Central Regulation Of Glucose Homeostasis Research Articles

A dahlia flower extract has antidiabetic properties by improving insulin function in the brain

Abstract Butein, a rare chalcone found in the toxic plant Toxicodendron vernicifluum, has been shown to regulate glucose homeostasis via inhibition of the nuclear factor kappa-B kinase subunit beta (IKKβ)/nuclear factor kappa B (NF-κB) pathway in the brain. Here, we investigated whether the nonpoisonous plant Dahlia pinnata could be a source of butein as a potential treatment for type 2 diabetes (T2D). In mice fed a high-fat diet (HFD) to induce glucose intolerance, an oral D. pinnata petal extract improved glucose tolerance at doses of 3.3 mg/kg body weight and 10 mg/kg body weight. Surprisingly, this effect was not mediated by butein alone but by butein combined with the closely related flavonoids, sulfuretin and/or isoliquiritigenin. Mechanistically, the extract improved systemic insulin tolerance. Inhibition of phosphatidylinositol 3-kinase to block insulin signaling in the brain abrogated the glucoregulatory effect of the orally administered extract. The extract reinstated central insulin signaling and normalized astrogliosis in the hypothalamus of HFD-fed mice. Using NF-κB reporter zebrafish to determine IKKβ/NF-κB activity, a potent anti-inflammatory action of the extract was found. A randomized controlled crossover clinical trial on participants with prediabetes or T2D confirmed the safety and efficacy of the extract in humans. In conclusion, we identified an extract from the flower petals of D. pinnata as a novel treatment option for T2D, potentially targeting the central regulation of glucose homeostasis as a root cause of the disease.

Gastric Bypass Surgery Regulates Glucose Homeostasis Through the Hypothalamus

To explore the role of blood glucose regulation in gastric bypass surgery is a hot point in the treatment of diabetes in recent years. Current evidence is very clear that the gastric bypass surgery is one of the most promising therapy to cure type 2 diabetes. However, the mechanisms are not yet understood. Studying the mechanism of surgical treatment can not only understand the pathogenesis of diabetes, but also have important scientific and practical significance for clinically and safely carrying out this therapy. As is known to all, the body's energy metabolism and glucose homeostasis are regulated by the hypothalamus. Thus, we summarize the process mechanism of central regulation of glucose homeostasis in post-surgery and find that the hypothalamus after gastric bypass surgery showed enhanced expression of peripheral signal receptors, enhancement of leptin signal and insulin signal, and expression changes of certain related genes, then issued neuroendocrine signals to control peripheral insulin sensitivity and glucose metabolism. Then, we prove that the improvement of peripheral metabolic status is caused by the decisive role of central regulation in post-surgery. These funding provide scientific basis to improve the understanding of the neuroendocrine mechanism of diabetes and the development of clinical implication of gastric bypass surgery.

Central Regulation of Glucose Homeostasis.

The ability of the brain to directly control glucose levels in the blood independently of its effects on food intake and body weight has been known ever since 1854 when Claude Bernard, a French physiologist, discovered that lesioning the floor of the fourth ventricle in rabbits led to a rise of sugar in the blood. Despite this outstanding discovery at that time, it took more than 140 years before progress started to be made in identifying the underlying mechanisms of brain-mediated control of glucose homeostasis. Technological advances including the generation of brain insulin receptor null mice revealed that insulin action specifically in the central nervous system is required for the regulation of glucose metabolism, particularly in the modulation of hepatic glucose production. Furthermore, it was established that the hormone leptin, known for its role in regulating food intake and body weight, actually exerts its most potent effects on glucose metabolism, and that this function of leptin is mediated centrally. Under certain circumstances, high levels of leptin can replicate the actions of insulin, thus challenging the idea that life without insulin is impossible. Disruptions of central insulin signaling and glucose metabolism not only lead to impairments in whole body glucose homeostasis, they also have other serious consequences, including the development of Alzheimer's disease which is sometimes referred to as type 3 diabetes reflecting its common etiology with type 2 diabetes. © 2017 American Physiological Society. Compr Physiol 7:471-764, 2017.

