Upper Small Intestinal Protein Sensing Improves Glucose Tolerance Through Suppression of Hepatic Glucose Production

Objectives: Ceramides have been shown as lipotoxic inducers, which can trigger apoptosis, inflammation and disturb numerous cell signalling pathways leading to metabolic disorders such as type 2 diabetes (T2D). In this study, we aimed to determine the role of de novo hepatic ceramide synthesis on energy and liver homeostasis in mice. Methods: In order to investigate hepatic role of de novo ceramides synthesis, we generated mice lacking serine palmitoyltransferase 2 (Sptlc2) in hepatocytes using the cre-lox system. SPTLC2 allows condensation of serine and palmitoylCoA and is the rate limiting-enzyme necessary for ceramide de novo synthesis. Sptlc2ΔHep and their littermate controls were fed with high fat diet (HFD) to induce metabolic disorders. Liver ceramides content and metabolic parameters as glucose tolerance, insulin sensitivity, and hepatic glucose production were assessed. As ceramides may have impact on bile acids (BA), we investigated BA pool composition, synthesis and transport. Finally, inflammation and apoptosis were measured in the liver using western blot analysis, pro-inflammatory cytokines expression level and immunohistochemistry. Results: Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic ceramides, especially C16:0-ceramide. Hepatic deletion of Sptlc2 in mice was also associated with an increased neutral sphingomyelinase 2 (nSmase2) expression, and a decreased sphingomyelin content in the liver. We showed that Sptlc2ΔHep mice are protected against body mass gain normally induced by HFD and displayed a decreased body fat mass. BA hydrophobicity was drastically decreased in Sptlc2ΔHep mice, and was associated with a defect in lipid absorption. In addition, an important increase of tauro-murocholic acid T-MCA in BA pool composition of Sptlc2ΔHep mice was associated with a downregulation of the nuclear bile acid receptor FXR target genes in ileum and liver. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production in an insulin-independent manner. Finally, Sptlc2 disruption promoted progressive development of hepatic fibrosis, apoptosis and inflammation in an age-related manner. Conclusion: Our data demonstrate for the first time a potential compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis. In addition, our results highlight the role of hepatic sphingolipid modulation on hepatic glucose production through bile acid composition changes.

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Elevated Gluconeogenesis and Lack of Suppression by Insulin Contribute to Cystic Fibrosis-Related Diabetes

Journal of Investigative Medicine ◽

10.2310/jim.0b013e3181671788 ◽

2008 ◽

Vol 56 (3) ◽

pp. 567-573 ◽

Cited By ~ 18

Author(s):

Dana S. Hardin ◽

Chul Ahn ◽

Julie Rice ◽

Mark Rice ◽

Randall Rosenblatt

Keyword(s):

Cystic Fibrosis ◽

Glucose Tolerance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Normal Glucose Tolerance ◽

Abnormal Glucose Tolerance ◽

Protein Breakdown ◽

Relative Contribution ◽

Hepatic Glucose ◽

Normal Glucose

The incidence of diabetes is high in cystic fibrosis (CF) and is an important cause of morbidity and mortality. Understanding the pathophysiology is imperative. Studies have documented increased endogenous (mostly hepatic) glucose production (HGP) but have not distinguished the relative contribution of gluconeogenesis (GNG). The purpose of this study was to quantitate GNG, to determine its contribution to high HGP, and to measure insulin's suppression of GNG.We recruited 31 adult CF subjects (age, 26.2 ± 7.9 years; 12 female subjects) and quantified GNG by measuring the incorporation of 2H into the second and fifth carbons of glucose. Hepatic glucose production was measured using [6,6-2H2]glucose. Protein breakdown was measured using [1-13C]leucine. Data were compared with that from 11 healthy volunteers (age, 27.5 ± 7.0 years) who underwent both GNG and clamp studies. Thirteen CF subjects and all controls had a hyperinsulinemic euglycemic clamp during measures of GNG. Other measures included glucose tolerance and glucagon and cortisol levels.Rate of GNG was higher in CF subjects than controls and comprised a greater percentage of fasting HGP (GNG as percent of HGP: CF = 68%; controls = 44%; P = 0.034). Suppression of GNG by insulin was significantly lower in CF than in controls and was lower in CF subjects with abnormal glucose tolerance than in those with normal glucose tolerance. Gluconeogenesis correlated with protein breakdown.These studies suggest that high HGP in CF is mostly from elevated rates of GNG and that resistance to insulin's suppression of GNG may contribute to abnormal glucose tolerance in CF.

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Alteration of Glucose Homeostasis in V1a Vasopressin Receptor-Deficient Mice

Endocrinology ◽

10.1210/en.2006-1315 ◽

2007 ◽

Vol 148 (5) ◽

pp. 2075-2084 ◽

Cited By ~ 61

Author(s):

Toshinori Aoyagi ◽

Jun-ichi Birumachi ◽

Masami Hiroyama ◽

Yoko Fujiwara ◽

Atsushi Sanbe ◽

...

