Approach to assessing determinants of glucose homeostasis in the conscious mouse

Hughey, Curtis C.; Wasserman, David H.; Lee, Robert S.; Lantier, Louise

doi:10.1007/s00335-014-9533-z

Cited by 44 publications

(43 citation statements)

References 144 publications

(203 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Slope of glycemia between 0–15 min of the ITT, an index of insulin sensitivity (Hughey et al, 2014), is also reduced in AdChREBP KO mice (Fig 2D). Glucose tolerance is impaired in female (Fig 2E), but not male (Fig S2D), AdChREBP KO mice relative to ChREBP fl/fl littermates.…”

Section: Resultsmentioning

confidence: 87%

Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

et al. 2017

View full text Add to dashboard Cite

Summary Lower adipose-ChREBP and de novo lipogenesis (DNL) are associated with insulin resistance in humans. Here we generated adipose-specific ChREBP knockout (AdChREBP KO) mice with negligible sucrose-induced DNL in adipose tissue (AT). Chow-fed AdChREBP KO mice are insulin-resistant with impaired insulin action in liver, muscle and AT, and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin-resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport which is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels.. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs) in serum and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause insulin resistance potentially by regulating AT glucose transport and flux through specific lipogenic pathways.

show abstract

Section: Resultsmentioning

confidence: 87%

Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Whole-body insulin resistance, representing primarily insulin resistance in muscle and fat, was assessed by an IPITT. To measure liver insulin sensitivity in vivo an IPPTT was used, which is a measurement of insulin-sensitive gluconeogenesis of the liver (40). In vivo glucose handling was assessed by an IPGTT.…”

Section: Resultsmentioning

confidence: 99%

“…To characterize the metabolic state of the mice, we used a set of techniques that were least invasive, such as excluding additional anesthetic episodes, to match them with the noninvasive character of our in vivo reporter-islet monitoring approach. We are well aware that for proper metabolic characterization of HFHSD-fed animals, appropriate clamp studies, as well as analysis involving metabolic cages, are necessary (40, 64). Moreover, as clearly stated, we performed a biased transcriptomic/proteomic analysis that aimed for genes that were documented to be compromised under conditions of β-cell insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

et al. 2018

View full text Add to dashboard Cite

Although convincing in genetic models, the relevance of β-cell insulin resistance in diet-induced type 2 diabetes (T2DM) remains unclear. Exemplified by diabetes-prone, male, C57B1/6J mice being fed different combinations of Western-style diet, we show that β-cell insulin resistance occurs early during T2DM progression and is due to a combination of lipotoxicity and increased β-cell workload. Within 8 wk of being fed a high-fat, high-sucrose diet, mice became obese, developed impaired insulin and glucose tolerances, and displayed noncompensatory insulin release, due, at least in part, to reduced expression of syntaxin-1A. Through reporter islets transplanted to the anterior chamber of the eye, we demonstrated a concomitant loss of functional β-cell mass. When mice were changed from diabetogenic diet to normal chow diet, the diabetes phenotype was reversed, suggesting a remarkable plasticity of functional β-cell mass in the early phase of T2DM development. Our data reinforce the relevance of diet composition as an environmental factor determining different routes of diabetes progression in a given genetic background. Employing the in vivo reporter islet-monitoring approach will allow researchers to define key times in the dynamics of reversible loss of functional β-cell mass and, thus, to investigate the underlying, molecular mechanisms involved in the progression toward T2DM manifestation.-Paschen, M., Moede, T., Valladolid-Acebes, I., Leibiger, B., Moruzzi, N., Jacob, S., García-Prieto, C. F., Brismar, K., Leibiger, I. B., Berggren, P.-O. Diet-induced β-cell insulin resistance results in reversible loss of functional β-cell mass.

show abstract

“…$ P < 0.05, MT compared with WT mice fed HFD. gluconeogenesis (28). It is simplified, as pyruvate is also able to be utilized by many tissues and can possibly affect glucose levels by competition oxidative processes in extrahepatic tissues, including skeletal muscles.…”

Section: Bap31-deletion In Hepatocytes Enhances Glucose Production Anmentioning

confidence: 99%

Hepatocyte-specific deletion of BAP31 promotes SREBP1C activation, promotes hepatic lipid accumulation, and worsens IR in mice

Wang

et al. 2018

Journal of Lipid Research

View full text Add to dashboard Cite

Conditional knockout mice with targeted disruption of B-cell associated protein (BAP)31 in adult mouse liver were generated and challenged with a high-fat diet (HFD) for 36 or 96 days and markers of obesity, diabetes, and hepatic steatosis were determined. Mutant mice were indistinguishable from WT littermates, but exhibited increased HFD-induced obesity. BAP31-deletion in hepatocytes increased the expression of SREBP1C and the target genes, including acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase-1, and increased hepatic lipid accumulation and HFD-induced liver steatosis. Immunoprecipitation assay showed that BAP31 interacts with SREBP1C and insulin-induced gene 1 (INSIG1), and BAP31-deletion reduces INSIG1 expression, suggesting that BAP31 may regulate SREBP1C activity by modulating INSIG1 protein levels. Additionally, BAP31-deletion induced glucose and insulin intolerance, decreased Akt and glycogen synthase kinase 3β phosphorylation, and enhanced hepatic glucose production in mice. Expression of endoplasmic reticulum (ER) stress markers was significantly induced in BAP31-mutant mice. HFD-induced inflammation was aggravated in mutant mice, along with increased c-Jun N-terminal kinase and nuclear factor-κB activation. These findings demonstrate that BAP31-deletion induces SREBP activation and promotes hepatic lipid accumulation, reduces insulin signaling, impairs glucose/insulin tolerance, and increases ER stress and hepatic inflammation, explaining the protective roles of BAP31 in the development of liver steatosis and insulin resistance in HFD-induced obesity in animal models.

show abstract

Approach to assessing determinants of glucose homeostasis in the conscious mouse

Cited by 44 publications

References 144 publications

Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

Hepatocyte-specific deletion of BAP31 promotes SREBP1C activation, promotes hepatic lipid accumulation, and worsens IR in mice

Contact Info

Product

Resources

About