scholarly journals Central KATP channels modulate glucose effectiveness in humans and rodents

2020 ◽  
Author(s):  
Ada Admin ◽  
Michelle Carey ◽  
Eric Lontchi-Yimagou ◽  
William Mitchell ◽  
Sarah Reda ◽  
...  
Keyword(s):  
Katp Channel ◽  
Glucose Production ◽  
Katp Channels ◽  
Endogenous Glucose Production ◽  
Elevated Plasma ◽  
Sprague Dawley ◽  
Glucose Effectiveness ◽  
Sprague Dawley Rats ◽  
The Central Nervous System

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (K<sub>ATP</sub> channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central K<sub>ATP</sub> channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of K<sub>ATP</sub> channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central K<sub>ATP</sub> channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

Central KATP channels modulate glucose effectiveness in humans and rodents

2020 ◽  
Author(s):  
Ada Admin ◽  
Michelle Carey ◽  
Eric Lontchi-Yimagou ◽  
William Mitchell ◽  
Sarah Reda ◽  
...  
Keyword(s):  
Katp Channel ◽  
Glucose Production ◽  
Katp Channels ◽  
Endogenous Glucose Production ◽  
Elevated Plasma ◽  
Sprague Dawley ◽  
Glucose Effectiveness ◽  
Sprague Dawley Rats ◽  
The Central Nervous System

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (K<sub>ATP</sub> channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central K<sub>ATP</sub> channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of K<sub>ATP</sub> channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central K<sub>ATP</sub> channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

scholarly journals Central KATP channels modulate glucose effectiveness in humans and rodents

2020 ◽  
Author(s):  
Ada Admin ◽  
Michelle Carey ◽  
Eric Lontchi-Yimagou ◽  
William Mitchell ◽  
Sarah Reda ◽  
...  
Keyword(s):  
Katp Channel ◽  
Glucose Production ◽  
Katp Channels ◽  
Endogenous Glucose Production ◽  
Elevated Plasma ◽  
Sprague Dawley ◽  
Glucose Effectiveness ◽  
Sprague Dawley Rats ◽  
The Central Nervous System

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (K<sub>ATP</sub> channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central K<sub>ATP</sub> channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of K<sub>ATP</sub> channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central K<sub>ATP</sub> channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

scholarly journals Central KATP channels modulate glucose effectiveness in humans and rodents

2020 ◽  
Author(s):  
Ada Admin ◽  
Michelle Carey ◽  
Eric Lontchi-Yimagou ◽  
William Mitchell ◽  
Sarah Reda ◽  
...  
Keyword(s):  
Katp Channel ◽  
Glucose Production ◽  
Katp Channels ◽  
Endogenous Glucose Production ◽  
Elevated Plasma ◽  
Sprague Dawley ◽  
Glucose Effectiveness ◽  
Sprague Dawley Rats ◽  
The Central Nervous System

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (K<sub>ATP</sub> channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central K<sub>ATP</sub> channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of K<sub>ATP</sub> channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central K<sub>ATP</sub> channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

scholarly journals Central KATP channels modulate glucose effectiveness in humans and rodents

2020 ◽  
Author(s):  
Ada Admin ◽  
Michelle Carey ◽  
Eric Lontchi-Yimagou ◽  
William Mitchell ◽  
Sarah Reda ◽  
...  
Keyword(s):  
Katp Channel ◽  
Glucose Production ◽  
Katp Channels ◽  
Endogenous Glucose Production ◽  
Elevated Plasma ◽  
Sprague Dawley ◽  
Glucose Effectiveness ◽  
Sprague Dawley Rats ◽  
The Central Nervous System

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (K<sub>ATP</sub> channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central K<sub>ATP</sub> channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of K<sub>ATP</sub> channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central K<sub>ATP</sub> channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

Endogenous glucose production and glucose effectiveness in type 2 diabetic subjects derived from stable-labeled minimal model approach

Diabetes ◽  
1999 ◽  
Vol 48 (5) ◽  
pp. 1054-1060 ◽  
Author(s):  
S. Nagasaka ◽  
K. Tokuyama ◽  
I. Kusaka ◽  
H. Hayashi ◽  
K. Rokkaku ◽  
...  
Keyword(s):  
Minimal Model ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Effectiveness ◽  
Endogenous Glucose ◽  
Type 2 Diabetic ◽  
Model Approach

Type 1 corticotropin-releasing factor receptors in the ventromedial hypothalamus promote hypoglycemia-induced hormonal counterregulation