Keyword(s):

Glucose Tolerance ◽

Glucose Homeostasis ◽

Plasma Volume ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Mutant Mice ◽

Calorie Intake ◽

Vasopressin Receptor ◽

V1a Receptor ◽

Hepatic Glucose

Arginine-vasopressin (AVP) is known to be involved in maintaining glucose homeostasis, and AVP-resistance is observed in poorly controlled non-insulin-dependent diabetes mellitus subjects, resulting in a lowered plasma volume. Recently we reported that V1a vasopressin receptor-deficient (V1aR−/−) mice exhibited a decreased circulating blood volume and hypermetabolism of fat accompanied with impaired insulin-signaling. Here we further investigated the roles of the AVP/V1a receptor in regulating glucose homeostasis and plasma volume using V1aR−/− mice. The plasma glucose levels at the baseline or during a glucose tolerance test were higher in V1aR−/− than wild-type (WT) mice. Moreover, a hyperinsulinemic-euglycemic clamp revealed that the glucose infusion rate was significantly lower in V1aR−/− mice than in WT mice and that hepatic glucose production was higher in V1aR−/− mice than WT mice. In contrast to the increased hepatic glucose production, the liver glycogen content was decreased in the mutant mice. These results indicated that the mutant mice had impaired glucose tolerance. Furthermore, feeding V1aR−/− mice a high-fat diet accompanied by increased calorie intake resulted in significantly overt obesity in comparison with WT mice. In addition, we found that the circulating plasma volume and aldosterone level were decreased in V1aR−/− mice, although the plasma AVP level was increased. These results suggested that the effect of AVP on water recruitment was disturbed in V1aR−/− mice. Thus, we demonstrated that one of the AVP-resistance conditions resulting from deficiency of the V1a receptor leads to decreased plasma volume as well as impaired glucose homeostasis, which can progress to obesity under conditions of increased calorie intake.

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NSAID-Induced Enteropathy Affects Regulation of Hepatic Glucose Production by Decreasing GLP-1 Secretion

Nutrients ◽

10.3390/nu14010120 ◽

2021 ◽

Vol 14 (1) ◽

pp. 120

Author(s):

Hussein Herz ◽

Yang Song ◽

Yuanchao Ye ◽

Liping Tian ◽

Benjamin Linden ◽

...

Keyword(s):

Glucose Tolerance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Treated Group ◽

Endogenous Glucose Production ◽

Glucose Disposal ◽

Control Group ◽

Euglycemic Hyperinsulinemic Clamp ◽

Insulin Levels ◽

Hepatic Glucose

Background/Aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9—a GLP-1 receptor antagonist—worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

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Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.256.5.e676 ◽

1989 ◽

Vol 256 (5) ◽

pp. E676-E681 ◽

Cited By ~ 8

Author(s):

N. L. Bodkin ◽

B. L. Metzger ◽

B. C. Hansen

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Significant Deterioration ◽

Peripheral Insulin Sensitivity ◽

Euglycemic Clamp ◽

Hepatic Glucose

The purpose of this study was to identify the relationship between basal hepatic glucose production (HGP) and peripheral insulin sensitivity as assessed by the hyperinsulinemic euglycemic clamp prior to and during the development of non-insulin-dependent (type 2) diabetes mellitus in rhesus monkeys. Twenty-six male monkeys (Macaca mulatta), including normal animals and monkeys in various phases of the development of spontaneous obesity-associated type 2 diabetes were studied. Fasting plasma glucose (FPG) and insulin (FIRI), basal HGP using a [3H]glucose infusion, and peripheral insulin sensitivity (as determined by the euglycemic clamp technique) were examined. The earliest change that could be detected was a significant reduction in peripheral insulin sensitivity accompanied by increased FIRI. These changes preceded a significant deterioration of glucose tolerance. Basal HGP changed in parallel with FPG (r = 0.90, P less than 0.001), becoming significantly elevated only when FPG rose to levels diagnostic of diabetes (greater than 140 mg/dl). Thus basal HGP and fasting glucose levels showed no significant changes early in the development of type 2 diabetes. We conclude that the early serial decreases in insulin sensitivity and progressive increases in FIRI, with or without decreased glucose tolerance, are prognostic of the future development of diabetes in obese monkeys, a longitudinal process that is also likely to be observed in most if not all obese humans progressing to diabetes.

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Inhibition of Upper Small Intestinal mTOR Lowers Plasma Glucose Levels by Inhibiting Hepatic Glucose Production

Canadian Journal of Diabetes ◽

10.1016/j.jcjd.2018.08.186 ◽

2018 ◽

Vol 42 (5) ◽

pp. S60

Author(s):

T.M. Zaved Waise ◽

Mozhgan Rasti ◽

Frank A. Duca ◽

Paige V. Bauer ◽

Christopher J. Rhodes ◽

...

