Central Regulation Of Glucose Metabolism Research Articles

1539-P: Effects of Free Fatty Acids (FFA) on Central Regulation of Glucose Metabolism

Activation of hypothalamic KATP channels reduces endogenous glucose production (EGP) in nondiabetic rodents and humans, but this response is lost in T2D. Lowering FFA with nicotinic acid (NA) restored central regulation of EGP in T2D subjects (Diabetes 2019; 1799P). High FFA levels, typical of T2D, may increase endoplasmic reticulum (ER) stress and thereby impair hypothalamic control of EGP. To explore how increased FFA might impact central regulation of EGP, we harvested hypothalamic wedges from n=10 Zucker Diabetic Fatty (ZDF) rats (glucose ~ 370 mg/dL) following infusion of NA or saline (Alzet minipump) for 18 h. Nondiabetic rats (n=5) were studied as controls. Gene expression of KATP channel subunit Kir6.2 was decreased in ZDF rats. Upon lowering FFA with NA, hypothalamic expression of this major subunit was restored (Fig 1a). Conversely, increased expression of genes regulating ER stress was reversed by NA (Fig 1b). Directly treating ZDF rat brain slices with NA did not alter the expression of these genes, suggesting that NA's effects were mediated by lowering FFA (Fig 1c). In conclusion, hypothalamic effects of elevated FFA include reduced KATPchannel expression and increased expression of ER stress genes, both of which may contribute reversibly to the loss of central regulation of EGP in T2D. These findings are consistent with our observations in humans noted above, suggesting that FFA could be a therapeutic target in T2D. Disclosure M. Nogueira Cordeiro: None. V.H. Routh: None. A. Manavalan: None. P.M. Mathias: None. C.E. Boyle: None. A.C. Rios Chen: None. N. Jiang: None. N. Friedman: None. Y. Demirhan: None. M. Hawkins: None. K. Zhang: None. Funding American Diabetes Association (7-08-CR-28 to M.H.); National Institutes of Health (R01DK069861); Diabetes Action Research and Education Foundation

Interactions between Intestinal Homeostasis and NAD+ Biology in Regulating Incretin Production and Postprandial Glucose Metabolism

The intestine has garnered attention as a target organ for developing new therapies for impaired glucose tolerance. The intestine, which produces incretin hormones, is the central regulator of glucose metabolism. Glucagon-like peptide-1 (GLP-1) production, which determines postprandial glucose levels, is regulated by intestinal homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) biosynthesis in major metabolic organs such as the liver, adipose tissue, and skeletal muscle plays a crucial role in obesity- and aging-associated organ derangements. Furthermore, NAMPT-mediated NAD+ biosynthesis in the intestines and its upstream and downstream mediators, adenosine monophosphate-activated protein kinase (AMPK) and NAD+-dependent deacetylase sirtuins (SIRTs), respectively, are critical for intestinal homeostasis, including gut microbiota composition and bile acid metabolism, and GLP-1 production. Thus, boosting the intestinal AMPK-NAMPT-NAD+-SIRT pathway to improve intestinal homeostasis, GLP-1 production, and postprandial glucose metabolism has gained significant attention as a novel strategy to improve impaired glucose tolerance. Herein, we aimed to review in detail the regulatory mechanisms and importance of intestinal NAMPT-mediated NAD+ biosynthesis in regulating intestinal homeostasis and GLP-1 secretion in obesity and aging. Furthermore, dietary and molecular factors regulating intestinal NAMPT-mediated NAD+ biosynthesis were critically explored to facilitate the development of new therapeutic strategies for postprandial glucose dysregulation.

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis.

26RFa (pyroglutamilated RFamide peptide [QRFP]) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localised in the hypothalamus. In this study we investigated whether 26RFa neurons are involved in the hypothalamic regulation of glucose homeostasis. 26Rfa+/+, 26Rfa-/- and insulin-deficient male C57Bl/6J mice were used in this study. Mice received an acute intracerebroventricular (i.c.v.) injection of 26RFa, insulin or the 26RFa receptor (GPR103) antagonist 25e and were subjected to IPGTTs, insulin tolerance tests, acute glucose-stimulated insulin secretion tests and pyruvate tolerance tests (PTTs). Secretion of 26RFa by hypothalamic explants after incubation with glucose, leptin or insulin was assessed. Expression and quantification of the genes encoding 26RFa, agouti-related protein, the insulin receptor and GPR103 were evaluated by quantitative reverse transcription PCR and RNAscope in situ hybridisation. Our data indicate that i.c.v.-injected 26RFa induces a robust antihyperglycaemic effect associated with an increase in insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26Rfa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26Rfa are mainly localised in the lateral hypothalamic area, that they co-express the gene encoding the insulin receptor and that insulin induces the expression of 26Rfa in these neurons. Concurrently, the central antihyperglycaemic effect of insulin is abolished in the presence of a GPR103 antagonist and in 26RFa-deficient mice. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. We have identified a novel mechanism in the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system, and we provide evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

Elaborating the Physiological Role of YAP as a Glucose Metabolism Regulator:A Systematic Review.