2007 ◽  
Vol 293 (3) ◽  
pp. E705-E712 ◽  
Author(s):  
Haiying Cheng ◽  
Ligang Zhou ◽  
Wanling Zhu ◽  
Ajin Wang ◽  
Chuyan Tang ◽  
...  
Keyword(s):  
Glucose Utilization ◽  
Glucose Production ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Endogenous Glucose Production ◽  
Corticotropin Releasing Factor ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Acute Hypoglycemia ◽  
Glucose Dynamics

Type 2 corticotropin-releasing factor (CRF) receptors (CRFR2) within the ventromedial hypothalamus (VMH), a key glucose-sensing region, play a major role in regulating the hormonal counterregulatory responses (CRRs) to acute hypoglycemia. The VMH expresses both subtypes of CRF receptors, CRFR1 and CRFR2. The objective of this study was to examine the role of the CRFR1 receptor in the VMH in the regulation of the CRR to acute hypoglycemia. To compare the hormonal CRR to hypoglycemia, awake and unrestrained Sprague-Dawley rats were bilaterally microinjected to the VMH with either 1) aECF, 2) CRF (1 pmol/side), 3) CRFR1 antagonist Antalarmin (500 pmol/side), or 4) CRF + Antalarmin prior to undergoing a hyperinsulinemic hypoglycemic (2.8 mM) clamp. A second series of studies also incorporated an infusion of [3H]glucose to allow the calculation of glucose dynamics. In addition the effect of CRFR1 antagonism in the paraventricular nucleus (PVN) was studied. Activation of VMH CRFR1 increased, whereas inhibition of CRFR1 suppressed hypoglycemia-induced CRRs. Inhibition of VMH CRFR1 also increased peripheral glucose utilization and reduced endogenous glucose production during hypoglycemia, whereas VMH CRF reduced peripheral glucose utilization. In contrast CRFR1 inhibition in the PVN blunted corticosterone but not epinephrine or glucagon CRR to hypoglycemia. In contrast to CRFR2 activation, CRFR1 activation within the VMH amplifies CRRs to acute hypoglycemia. The balance between these two opposing CRFRs in this key glucose-sensing region may play an important role in determining the magnitude of CRRs to acute hypoglycemia.

scholarly journals Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production

2009 ◽  
Vol 297 (1) ◽  
pp. E165-E173 ◽  
Author(s):  
Sylvia Kehlenbrink ◽  
Julia Tonelli ◽  
Sudha Koppaka ◽  
Visvanathan Chandramouli ◽  
Meredith Hawkins ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Negative Impact ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Effectiveness ◽  
Plasma Ffa ◽  
Endogenous Glucose

Glucose effectiveness, the ability of glucose per se to suppress endogenous glucose production (EGP), is lost in type 2 diabetes mellitus (T2DM). Free fatty acids (FFA) may contribute to this loss of glucose effectiveness in T2DM by increasing gluconeogenesis (GNG) and impairing the response to hyperglycemia. Thus, we first examined the effects of increasing plasma FFA levels for 3, 6, or 16 h on glucose effectiveness in nondiabetic subjects. Under fixed hormonal conditions, hyperglycemia suppressed EGP by 61% in nondiabetic subjects. Raising FFA levels with Liposyn infusion for ≥3 h reduced the normal suppressive effect of glucose by one-half. Second, we hypothesized that inhibiting GNG would prevent the negative impact of FFA on glucose effectiveness. Raising plasma FFA levels increased gluconeogenesis by ∼52% during euglycemia and blunted the suppression of EGP by hyperglycemia. Infusion of ethanol rapidly inhibited GNG and doubled the suppression of EGP by hyperglycemia, thereby restoring glucose effectiveness. In conclusion, elevated FFA levels rapidly increased GNG and impaired hepatic glucose effectiveness in nondiabetic subjects. Inhibiting GNG could have therapeutic potential in restoring the regulation of glucose production in type 2 diabetes mellitus.

Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects

2002 ◽  
Vol 282 (6) ◽  
pp. E1360-E1368 ◽  
Author(s):  
Thongchai Pratipanawatr ◽  
Wilailak Pratipanawatr ◽  
Clifford Rosen ◽  
Rachele Berria ◽  
Mandeep Bajaj ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Control Subjects ◽  
Igf I ◽  
Plasma Ffa ◽  
Type 2 Diabetic

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU · kg−1 · min−1) clamp and a two-step euglycemic IGF-I (26 and 52 pmol · kg−1 · min−1) clamp with [3-3H]glucose, [1-14C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (Rd) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of Rd (second clamp step) in response to both insulin and IGF-I was reduced by ∼40–50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin ( P < 0.01–0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects ( P < 0.05–0.01). Conclusions: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.

