Control of Blood Glucose in the Absence of Hepatic Glucose Production During Prolonged Fasting in Mice

Mutel, E.; Gautier‐Stein, Amandine; Abdul-Wahed, Aya; Amigó-Correig, Marta; Zitoun, Carine; Stefanutti, A.; Houberdon, I.; Tourette, Jean-André; Mithieux, Gilles; Rajas, Fabienne

doi:10.2337/db11-0571

Cited by 151 publications

(124 citation statements)

References 46 publications

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“…The rise in EGP offsets in part the glucose lost through the urine, thereby blunting the expected decline in glycaemia. The increased EGP can be attributed, at least in part, to the lower insulin and glucose and higher glucagon levels, but other mechanisms cannot be ruled out [22].…”

Section: Introductionmentioning

confidence: 99%

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes

et al. 2015

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Aims/hypothesis Sodium glucose co-transporter 2 (SGLT2) inhibitors lower glycaemia by inducing glycosuria, but raise endogenous glucose production (EGP). Metformin lowers glycaemia mainly by suppressing EGP. We compared the effects of the SGLT2 inhibitor empagliflozin in treatment-naive (TN) and metformin pretreated (Met) patients with type 2 diabetes. Methods A total of 32 TN and 34 patients on a stable dose of metformin, two subgroups of a study that we previously reported, received a mixed meal with double-tracer glucose administration and indirect calorimetry at baseline, after a single 25 mg dose of empagliflozin, and after 4 weeks of treatment with empagliflozin 25 mg/day. Results At baseline, compared with the TN group, the Met group had higher fasting glycaemia (9.1 ± 1.7 vs 8.2 ± 1.3 mmol/l), lower fasting and postmeal insulin secretion, lower beta cell glucose sensitivity (37 [18]

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Section: Introductionmentioning

confidence: 99%

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes

et al. 2015

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“…The transcription factors and coactivators involved in the control of gluconeogenesis have been studied by several authors and confirmed by chromatin immunoprecipitation assay. [32][33][34][35][36] FoxO1 is also known to inhibit the mRNA expression of CYP7A1. 37 Consistently, CYP7b1 expression is dramatically decreased in the liver of obB2KO mice.…”

Section: Discussionmentioning

confidence: 99%

Bradykinin inhibits hepatic gluconeogenesis in obese mice

Barros

Haro

Russo

et al. 2012

Laboratory Investigation

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The kallikrein-kinin system (KKS) has been previously linked to glucose homeostasis. In isolated muscle or fat cells, acute bradykinin (BK) stimulation was shown to improve insulin action and increase glucose uptake by promoting glucose transporter 4 translocation to plasma membrane. However, the role for BK in the pathophysiology of obesity and type 2 diabetes remains largely unknown. To address this, we generated genetically obese mice (ob/ob) lacking the BK B2 receptor (obB2KO). Despite similar body weight or fat accumulation, obB2KO mice showed increased fasting glycemia (162.3±28.2 mg/dl vs 85.3±13.3 mg/dl), hyperinsulinemia (7.71±1.75 ng/ml vs 4.09±0.51 ng/ml) and impaired glucose tolerance when compared with ob/ob control mice (obWT), indicating insulin resistance and impaired glucose homeostasis. This was corroborated by increased glucose production in response to a pyruvate challenge. Increased gluconeogenesis was accompanied by increased hepatic mRNA expression of forkhead box protein O1 (FoxO1, four-fold), peroxisome proliferator-activated receptor gamma co-activator 1-alpha (seven-fold), phosphoenolpyruvate carboxykinase (PEPCK, three-fold) and glucose-6-phosphatase (eight-fold). FoxO1 nuclear exclusion was also impaired, as the obB2KO mice showed increased levels of this transcription factor in the nucleus fraction of liver homogenates during random feeding. Intraportal injection of BK in lean mice was able to decrease the hepatic mRNA expression of FoxO1 and PEPCK. In conclusion, BK modulates glucose homeostasis by affecting hepatic glucose production in obWT. These results point to a protective role of the KKS in the pathophysiology of type 2 diabetes mellitus. KEYWORDS: bradykinin; gluconeogenesis; kinin receptor; leptin; ob/ob; obesity The pathophysiology of type 2 diabetes mellitus (T2DM) involves innumerous metabolic and endocrine alterations, including changes in the carbohydrate, lipid and protein metabolisms. T2DM is directly linked with insulin resistance and the inability of pancreatic beta cells to compensate for these changes. 1 There is also a strong association between T2DM and obesity 1,2 that persists independently of gender or ethnic group. In this interaction, the weight gain of obese subjects seems to precede the development of T2DM. 3 Kinins are vasoactive peptides produced in the circulatory system and other tissues by the action of serine proteases called kallikreins. The kallikrein-kinin system (KKS) modulates pain, vasodilatation, vascular permeability, inflammation and edema and has been linked to insulin resistance. [4][5][6][7] Bradykinin (BK), the agonist of the constitutively expressed BK B2 receptor (BKB2R), has been reported to increase glucose uptake in skeletal muscle and adipose tissue. 8 At the same time, the kinin B1 receptor and its agonist, the des-arg 9 -kinin, have been shown to control leptin sensitivity 7 and insulin secretion. 9 Despite evidence that acute BK stimulation improves glucose uptake, the role for BK and BKB2R in the pathophysiology of T2DM is s...

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“…Levels of blood glucose and serum insulin were measured using a Glucometer Elite monitor or Mercodia Ultrasensitive Rat Insulin ELISA kit (ALPCO Diagnostics, Salem, NH), respectively. An L-alanine tolerance test was performed by intraperitoneal injection of 2 g/kg L-alanine after 24-h fasting as described previously (20). Glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) were performed by intraperitoneal injection of 2 g/kg glucose after overnight fasting and 0.75 units/kg insulin after 4-h fasting, respectively.…”

Section: Luciferase Assaymentioning

confidence: 99%

A Novel Function of MicroRNA 130a-3p in Hepatic Insulin Sensitivity and Liver Steatosis

Xiao

Liu

et al. 2014

Diabetes

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MicroRNAs (miRNAs) are endogenous, noncoding, short, single-stranded RNAs that are evolutionarily conserved and believed to play a role in controlling a variety of biological processes. The roles of miRNAs in insulin resistance and liver steatosis, however, are largely unknown. The objective of this study was to evaluate the roles of miR-130a in the regulation of insulin sensitivity and liver steatosis. In our current study, we observed that overexpression of miR-130a-3p increases insulin signaling in both HepG2 cells and primary mouse hepatocytes, and silencing of miR-130a-3p has the opposite effects. However, miR-130a-5p has no effect in the regulation of insulin signaling. Consistently, whole-body and hepatic insulin sensitivity are improved in mice injected with adenoviruses that overexpress miR-130a-3p. Furthermore, we provided evidence showing that growth factor receptor–bound protein 10 is required for miR-130a-3p–regulated insulin sensitivity. On the other hand, we observed that expression of miR-130a-3p is decreased in the livers of db/db mice and that adenovirus-mediated overexpression of miR-130a-3p reverses insulin resistance and liver steatosis, the latter of which is achieved via suppressing fatty acid synthase expression in these mice. This study identifies a novel function for hepatic miR-130a-3p in the regulation of insulin sensitivity and liver steatosis.

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Control of Blood Glucose in the Absence of Hepatic Glucose Production During Prolonged Fasting in Mice

Cited by 151 publications

References 46 publications

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes

Bradykinin inhibits hepatic gluconeogenesis in obese mice

A Novel Function of MicroRNA 130a-3p in Hepatic Insulin Sensitivity and Liver Steatosis

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