Yes-associated protein (YAP) is one of the Hippo pathway's two effectors, a pathway associated with organ size control. Research on YAP has focused on its oncogenic potential. However, in cancer cells, aside from inducing growth, YAP was also found to regulate glucose metabolism. The present review explores YAP's control of glucose metabolism and whether these findings are translatable to physiological conditions. According to current literature, YAP induces the transcriptional activity of most genes associated with glucose metabolism from enzymes to transport proteins. In glycolysis and gluconeogenesis, YAP upregulates all enzymes except for enolase and pyruvate kinase. Multiple research has also shown YAP's ability to regulate the expression of glucose transporter of the GLUT family. Additionally, glucose concentration, hypoxia, and hormones such as insulin and glucagon regulate YAP activity and depend on YAP to exert their biological activity. YAP is thus a central regulator of glucose metabolism, controlling both enzymes and proteins involved in glucose transport. YAP is also situated strategically in several pathways controlling glucose and was found to mediate their effects. If these results were consistent in physiological conditions and across glucose-associated metabolic disturbances, then YAP may become a prospective therapeutic target.

Central regulation of glucose metabolism in an insulin-dependent and -independent manner.

The central nervous system (CNS) contributes significantly to glucose homeostasis. The available evidence indicates that insulin directly acts on the CNS, in particular the hypothalamus, to regulate hepatic glucose production, thereby controlling whole-body glucose metabolism. Additionally, insulin also acts on the brain to regulate food intake and fat metabolism, which may indirectly regulate glucose metabolism. Studies conducted over the last decade have found that the CNS can regulate glucose metabolism in an insulin-independent manner. Enhancement of central leptin signalling reverses hyperglycaemia in insulin-deficient rodents. Here, I review the mechanisms by which central insulin and leptin actions regulate glucose metabolism. Although clinical studies have shown that insulin treatment is currently indispensable for managing diabetes, unravelling the neuronal mechanisms underlying the central regulation of glucose metabolism will pave the way for the design of novel therapeutic drugs for diabetes.

Central Regulation of Glucose Metabolism in Humans: Fact or Fiction?

In the past few years, insulin action in the central nervous system (CNS) has attracted a growing interest to better understand the association between neurodegenerative diseases and insulin resistance (IR). Rodent studies have indicated that insulin signaling in the CNS is critical for the suppression of endogenous glucose production (EGP) in the liver (1) and for the regulation of adipose tissue lipolysis (2). These central insulin effects likely depend on PI3K-mediated regulation of several proteins and transcription factors, among which are FoxO1 (3) and AMPK (4), and on the activation of KATP channels (5) in the hypothalamus (Fig. 1). Recent findings show that subsequent activation of hepatic Kupffer cells and an increase in hepatic interleukin-6 induce signal transducer and activator of transcription 3 (STAT3) phosphorylation to inhibit gluconeogenic gene expression (6). Suppression of lipolysis in adipose tissue by brain insulin signaling reduces the availability of gluconeogenic substrates for the liver, which will further decrease EGP (2). In contrast, studies in dogs did not support the concept of a physiological relevance of CNS insulin action for controlling EGP (7). Figure 1 Brain insulin regulation of hepatic glucose production and adipose tissue lipolysis. The insulin-signaling pathway in the arcuate hypothalamus involves the activation of PI3K and AKT and the subsequent inactivation of FoxO1. Also, the inhibition of AMPK and opening of KATP channels are linked to brain insulin’s peripheral metabolic effects. In addition …

Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation

Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism.

Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes.

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes.

Nighttime Administration of Nicotine Improves Hepatic Glucose Metabolism via the Hypothalamic Orexin System in Mice

Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we here investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content, and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepatic gluconeogenic activity, the oral nicotine treatment moderately suppressed glucose elevations in normal mice and mice lacking dopamine receptors, whereas this effect was abolished in orexin-deficient mice and hepatic parasympathectomized mice. Under high-fat diet conditions, the oral intake of nicotine lowered blood glucose levels at the daytime resting period in wild-type, but not orexin-deficient, mice. These results indicated that the chronic daily administration of nicotine suppressed hepatic gluconeogenesis via the hypothalamic orexin-parasympathetic nervous system. Thus, the results of the present study may provide an insight into novel chronotherapy for type 2 diabetes that targets the central cholinergic and orexinergic systems.