Increased renal α-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape

2006 ◽  
Vol 291 (1) ◽  
pp. F49-F57 ◽  
Author(s):  
Swasti Tiwari ◽  
Randall K. Packer ◽  
Xinqun Hu ◽  
Yoshihisa Sugimura ◽  
Joseph G. Verbalis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Sprague Dawley ◽  
Α Subunit ◽  
Water Load ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Solid Diet ◽  
Epithelial Sodium Channel Enac

Previously, we demonstrated that rats undergoing vasopressin escape had increased mean arterial blood pressure (MAP), plasma and urine aldosterone, and increased renal protein abundance of the α-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter (NCC), and the 70-kDa band of γ-ENaC (Song J, Hu X, Khan O, Tian Y, Verbalis JG, and Ecelbarger CA. Am J Physiol Renal Physiol 287: F1076–F1083, 2004; Ecelbarger CA, Knepper MA, and Verbalis JG. J Am Soc Nephrol 12: 207–217, 2001). Here, we determine whether changes in these renal proteins and MAP require elevated aldosterone levels. We performed adrenalectomies (ADX) or sham surgeries on male Sprague-Dawley rats. Corticosterone and aldosterone were replaced to clamp these hormone levels. MAP was monitored by radiotelemetry. Rats were infused with 1-deamino-[8-d-arginine]-vasopressin (dDAVP) via osmotic minipumps (5 ng/h). At day 3 of dDAVP infusion, seven rats in each group were offered a liquid diet [water load (WL)] or continued on a solid diet (SD). Plasma aldosterone and corticosterone and urine aldosterone were increased by WL in sham rats. ADX-WL rats escaped, as assessed by early natriuresis followed by diuresis; however, urine volume and natriuresis were somewhat blunted. WL did not reduce the abundance or activity of 11-β-hydroxsteroid dehydrogenase type 2. Furthermore, the previously observed increase in renal aldosterone-sensitive proteins and escape-associated increased MAP persisted in clamped rats. The densitometry of immunoblots for NCC, α- and γ-70 kDa ENaC, respectively, were (% sham-SD): sham-WL, 159, 278, 233; ADX-SD, 69, 212, 171; ADX-WL, 116, 302, 161. However, clamping corticosteroids blunted the rise at least for NCC and γ-ENaC (70 kDa). Overall, the increase in aldosterone observed in vasopressin escape is not necessary for the increased expression of NCC, α- or γ-ENaC or increased MAP associated with “escape.”

scholarly journals Identification of Potential Therapeutic Targets in the Liver of Pioglitazone-Treated Type 2 Diabetes Sprague-Dawley Rats via Expression Profile Chip and iTRAQ Assay

2018 ◽  
Vol 2018 ◽  
pp. 1-9
Author(s):  
Zhong-Xia Lu ◽  
Wen-Jun Xu ◽  
Yang-Sheng Wu ◽  
Chang-Yu Li ◽  
Yi-Tao Chen
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Differentially Expressed Genes ◽  
Fasting Blood Glucose ◽  
Treated Group ◽  
Differentially Expressed ◽  
Model Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

The aim of the present study was to identify key antidiabetic nodes in the livers of pioglitazone-treated type 2 diabetes mellitus Sprague-Dawley rats by transcriptomic and proteomic analysis. Rats were randomly divided into the control, the diabetes model, and the pioglitazone-treated groups. After treatment with pioglitazone for 11 weeks, the effects on fasting blood glucose, body weight, and blood biochemistry parameters were evaluated. Microarray and iTRAQ analysis were used to determine the differentially expressed genes/proteins in rat livers. 1.5-fold changes in gene expression and 1.2-fold changes in protein were set as the screening criteria. After treatment with pioglitazone for 11 weeks, fasting blood glucose in pioglitazone-treated rats was significantly lower than that in the model group. There was a tendency for pioglitazone to reduce TC, TG, TP, ALB, BUN, and HDL-c levels. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) were applied to analyze differentially expressed genes/proteins. Furthermore, Western blotting and RT-qPCR were used to validate the results of microarray and iTRAQ. In conclusion, Cyp7a1, Cp, and RT1-EC2 are differentially expressed genes/proteins since they showed a similar trend in rats in the model group and the pioglitazone-treated group.

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