Keyword(s):

Plasma Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Levels ◽

Hepatic Glucose ◽

Small Intestinal

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Glucagon Deficiency Reduces Hepatic Glucose Production and Improves Glucose Tolerance In Adult Mice

Molecular Endocrinology ◽

10.1210/me.2010-0120 ◽

2010 ◽

Vol 24 (8) ◽

pp. 1605-1614 ◽

Cited By ~ 62

Author(s):

Aidan S. Hancock ◽

Aiping Du ◽

Jingxuan Liu ◽

Mayumi Miller ◽

Catherine L. May

Keyword(s):

Glucose Tolerance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Adult Mice ◽

Hepatic Glucose

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Mentha Longifolia L. Improves Antioxidant Status, Glucose Tolerance, Insulin Resistance and Hepatic Glucose Production In Diet-Induced Obesity

Current Developments in Nutrition ◽

10.1093/cdn/nzab037_004 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 294-294

Author(s):

Hana Alkhalidy ◽

Wafaa Sarhan ◽

Mohammad Al-Gharaibeh ◽

Aseel Hasan ◽

Dongmin Liu

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Antioxidant Status ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Calorie Intake ◽

Metabolic Abnormalities ◽

Hepatic Glucose ◽

Leaf Powder ◽

Oil Extract

Abstract Objectives Obesity is associated with several metabolic abnormalities including insulin resistance (IR), which is a key risk factor of type 2 diabetes mellitus (T2DM). Oxidative stress is linked to both obesity and IR development. Improving antioxidant status using medicinal plants or their bioactive components can be a safe and low-cost alternative approach to reduce obesity and IR thus T2DM development. This study aims to evaluate the antioxidant activities of Mentha longifolia L. (M. longifolia) leaf powder and oil extract on obesity-induced metabolic abnormalities. Methods High-fat-sucrose diet (HFS)-induced obese Wistar rats were orally given M. longifolia essential oil (50 mg/kg), leaf powder (120 mg/kg), or vehicle for 6 weeks. Bodyweight and calorie intake were recorded periodically, and glucose and pyruvate tolerance were evaluated. At the end of the study, plasma insulin and triglyceride levels were measured, and organs weight and the degree of adiposity were determined. Antioxidant status for the plasma was measured using plasma ferric ion reducing antioxidant power test (FRAP). Results M. longifolia leaf powder and oil extract improved glucose tolerance, and hepatic glucose production after being challenged with glucose or pyruvate compared to untreated obese rats. M. longifolia reduced IR (HOMA-IR: oil = 2.30 ± 0.279, powder = 2.13 ± 0.057, HFS = 2.54 ± 0.136). Antioxidant status was also improved in rats treated with M. longifolia (FRAP: oil = 300.5 ± 25.4, powder = 341.8 ± 47.2, HFS = 263.5 ± 13.0). These outcomes were not associated with changes in body weight, calorie intake, adiposity, or plasma triglycerides. Conclusions M. longifolia oil and powder improved the antioxidant status and ameliorated HFS diet-induced metabolic abnormalities, suggesting that this plant a promising natural agent for reducing the risk of T2DM. Further studies are needed to elucidate the mechanism of this action. Funding Sources Deanship of Scientific Research at Jordan University of Science and Technology.

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Evidence of a Role for Insulin-Like Growth Factor Binding Protein (IGFBP)-3 in Metabolic Regulation

Endocrinology ◽

10.1210/en.2010-0672 ◽

2010 ◽

Vol 151 (12) ◽

pp. 5741-5750 ◽

Cited By ~ 33

Author(s):

P. M. Yamada ◽

H. H. Mehta ◽

D. Hwang ◽

K. P. Roos ◽

A. L. Hevener ◽

...

Keyword(s):

Glucose Tolerance ◽

Hepatic Steatosis ◽

Metabolic Regulation ◽

Binding Protein ◽

Hepatic Glucose Production ◽

Fasting Blood Glucose ◽

Glucose Production ◽

Glucose Turnover ◽

Hepatic Glucose ◽

Igfbp 3

IGF-binding protein (IGFBP)-3 is a metabolic regulator that has been shown to inhibit insulin-stimulated glucose uptake in murine models. This finding contrasts with epidemiological evidence of decreased serum IGFBP-3 in patients with type 2 diabetes. The purpose of this study was to clarify the role of IGFBP-3 in metabolism. Four-week-old male IGFBP-3−/− and control mice were subjected to a high-fat diet (HFD) for 12 wk. IGFBP-3−/− mice were heavier before the initiation of HFD and at the end of the study period. Resting metabolic rate was significantly decreased in knockout mice; however, respiratory exchange ratio was not significantly different. Fasting blood glucose and insulin levels were significantly elevated in IGFBP-3−/− mice. However, IGFBP-3−/− mice had relatively normal glucose tolerance because the relative glucose excursion over time was not different between the groups. During hyperinsulinemic clamps, IGFBP-3−/− mice had increased basal hepatic glucose production, but after insulin stimulation, no differences in hepatic glucose production were observed. A second cohort of older IGFBP-3−/− mice on HFD displayed unexpected evidence of hepatic steatosis. In summary, glucose tolerance and clamp testing indicate that IGFBP-3−/− mice preserve insulin sensitivity despite evidence of increased basal glucose turnover and hepatic steatosis. We provide evidence that genetic deletion of IGFBP-3 modulates hepatic carbohydrate and lipid metabolism.

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