Fig.

The results extend a study using K IR 6. Sur1KO mice have an impaired glucagon response to insulin-induced hypoglycemia.

A, Changes in blood glucose after ip injection of insulin 0. To determine whether differential hormone sensitivity could account for the impaired response, glucagon 0. WT mice exhibited a transient, less than 2-fold, increase in blood glucose that returned to the control value within 60 min, whereas the Sur1KO animals displayed a greater, sustained hyperglycemia Fig.

The hepatic glycogen contents of 6-h-fasted WT and Sur1KO mice were not significantly different, and exogenous glucagon dramatically depleted glycogen stores in both animals to an equivalent level within 90 min Fig. The plasma insulin levels were significantly lower in Sur1KO vs. WT mice Fig. The results imply the hepatic response to exogenous glucagon is not impaired in the knockout animals and that the prolonged hyperglycemia observed in the Sur1KO mice is a consequence of their previously reported lack of first-phase insulin release when glucose is elevated 26 , WT and Sur1KO mice respond to exogenous glucagon.

A, Blood glucose changes after injection of 0. A previous study reported that glucagon release from K IR 6. This report focused on the central nervous system CNS component, concluding it is impaired. When tested under hypoglycemic conditions 2 h in 1.

Isolated Sur1KO islets have an attenuated response to low glucose. Figure 3B illustrates the normal biphasic insulin response of WT islets to a stepwise change in glucose concentration. Figure 3D shows that switching WT islets from low to high glucose 2. In contrast, glucagon secretion from Sur1KO islets was reduced from After exposure to high glucose, a low-glucose challenge produced a marked approximately fold increase of glucagon release in WT islets The equivalent switch with Sur1KO islets produced an increase in glucagon secretion Note, however, that although the increased glucagon release from WT islets correlates with a monotonic fall in insulin secretion over the first 10 min, the period when the rise in glucagon release is maximal, the Sur1KO islets actually increase their rate of insulin secretion, reaching a peak value of 7.

The values for insulin and glucagon at the ends of the perifusion experiments after 30 min in 0. P values comparing WT vs. Glibenclamide strongly stimulates insulin secretion from WT islets in 0. Note that the levels of glucagon secretion from WT islets treated with glibenclamide mimic the impaired release observed for Sur1KO islets compare Fig. A, Response of WT islets. B, Response of Sur1KO islets. The perifusion protocol is the same as shown in Fig.

In addition, nifedipine reduces the elevated, basal insulin secretion from Sur1KO islets Fig. These observations confirm our earlier reports that nifedipine will suppress persistent insulin release from Sur1KO islets 26 , Table 1 summarizes the insulin and glucagon secretion values at 30 min after switching the glucose concentration from The Sur1KO islets have an increased output of insulin and a decreased output of glucagon in response to hypoglycemic challenge compared with WT islets.

Glibenclamide does not affect hormone secretion from Sur1KO islets after 30 min of incubation, whereas blocking L-type calcium channels with nifedipine effectively inhibits insulin secretion in both WT and Sur1KO islets. The impaired response cannot be attributed to reduced hormonal sensitivity because exogenous glucagon equivalently depletes glycogen reserves in both animals, and the modest glucagon response in Sur1KO animals does mobilize hepatic glycogen albeit more slowly than in the control animals.

Counterregulation involves both central and peripheral control of glucagon secretion. The results extend the analysis reported for K IR 6. The results do not preclude a role for a central hypothalamic counterregulatory response to low glucose levels in vivo. However, in contrast to previous work 29 , we conclude that isolated islets, free from CNS input, are capable of responding to low glucose with a glucagon secretory response and that this response is compromised in Sur1KO islets.

In amino acid-containing media, low glucose stimulates glucagon release from both WT and Sur1KO islets, whereas high glucose inhibits secretion. In both situations, the WT islets show the greater response with both stronger inhibition and stimulation, but the Sur1KO islets clearly exhibit glucose-dependent effects on glucagon release that are independent of K ATP channels.

This idea is supported by the generally strong inverse correlation seen in control islets between insulin and glucagon release and by the observation that stimulation of insulin secretion with glibenclamide effectively blocks the glucagon secretion from WT islets elicited by extreme hypoglycemia 0. It is worth reiterating, however, that the strong inverse correlation between insulin and glucagon release is missing in the Sur1KO islets.

