Inhibition of central GABAA receptors enhances hepatic glucose production and peripheral glucose uptake

doi:10.1016/0361-9230(95)00052-G

Brain Research Bulletin

Volume 37, Issue 6, 1995, Pages 611-616

https://doi.org/10.1016/0361-9230(95)00052-G Get rights and content

Abstract

Previous studies have demonstrated that intracerebroventricular (ICV) injection of bicuculline methiodide (BMI), a gamma-amkrobutyric acid receptor antagonist, increases plasma glucose concentrations. The purpose of the present study was to determine whether the hyperglycemic response was due to an increased rate of hepatic glucose production (HGP) or a change in the rate of glucose utilization. In vivo glucose flux was assessed in catheterized, conscious overnight fasted rats using [3-³H]glucose. ICV injection of BMI (10 nmol) increased glucose levels 60% after 30 min. This hyperglycemia resulted from a rapid increase in HGP that exceeded an increased rate of glucose utilization. No alteration in the glucose metabolic clearance rate, an index of the avidity of the body's tissues for glucose, was detected in BMI-Injected rats. BMI enhanced both hepatic gluconeogermals and glycogenolysis, since the reduction in War glycogen (19 μmol/g liver) could not totally account for all of the increased HGP. These metabolic alterations were associated with sustained increases in circulating concentrations of corticosterone, giucagon and catecholamines. Prior adrenalectomy completely abolished the BMI-induced increase in glucose flux and the reduction in tissue glycogen, despite the persistent hyperglucagonemia. These data indicate that, in the fasted condition, the hyperglycemia produced by central administration of BMI results from an increased rate of HGP (both gluconeogenesis and glycogenolysis) and not a reduction in the ability of tissues to use glucose. The concomitant elevation in glucose disposal was the result of an increased mass action effect. The enhanced glucose metabolic response to BMI appears mediated exclusively by an increased secretion of epinephrine from the adrenal medulla.