Multilevel control of glucose homeostasis by adenylyl cyclase 8

Nutrient homeostasis requires integration of signals generated by glucose metabolism and hormones. Expression of the calcium-stimulated adenylyl cyclase ADCY8 is regulated by glucose and the enzyme is capable of integrating signals from multiple pathways. It may thus have an important role in glucose-induced signalling and glucose homeostasis. We used pharmacological and genetic approaches in beta cells to determine secretion and calcium metabolism. Furthermore, Adcy8 knockout mice were characterised. In clonal beta cells, inhibitors of adenylyl cyclases or their downstream targets reduced the glucose-induced increase in cytosolic calcium and insulin secretion. This was reproduced by knock-down of ADCY8, but not of ADCY1. These agents also inhibited glucose-induced increase in cytosolic calcium and electrical activity in primary beta cells and similar effects were observed after ADCY8 knock-down. Moreover, insulin secretion was diminished in islets from Adcy8 knockout mice. These mice were glucose intolerant after oral or intraperitoneal administration of glucose whereas their levels of glucagon-like peptide-1 remained unaltered. Finally, we knocked down ADCY8 in the ventromedial hypothalamus to evaluate the need for ADCY8 in the central regulation of glucose homeostasis. Whereas mice fed a standard diet had normal glucose levels, high-fat diet exacerbated glucose intolerance and knock-down mice were incapable of raising their plasma insulin levels. Finally we confirmed that ADCY8 is expressed in human islets. Collectively, our findings demonstrate that ADCY8 is required for the physiological activation of glucose-induced signalling pathways in beta cells, for glucose tolerance and for hypothalamic adaptation to a high-fat diet via regulation of islet insulin secretion.

Central Adiponectin Acutely Improves Glucose Tolerance in Male Mice

Adiponectin, an adipocyte-derived hormone, regulates glucose and lipid metabolism. It is also antiinflammatory. During obesity, adiponectin levels and sensitivity are reduced. Whereas the action of adiponectin in the periphery is well established the neuroendocrine role of adiponectin is largely unknown. To address this we analyzed the expression of adiponectin and the 2 adiponectin receptors (AdipoR1 and AdipoR2) in response to fasting and to diet-induced and genetic obesity. We also investigated the acute impact of adiponectin on central regulation of glucose homeostasis. Adiponectin (1 μg) was injected intracerebroventricularly (ICV), and glucose tolerance tests were performed in dietary and genetic obese mice. Finally, the influence of ICV adiponectin administration on central signaling cascades regulating glucose homeostasis and on markers of hypothalamic inflammation was assessed. Gene expression of adiponectin was down-regulated whereas AdipoR1 was up-regulated in the arcuate nucleus of fasted mice. High-fat (HF) feeding increased AdipoR1 and AdipoR2 gene expression in this region. In mice on a HF diet and in leptin-deficient mice acute ICV adiponectin improved glucose tolerance 60 minutes after injection, whereas normoglycemia in control mice was unaffected. ICV adiponectin increased pAKT, decreased phospho-AMP-activated protein kinase, and did not change phospho-signal transducer and activator of transcription 3 immunoreactivity. In HF-fed mice, ICV adiponectin reversed parameters of hypothalamic inflammation and insulin resistance as determined by the number of phospho-glycogen synthase kinase 3 β(Ser9) and phospho-c-Jun N-terminal kinase (Thr183/Tyr185) immunoreactive cells in the arcuate nucleus and ventromedial hypothalamus. This study demonstrates that the insulin-sensitizing properties of adiponectin are at least partially based on a neuroendocrine mechanism that involves centrally synthesized adiponectin.

