Lifetime Exposure to a Constant Environment Amplifies the Impact of a Fructose-Rich Diet on Glucose Homeostasis during Pregnancy

Abstract Aims/hypothesis Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified. Methods Plasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor α (ERRα) knockdown on leucine oxidation. Results Impairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37–56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific Ppargc1a knockout mice. ESRRA (encoding ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes. Conclusions/interpretation Metabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1α is ERRα-dependent. Graphical abstract

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APOE4 Genotype Exerts Greater Benefit in Lowering Plasma Cholesterol and Apolipoprotein B than Wild Type (E3/E3), after Replacement of Dietary Saturated Fats with Low Glycaemic Index Carbohydrates

Nutrients ◽

10.3390/nu10101524 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1524 ◽

Cited By ~ 5

Author(s):

Bruce Griffin ◽

Celia Walker ◽

Susan Jebb ◽

Carmel Moore ◽

Gary Frost ◽

...

Keyword(s):

Glucose Homeostasis ◽

Apolipoprotein B ◽

Dietary Intervention ◽

Plasma Lipids ◽

Plasma Cholesterol ◽

Apoe Genotype ◽

Density Lipoprotein ◽

Glycaemic Index ◽

Apo B ◽

The Impact

We examined the impact of APOE genotype on plasma lipids and glucose in a secondary analysis of data from a five-arm, randomised controlled, parallel dietary intervention trial (‘RISCK’ study), to investigate the impact of replacing saturated fatty acids (SFA) with either monounsaturated fat (MUFA) or carbohydrate of high or low glycaemic index (GI) on CVD risk factors and insulin sensitivity. We tested the impact of APOE genotype (carriage of E2 and E4 alleles versus E3/E3), determined retrospectively, on plasma lipids, lipoproteins and glucose homeostasis at baseline (n = 469), and on the change in these variables after 24 weeks of dietary intervention (n = 389). At baseline, carriers of E2 (n = 70), E4 (n = 125) and E3/E3 (n = 274) expressed marked differences in total plasma cholesterol (TC, p = 0.001), low density lipoprotein cholesterol (LDL-C, p < 0.0001), apolipoprotein B (apo B, p < 0.0001) and total to high density lipoprotein cholesterol ratio (TC:HDL-C, p = 0.002), with plasma concentrations decreasing in the order E4 > E3/E3 > E2. Following intervention, there was evidence of a significant diet x genotype interaction with significantly greater decreases in TC (p = 0.02) and apo B (p = 0.006) among carriers of E4 when SFA was replaced with low GI carbohydrate on a lower fat diet (TC −0.28 mmol/L p = 0.03; apo B −0.1 g/L p = 0.02), and a relative increase in TC (in comparison to E3/E3) when SFA was replaced with MUFA and high GI carbohydrates (TC 0.3 mmol/L, p = 0.03). Among carriers of E2 (compared with E3/E3) there was an increase in triacylglycerol (TAG) when SFA was replaced with MUFA and low GI carbohydrates 0.46 mmol/L p = 0.001). There were no significant interactions between APOE genotype and diet for changes in indices of glucose homeostasis. In conclusion, variations in APOE genotype led to differential effects on the lipid response to the replacement of SFA with MUFA and low GI carbohydrates.

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SUN-637 The Impact of Hyperandrogenemia and Western-Style Diet on Post-Pregnancy Metabolism in Nonhuman Primates

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1274 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Diana Lynn Takahashi ◽

Emily Mishler ◽

Ov Daniel Slayden ◽

Jon D Hennebold ◽

Charles T Roberts ◽

...

Keyword(s):

Insulin Resistance ◽

Body Fat ◽

Glucose Homeostasis ◽

Polycystic Ovary ◽

Mean Value ◽

Fat Percentage ◽

Primate Model ◽

Intravenous Glucose ◽

Intravenous Glucose Tolerance Tests ◽

The Impact

Abstract Polycystic ovary syndrome (PCOS) often is associated with hyperandrogenemia and an increased incidence of obesity and type 2 diabetes. To understand the separate and combined effects of androgens and obesity on reproductive and metabolic parameters, our group established a nonhuman primate model consisting of animals receiving either testosterone (T, mean value of 1.4 ng/mL), an obesogenic western-style diet (WSD, 36% of calories from fat compared to 16% in normal monkey chow), or a combination of T+WSD. T+WSD increased insulin resistance compared to WSD alone after three years of treatment and reduced fertility. Those T+WSD animals that became pregnant had a mild worsening of glucose homeostasis during pregnancy. The current study sought to determine how T+WSD affected post-pregnancy metabolic health and whether T+WSD led to the worsening of insulin resistance after pregnancy. Intravenous glucose tolerance tests (ivGTT) were performed 1) before pregnancy, 2) approximately 3-4 months after C-section, which occurred between gestational day 130-135 (3rd trimester), and 3) one year post C-section. All animal groups tended to show increases in weight, BMI, and body fat percentage after pregnancy. Both WSD groups (WSD and T+WSD) had higher overall weights, BMI, and body fat percentages. Measures of insulin sensitivity such as fasting insulin, glucose, and insulin area under the curves during an ivGTT and homeostatic model of insulin resistance (HOMA-IR) all increased over time, but there were no differences between groups. The lack of treatment effect on measures of insulin resistance may be due to the fact that animals that did not become pregnant had significantly higher indices of insulin resistance. Experimental animals underwent a second round of fertility trials thereby allowing for a comparison of glucose homeostasis for those animals that became pregnant in both the 1st and 2nd trial. The WSD group demonstrated increased fasting glucose and glucose AUC during an early third trimester ivGTT in the second pregnancy compared to the first. The control, T, and T+WSD groups did not show significant differences in glucose homeostasis between the first and second pregnancy. These findings indicate that WSD consumption may increase the risk of worsened glucose homeostasis after pregnancy and during subsequent pregnancies. Testosterone, either in isolation or in combination with WSD, did not appear to have a significant impact on post-pregnancy metabolism or worsen metabolic outcomes in a second pregnancy.