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GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet
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Citation Excerpt :
Other studies reported that insulin sensitivity was not altered, while glucose tolerance was significantly improved (Palak and Dipa, 2013). Lang and colleagues reported that injection of intra cerebroventricular GABA antagonist increased glucagon level and gluconeogenesis and led to hyperglycemia (Lang, 1995). This finding raises the question of possible brain-mediated effects of GABA on islet secretion and possibly, insulin resistance.
Skeletal muscle, hepatic insulin resistance, and beta cell dysfunction are the characteristic pathophysiological features of type 2 diabetes mellitus. GABA has an important role in pancreatic islet cells. The present study attempted to clarify the possible mechanism of GABA to improve glucose tolerance in a model of type 2 diabetes mellitus in rats. Fifty Wistar rats were divided into five groups: NDC that was fed the normal diet, CD which received a high-fat diet with streptozotocin, CD-GABA animals that received GABA via intraperitoneal injection, plus CD-Ins1 and CD-Ins2 groups which were treated with low and high doses of insulin, respectively. Body weight and blood glucose were measured weekly. Intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), urine volume, amount of water drinking, and food intake assessments were performed monthly. The hyperinsulinemic euglycemic clamp was done for assessing insulin resistance. Plasma insulin and glucagon were measured. Abdominal fat was measured. Glucagon receptor, Glucose 6 phosphatase, Phosphoenolpyruvate carboxykinase genes expression were evaluated in liver and Glucose transporter 4 (GLUT4) genes expression and protein translocation were evaluated in the muscle. GABA or insulin therapy improved blood glucose, insulin level, IPGTT, ITT, gluconeogenesis pathway, Glucagon receptor, body weight and body fat in diabetic rats. GLUT4 gene and protein expression increased. GABA whose beneficial effect was comparable to that of insulin, also increased glucose infusion rate during an euglycemic clamp. GABA could improve insulin resistance via rising GLUT4 and also decreasing the gluconeogenesis pathway and Glucagon receptor gene expression.
The hypothalamic clock and its control of glucose homeostasis
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Published data on the hypothalamic control of peripheral glucose uptake (other than that induced by the mass action of glucose) are scarce. ICV injections of NMDA cause a profound increase of glucose uptake in muscle tissue [28]. The effect of NMDA was neurally mediated and independent of circulating insulin levels.
The everyday life of mammals, including humans, exhibits many behavioral, physiological and endocrine oscillations. The major timekeeping mechanism for these rhythms is contained in the central nervous system (CNS). The output of the CNS clock not only controls daily rhythms in sleep/wake (or feeding/fasting) behavior but also exerts a direct control over glucose metabolism. Here, we show how the biological clock plays an important role in determining early morning (fasting) plasma glucose concentrations by affecting hepatic glucose production and glucose uptake, as well as glucose tolerance, by determining feeding-induced insulin responses. Recently, large-scale genetic studies in humans provided the first evidence for the involvement of disrupted (clock gene) rhythms in the pathogenesis of type 2 diabetes.
Chapter 17: The hypothalamic clock and its control of glucose homeostasis
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Citation Excerpt :
Together, these functional studies demonstrate that a stimulation of neuronal activity in the PVN results in hyperglycemia through an activation of the sympathetic input to the liver. In our experiments hepatic glucose production was not assessed directly, but previously Lang (1995) had demonstrated a stimulatory effect of intracerebroventricularly applied BIC on portal glucose levels using the euglycemic clamp technique. Moreover, our data fit in nicely with previous experiments showing increased glucose production or glucose release by the liver upon electrical stimulation of its sympathetic input (Shimazu, 1996; Takahashi et al., 1996; Nonogaki, 2000).
Major components of energy metabolism, including feeding, thermogenesis, and glucose and lipid metabolism, show profound fluctuations along the daily light/dark (L/D)-cycle. In mammals, these periodic changes in the environment are ‘‘internalized’’ in the form of an endogenous circadian clock. In the case of energy metabolism, the biological clock output acts to synchronize energy intake and expenditure to changes in the external environment imposed by the rising and setting of the sun. According to a hypothesis, the suprachiasmatic nucleus (SCN) plays an important role in anticipating major physiological events, such as increased behavioral activity, feeding activity or sleep. This chapter employs two different research strategies to reveal the direct role played by the SCN. The first strategy involves a regular feeding schedule with six meals equispaced throughout the 24-h L/D-cycle (i.e. one standard meal every four hour) to remove the strong masking impact of the rhythmic feeding behavior and to unmask a possible direct control of the circadian clock. The second strategy involves the viral retrograde tracing technique to investigate the existence of multi-synaptic neural connections between the hypothalamic biological clock and peripheral organs such as the (endocrine) pancreas, the liver, and white adipose tissue (WAT). The chapter also presents the evidence for a direct control of the biological clock on the release of metabolic hormones, independent of the clock control on the temporal distribution of feeding behavior. Additionally, an overview of the neural mechanisms, pathways, and transmitters used by the SCN is presented to incorporate its time-of-day message into this homeostatic system.
Role of central neural mechanisms in the regulation of hepatic glucose metabolism
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Central monoamine neurotransmitters affect blood glucose homeostasis. Activation of central cholinergic, noradrenergic histaminergic, and serotonergic neurons rapidly increase hepatic glucose output via the sympathetic nervous system. Acute hyperglycemia is mediated by three distinct pathways: the action of epinephrine on the liver, the action of glucagon on the liver, and the direct innervation of the liver. The relative contribution of these factors to hyperglycemia can be altered by diet and the kinds of neurotransmitters evoked in the central nervous system, but the magnitude of epinephrine secretion is closely related to the magnitude of hyperglycemia. On the other hand, neuropharma-cological stimulation of central cholinergic muscarinic receptors, histaminergic H₁ receptors, and serotonergic 5-HT₂ receptors increases hypothalamic noradrenergic neuronal activity, which is associated with hyperglycemia. In contrast, central GABA_A receptors play an inhibitory role in the regulation of hepatic glucose metabolism. Thus, central monoaminergic neurons could be linked together, and play a homeostatic role in the regulation of hepatic glucose metabolism.
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ArticleInhibition of central GABAA receptors enhances hepatic glucose production and peripheral glucose uptake

Abstract

Medical Hypothesis

Metabolism

Metabolism

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain stem infusion of the gamma-aminobutyric acid antagonist bicuculline increases plasma insulin levels in the rat

Endocrinology

Effect of epinephrine on glycogenolysis and gluconeogenesis in conscious overnightfasted dogs

Am. J. Physiol.

Glycogen determination with amyloglucosidase

Article
Inhibition of central GABA_A receptors enhances hepatic glucose production and peripheral glucose uptake