This can be seen clearly, for example, in Fig. Therefore, we attempted to inhibit insulin secretion from Sur1KO islets with nifedipine in an effort to mimic the fall in insulin seen in WT islets and test the idea that falling insulin and falling glucose would enhance glucagon secretion in the absence of K ATP channels. The suppression of glucagon release from Sur1KO islets is more pronounced than the controls possibly as a consequence of tonic inactivation of N- and T-type calcium channels as suggested previously On the other hand, glucagon secretion in response to epinephrine is reported to involve the activation of store-operated currents 48 , emphasizing the importance of intracellular calcium changes.

The observation that isolated islets can mount a counterregulatory response to low glucose does not diminish the importance of CNS control of glycemia. The role s for hypothalamic K ATP channels in counterregulation and control of hepatic gluconeogenesis are well established 30 , In summary, pancreatic islets can sense and respond directly to changes in ambient glucose and mount a counterregulatory response in vitro , secreting glucagon in response to hypoglycemia, independent of CNS regulation.

Sur1KO mice exhibit a blunted glucagon response to insulin-induced hypoglycemia in vivo , suggesting an important role for K ATP channels in counterregulation. Google Scholar. Am J Physiol : E — E Diabetologia 45 : — Cryer PE Diverse causes of hypoglycemia-associated autonomic failure in diabetes.

N Engl J Med : — Ann Neurol 17 : — Overview of 6 years therapy of type II diabetes: a progressive disease. Prospective Diabetes Study Group.

CNS control of the endocrine pancreas

Ever since Claude Bernards discovery in the mid 19th-century that a lesion in the floor of the third ventricle in dogs led to altered systemic glucose levels, a role of the CNS in whole-body glucose regulation has been acknowledged. However, this finding was later overshadowed by the isolation of pancreatic hormones in the 20th century. Since then, the understanding of glucose homeostasis and pathology has primarily evolved around peripheral mechanism. Due to scientific advances over these last few decades, however, increasing attention has been given to the possibility of the brain as a key player in glucose regulation and the pathogenesis of metabolic disorders such as type 2 diabetes. Studies of animals have enabled detailed neuroanatomical mapping of CNS structures involved in glucose regulation and key neuronal circuits and intracellular pathways have been identified. Furthermore, the development of neuroimaging techniques has provided methods to measure changes of activity in specific CNS regions upon diverse metabolic challenges in humans. In this narrative review, we discuss the available evidence on the topic.

Is the Brain a Key Player in Glucose Regulation and Development of Type 2 Diabetes?

It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases.

Background

Increasing evidence suggests that, although pancreatic islets can function autonomously to detect and respond to changes in the circulating glucose level, the brain cooperates with the islet to maintain glycaemic control. Here, we review the role of the central and autonomic nervous systems in the control of the endocrine pancreas, including mechanisms whereby the brain senses circulating blood glucose levels. We also examine whether dysfunction in these systems might contribute to complications of type 1 diabetes and the pathogenesis of type 2 diabetes. Blood glucose levels are maintained within narrow physiological limits. Whenever glucose levels deviate from their defended level, adaptive metabolic responses are engaged to ensure glucose levels return to the normal range. Critical to these responses are the capacities of pancreatic islet alpha and beta cells to coordinately adjust glucagon and insulin secretion, respectively, in response to changes in blood glucose concentrations. However, accumulating evidence suggests that the central nervous system CNS works in tandem with the islet to maintain glucose homeostasis [ 1 ].

Insulin and glucagon have opposite effects on glycaemia as well as on the metabolism of nutrients. Insulin acts mainly on muscle, liver and adipose tissue with an anabolic effect, inducing the incorporation of glucose into these tissues and its accumulation as glycogen and fat. By contrast, glucagon induces a catabolic effect, mainly by activating liver glycogenolysis and gluconeogenesis, which results in the release of glucose to the bloodstream. An abnormal function of these cells can generate failures in the control of glycaemia, which can lead to the development of diabetes Dunning et al. Actually, diabetes is associated with disorders in the normal levels of both insulin and glucagon. An excess of glucagon plasma levels relative to those of insulin can be determinant in the higher rate of hepatic glucose output, which seems to be critical in maintaining hyperglycaemia in diabetic patients Dunning et al. Several factors may explain this lack of information about glucagon secretion.

CNS control of the endocrine pancreas

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