Role of orexin in the central regulation of glucose and energy homeostasis [Review

Hypothalamic orexin neurons are known to regulate sleep/wake stability, feeding behavior, emotions, autonomic nerve activity, and whole-body energy metabolism. In addition, emerging evidence indicates that orexin contributes to central regulation of glucose homeostasis. Intriguingly, central administration of orexin is reported to cause blood glucose-elevating effect or blood glucose-lowering effect in rodents, depending on the experimental conditions. Here we reviewed the recent reports regarding the mode and mechanism of actions of orexin on these two opposing effects, and discuss the functional significance for the maintenance of glucose homeostasis. The fact that orexin exhibits biphasic effects on autonomic nerve activity and lipolysis suggests that orexin dually regulates the glucose appearance. In fact, orexin neurons are activated not only depending on the demand for glucose but also according to a circadian rhythm in the suprachiasmatic nucleus. The excited orexin neurons appear to alter the sympathetic or parasympathetic outflow to the periphery, and modulate the glucose production and utilization. Furthermore, deficiency of orexin action, particularly reduction of orexin 2 receptor-signaling, disrupts the mechanism for protection against insulin resistance associated with aging or induced by chronic high fat feeding in mice. Taken together, hypothalamic orexin system may manage multiple tasks to coordinate the interconnection among the arousal, feeding, circadian, and glucose homeostasis pathways.

Glucose sensitivity in mouse substantia nigra pars reticulata neurons in vitro

Glucose sensitivity of substantia nigra pars reticulata (SNr) GABAergic neurons was investigated by extracellular recording in acute slice. Approximately two thirds of the GABAergic SNr neurons tested exhibited a significant increase in spontaneous firing rate as the extracellular glucose concentration was lowered from 10 to 4–6 mM. At lower glucose concentrations, a small proportion of these glucose-sensitive GABAergic SNr neurons exhibited multiple, robust increases in spontaneous firing rate with periods ranging in minutes. Similar changes in firing rate of SNr neurons in response to lowered glucose were detected under blockade of GABA A, NMDA, and non-NMDA receptors, indicating that mechanisms other than those mediated by the major synaptic transmissions in the SNr are involved. These findings suggest involvement of previously unknown glucose dependent alterations of GABAergic SNr neuronal activity in the central regulation of glucose homeostasis.

Electrical stimulation of the suprachiasmatic nucleus of the hypothalamus causes hyperglycemia.

We have presented evidence suggesting that the suprachiasmatic nucleus (SCN) is involved in central regulation of glucose homeostasis. To elucidate this role of the SCN, we examined the effects of its electrical stimulation on glucose metabolism in male Wistar rats. During and shortly after this stimulation, we observed hyperglycemia associated with enhanced hyperglucagonemia but no immediate hyperinsulinemia. In addition, we detected significant increase in liver glycogen phosphorylase alpha activity and significant decrease in the liver glycogen content. These findings suggest that the SCN is important in control of glucose homeostasis through effects on glucagon and insulin secretions and liver glycogen metabolism.

Naloxone decreases centrally induced hyperglycemia in dogs. Evidence for an opioid role in glucose homeostasis.

Intracerebroventricular (ICV) instillation of morphine and beta-endorphin causes centrally induced hyperglycemia. Locally active, endogenous opioids in the central nervous system may, therefore, also be involved in the elevation of blood sugar. This possibility was tested by examining the glucoregulatory response to central glucoprivation induced by ICV administration of 2-deoxy-D-glucose (2DG) in dogs. Administration of 2DG resulted in a rise in plasma glucose and immunoreactive glucagon (IRG) of 108 +/- 19 mg/dl and 70 +/- 20 pg/ml, respectively. These changes were attenuated by the simultaneous central infusion of the opiate antagonist naloxone: plasma glucose levels increased by 77 +/- 14 mg/dl and IRG by 43 +/- 3 pg/ml, both significantly different from the effect of 2DG alone (P less than 0.05-0.01). These findings suggest that opiate receptors participate in the counterregulatory response to central glucoprivation. They also provide a mechanism by which endogenous opioid peptides may play a role in the central regulation of glucose homeostasis.