G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance

Boortz, Kayla A.; Syring, Kristen; Lee, Rebecca A.; Dai, Chunhua; Oeser, James K.; McGuinness, Owen P.; Wang, Jen-Chywan; O’Brien, Richard M.

doi:10.1210/en.2016-1678

Cited by 16 publications

(21 citation statements)

References 55 publications

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“…In our model of CORT administration, insulin resistance develops quickly (from the 1st week of treatment [data not shown]) and associates at 8 weeks with a strong pancreatic adaptation with simultaneous high insulin secretion and a dramatic increase of b-cell mass. In agreement with previously reported studies in mice (57) and macaques (58), CORT-treated mice do not develop hyperglycemia and present improved glucose tolerance. Therefore, CORT treatment can lead to insulin resistance and pancreatic adaptation with high insulin production.…”

Section: Discussionsupporting

confidence: 93%

Adaptive β-Cell Neogenesis in the Adult Mouse in Response to Glucocorticoid-Induced Insulin Resistance

et al. 2018

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Both type 1 and type 2 diabetes are characterized by deficient insulin secretion and decreased b-cell mass. Thus, regenerative strategies to increase b-cell mass need to be developed. To characterize mechanisms of b-cell plasticity, we studied a model of severe insulin resistance in the adult mouse and defined how b-cells adapt. Chronic corticosterone (CORT) treatment was given to adult mice and led to rapid insulin resistance and adaptive increased insulin secretion. Adaptive and massive increase of b-cell mass was observed during treatment up to 8 weeks. b-Cell mass increase was partially reversible upon treatment cessation and reinduced upon subsequent treatment. b-Cell neogenesis was suggested by an increased number of islets, mainly close to ducts, and increased Sox9 and Ngn3 mRNA levels in islets, but lineagetracing experiments revealed that neoformed b-cells did not derive from Sox9-or Ngn3-expressing cells. CORT treatment after b-cell depletion partially restored b-cells. Finally, b-cell neogenesis was shown to be indirectly stimulated by CORT because serum from CORT-treated mice increased b-cell differentiation in in vitro cultures of pancreatic buds. Altogether, the results present a novel model of b-cell neogenesis in the adult mouse and identify the presence of neogenic factors in the serum of CORT-treated mice.

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Section: Discussionsupporting

confidence: 93%

Adaptive β-Cell Neogenesis in the Adult Mouse in Response to Glucocorticoid-Induced Insulin Resistance

et al. 2018

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“…The experiments described here suggest that G6PC2 may have evolved to not only confer a beneficial elevation in FBG in response to stress [ 14 , 15 ] but also to prevent hypoglycemia in response to ketogenic diet feeding ( Figure 1 ) or prolonged fasting ( Figure 3 ). In contrast, in response to high fat diet feeding, as is common in the modern world, the presence of G6PC2 amplifies the hyperglycemia ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

“…A key question is the nature of the physiological benefit conferred by this glucokinase/G6PC2 substrate cycle. Experiments in mice in which glucocorticoids were injected or endogenous glucocorticoids were elevated by physical restraint induced G6pc2 expression [ 14 , 15 ]. The associated change in FBG in KO relative to WT mice suggests that G6PC2 may have evolved, in part, to confer a transient, beneficial elevation in FBG during periods of stress [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Experiments in mice in which glucocorticoids were injected or endogenous glucocorticoids were elevated by physical restraint induced G6pc2 expression [ 14 , 15 ]. The associated change in FBG in KO relative to WT mice suggests that G6PC2 may have evolved, in part, to confer a transient, beneficial elevation in FBG during periods of stress [ 14 , 15 ]. The experiments described here extend these studies by examining the role of G6PC2 in the response to different nutritional challenges and suggest that G6PC2 evolved to not only regulate FBG in response to stress, but also to prevent hypoglycemia associated with prolonged fasting and ketogenic diets.…”

Section: Introductionmentioning

confidence: 99%

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G6PC2 confers protection against hypoglycemia upon ketogenic diet feeding and prolonged fasting