Central sensibility of human cases with different body mass during oral glucose tolerance test using functional magnetic resonance imaging

Background Because of the limitation of technique, there are few researches on regulating function of central hypothalamus by metabolism, especially the researches on real-time function. Objective To evaluate the response of hypothalamus to oral glucose tolerance test (OGTT) in different body-weighted subjects by using functional magnetic resonance imaging (fMRI) so as to investigate the relationship between the sensitivity of hypothalamus in glycoregulation and disturbance of carbohydrate metabolism. Design Paired design. Setting Department of Radiology and Beijing Geriatrics Institute, Beijing Hospital, National Public Health Bureau. Participants A total of twenty healthy volunteers were selected from Beijing Geriatrics Institute, National Public Health Bureau, including 10 subjects with obesity (5 males and 5 females; body mass > 28.0 kg/m 2) and 10 subjects with normal body mass (5 males and 5 females; body mass from 18.5 to 23.9 kg/m 2). All subjects gave written informed consent before participating in the study. Methods fMRI study was performed on GE 1.5 T Signa Twinspeed Infinity with Excite. Each volunteer was ingested of glucose during the fMRI scan. T2* images were acquired using a single-shot gradient echo (EPI) technique. The parameters of EPI included: TR 3 000 ms, TE 40 ms, Flip angle 90°, field of view (FOV) 24 cm × 24 cm, thickness 5 mm, gap 0 mm, matrix 64 × 64, number of excitation 1. All 10 subjects with normal body mass underwent a repeat fMRI scan after consuming an equivalent amount of water without glucose on a separate day. The procedure for the fMRI scan with water intake was the same as for glucose ingestion. fMRI data were processed with Intensity Averaging Method. Main outcome measures The central response of hypothalamus and feedback orientation during OGTT in different body-weighted subjects. Results An acute transient decrease of fMRI intensity in posterior inferior and anterior inferior of hypothalamus was observed in all subjects within 2 minutes after oral glucose intake. This decrease was followed by a recovery to the baseline. However, obese subjects had a delayed intensity decrease [(1.96±1.06) minutes vs. (1.04±0.71) minutes, t =2.14, P < 0.05] and longer recovery time [(26.62±7.35) minutes vs. (16.29±6.42) minutes, t =3.67, P < 0.01] as compared with normal body-weight subjects. Furthermore, decreased fMRI intensity was significant different from baseline intensity [(5.7±2.5)% vs. (14.3±5.5)%, t =2.56, P < 0.05] in obese subjects, but not in normal body-weight subjects. The area of hypothalamus in normal body-weight volunteers demonstrated no significant signal change before and after oral water ingestion ( P > 0.05). Conclusion Hypothalamus response to glucose loading is different in normal body-weighted and obese subjects. This suggests that fMRI is a useful tool to evaluate the central regulation of glucose metabolism.

CNS inputs to the suprachiasmatic nucleus of the rat

The neural circuits that modulate the suprachiasmatic nucleus (SCN) of the rat were studied with the retrograde transneuronal tracer – pseudorabies virus. First-order afferents were also identified using cholera toxin β subunit. Olfactory processing regions (viz., main olfactory bulb, anterior olfactory nucleus, taenia tecta, endopiriform nucleus, medial amygdaloid nucleus, piriform cortex, and posteriomedial cortical amygdaloid nucleus) were virally labeled. The subfornical organ directly innervates SCN; two other circumventricular organs: organum vasculosum of the lamina terminalis and area postrema provide multisynaptic inputs. Direct limbic afferents arise from lateral septum, bed nucleus of the stria terminalis, amygdalohippocampal zone, and ventral subiculum; multineuronal connections come from the basolateral and basomedial amygdaloid nuclei, ventral hippocampus, amygdalopiriform area, as well as lateral entorhinal, perirhinal, and ectorhinal cortices. Most preoptic regions project directly to SCN. Multisynaptic inputs come from the lateral preoptic region. Hypothalamic inputs originate from the anterior, arcuate, dorsal, dorsomedial, lateral, paraventricular, posterior, periventricular posterior, retrochiasmatic, subparaventricular, ventromedial and tuberomammillary nuclei. Paraventricular thalamic nucleus, intergeniculate leaflet and zona incerta directly innervate SCN. Polyneuronal inputs arise from the subparafascicular parvicellular thalamic nucleus. Brainstem afferents originate from the pretectum, superior colliculus, periaqueductal gray matter, parabrachial nucleus, pedunculopontine nucleus, raphe system, locus coeruleus, nucleus incertus and reticular formation. Nucleus tractus solitarius, C3 catecholamine region, rostral ventrolateral medulla and spinal trigeminal nucleus provide indirect inputs. We propose that the SCN receives feedback primarily from interoceptive systems such as the circumventricular, autonomic, and neuroendocrine systems that are important in the central regulation of glucose metabolism (e.g., insulin and glucocorticoids).