Bosma

Rahim

Oeser

et al. 2020

Molecular Metabolism

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Objective G6PC2 is predominantly expressed in pancreatic islet beta cells. G6PC2 hydrolyzes glucose-6-phosphate to glucose and inorganic phosphate, thereby creating a futile substrate cycle that opposes the action of glucokinase. This substrate cycle determines the sensitivity of glucose-stimulated insulin secretion to glucose and hence regulates fasting blood glucose (FBG) but not fasting plasma insulin (FPI) levels. Our objective was to explore the physiological benefit this cycle confers. Methods We investigated the response of wild type (WT) and G6pc2 knockout (KO) mice to changes in nutrition. Results Pancreatic G6pc2 expression was little changed by ketogenic diet feeding but was inhibited by 24 hr fasting and strongly induced by high fat feeding. When challenged with either a ketogenic diet or 24 hr fasting, blood glucose fell to 70 mg/dl or less in G6pc2 KO but not WT mice, suggesting that G6PC2 may have evolved, in part, to prevent hypoglycemia. Prolonged ketogenic diet feeding reduced the effect of G6pc2 deletion on FBG. The hyperglycemia associated with high fat feeding was partially blunted in G6pc2 KO mice, suggesting that under these conditions the presence of G6PC2 is detrimental. As expected, FPI changed but did not differ between WT and KO mice in response to fasting, ketogenic and high fat feeding. Conclusions Since elevated FBG levels are associated with increased risk for cardiovascular-associated mortality (CAM), these studies suggest that, while G6PC2 inhibitors would be useful for lowering FBG and the risk of CAM, partial inhibition will be important to avoid the risk of hypoglycemia.

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“…The same authors independently extracted data from eligible studies including the name of the first author and publication year, location and duration, sample size, inclusion criteria, study arms and participants, and cotreatments. Fasting blood glucose (FBG) was entitled as the primary outcome, in line with other studies [20][21][22]. Secondary outcomes were glycosylated hemoglobin A1c (HbA1c); body mass index (BMI); lipid profiles including triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL); hematological indexes including hematocrit and platelet count; and systematic inflammatory level expressed as the C-reactive protein (CRP) level.…”

Section: Data Extractionmentioning

confidence: 54%

The Effect of Diacerein on Type 2 Diabetic Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis

Guo

Hong-ya³

et al. 2020

Journal of Diabetes Research

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Aims. To figure out the effect of diacerein supplementation on type 2 diabetes mellitus (T2DM). Methods. An electronic search was processed on Pubmed, Embase, and Cochrane library for randomized controlled trials (RCTs) comparing the efficacy of diacerein with placebo on T2DM. The primary outcome was fasting blood glucose (FBG). Trial sequential analysis (TSA) was used to test the reliability of this pooled outcome. Secondary outcomes were glycosylated hemoglobin A1c (HbA1c), body mass index (BMI), lipid profiles, hematological indexes including hematocrit and platelet count, and systematic inflammatory level expressed as a C-reactive protein (CRP) level. Safety outcome was the rate of complications. The difference in continuous data was measured by mean difference (MD) and 95% confidence interval (CI), while the difference of dichotomous data was calculated by relative risk (RR) and 95% CI. A two-tailed P<0.05 was regarded as statistically significant. Results. Five RCTs with 278 participants were included. Compared with control, diacerein provided significant improvement on FBG (MD -0.52; 95% CI (-0.89~-0.14); P=0.007), but TSA showed that this positive effect required more support. Besides, diacerein also significantly improved HbA1c (MD -0.71; 95% CI (-1.07~-0.36); P<0.001), BMI (MD -0.40; 95% CI (-0.49~-0.31); P<0.001), and CRP level (MD -1.49; 95% CI (-2.78~-0.19); P=0.02). No superiority was noted in favor of either treatment regarding lipid profiles or hematological indexes. Among all complications, diacerein caused significantly more gastrointestinal syndromes (RR 1.39; 95% CI (1.08~1.77); P=0.009). Conclusion. Based on the current analysis, diacerein as an add-on treatment provided better glycemic control for T2DM but this benefit requires more verification. Compared with control, additional diacerein also lowered body weight and CRP level in T2DM, but increased the rate of gastrointestinal syndromes.

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G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance

Cited by 16 publications

References 55 publications

Adaptive β-Cell Neogenesis in the Adult Mouse in Response to Glucocorticoid-Induced Insulin Resistance

Adaptive β-Cell Neogenesis in the Adult Mouse in Response to Glucocorticoid-Induced Insulin Resistance

G6PC2 confers protection against hypoglycemia upon ketogenic diet feeding and prolonged fasting

The Effect of Diacerein on Type 2 Diabetic Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis

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