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Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

Aging Cell ◽

10.1111/acel.12405 ◽

2015 ◽

Vol 15 (1) ◽

pp. 28-38 ◽

Cited By ~ 76

Author(s):

Sebastian I. Arriola Apelo ◽

Joshua C. Neuman ◽

Emma L. Baar ◽

Faizan A. Syed ◽

Nicole E. Cummings ◽

...

Keyword(s):

Immune System ◽

Glucose Homeostasis ◽

Rapamycin Treatment ◽

Treatment Regimens ◽

The Impact

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A systematic review and meta-analysis of the impact of mineralocorticoid receptor antagonists on glucose homeostasis

Medicine ◽

10.1097/md.0000000000008719 ◽

2017 ◽

Vol 96 (48) ◽

pp. e8719 ◽

Cited By ~ 9

Author(s):

Sandra Korol ◽

Fannie Mottet ◽

Sylvie Perreault ◽

William L. Baker ◽

Michel White ◽

...

Keyword(s):

Systematic Review ◽

Glucose Homeostasis ◽

Mineralocorticoid Receptor ◽

Meta Analysis ◽

Mineralocorticoid Receptor Antagonists ◽

Receptor Antagonists ◽

The Impact

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Antibiotic-induced microbiome depletion alters renal glucose metabolism and exacerbates renal injury after ischemia-reperfusion injury in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00111.2021 ◽

2021 ◽

Author(s):

Yuika Osada ◽

Shunsaku Nakagawa ◽

Kanako Ishibe ◽

Shota Takao ◽

Aimi Shimazaki ◽

...

Keyword(s):

Glucose Metabolism ◽

Glucose Homeostasis ◽

Phosphoenolpyruvate Carboxykinase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Kidney Injury ◽

Short Chain Fatty Acids ◽

Glucose Levels ◽

The Impact

Recent studies have revealed the impact of antibiotic-induced microbiome depletion (AIMD) on host glucose homeostasis. The kidney has a critical role in systemic glucose homeostasis; however, information regarding the association between AIMD and renal glucose metabolism remains limited. Hence, we aimed to determine the effects of AIMD on renal glucose metabolism by inducing gut microbiome depletion using an antibiotic cocktail (ABX) composed of ampicillin, vancomycin, and levofloxacin in mice. The results showed that the bacterial 16s rRNA expression, luminal concentrations of short-chain fatty acids and bile acids, and plasma glucose levels were significantly lower in ABX-treated mice than in vehicle-treated mice. In addition, ABX treatment significantly reduced renal glucose and pyruvate levels. The mRNA expression levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the renal cortex were significantly higher in ABX-treated mice than in vehicle-treated mice. We further examined the impact of AIMD on the altered metabolic status in mice after ischemia-induced kidney injury. After exposure to ischemia for 60 min, the renal pyruvate concentrations were significantly lower in ABX-treated mice than in vehicle-treated mice. ABX treatment caused a more severe tubular injury after ischemia-reperfusion (IR). Our findings confirm that AIMD is associated with decreased pyruvate levels in the kidney, which may have been caused by the activation of renal gluconeogenesis. Thus, we hypothesized that AIMD would increase the vulnerability of the kidney to IR injury.

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Glucose homeostasis is impaired in mice deficient in the neuropeptide 26RFa (QRFP)

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000942 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000942

Author(s):

Mouna El-Mehdi ◽

Saloua Takhlidjt ◽

Fayrouz Khiar ◽

Gaëtan Prévost ◽

Jean-Luc do Rego ◽

...

Keyword(s):

Glucose Metabolism ◽

Pancreatic Islets ◽

Glucose Homeostasis ◽

Gene Knockout ◽

Hepatic Glucose Production ◽

Biologically Active ◽

Mutant Mice ◽

Insulin Production ◽

Coding Region ◽

The Impact

Introduction26RFa (pyroglutamyl RFamide peptide (QRFP)) is a biologically active peptide that has been found to control feeding behavior by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism.Research design and methods26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated.ResultsOur data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibited an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. Two-dimensional and three-dimensional immunohistochemical experiments indicate that the insulin content of pancreatic β cells is much lower in the 26RFa−/− mice as compared with the wild-type littermates.ConclusionDisruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis, with in particular a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis.

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THE IMPACT OF DIFFERENT REGIMENS OF VITAMIN D3 ON GLUCOSE HOMEOSTASIS IN TYPE 2 DIABETIC PATIENTS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i12.35602 ◽

2019 ◽

pp. 21-26

Author(s):

SAMIA MOHAMED ALI ◽

YEHIA MOSTAFA GHANEM ◽

OLA ATEF SHARAKI ◽

WAFAA AHMED HEWEDY ◽

ESRAA SAEED HABIBA

Keyword(s):

Vitamin D ◽

Glucose Homeostasis ◽

Vitamin D3 ◽

Antidiabetic Drugs ◽

Diabetic Patients ◽

Model Assessment ◽

Parenteral Dose ◽

Vitamin D Levels ◽

The Impact

Objective: Vitamin D has a role in the regulation of pancreatic β-cell function and insulin sensitivity. Accordingly, Vitamin D deficiency is considered to be a risk factor for the development of type 2 diabetes mellitus (T2DM) and its complications. Therefore, the aim of the study was to assess and compare the effect of different regimens of Vitamin D3 on glucose homeostasis in patients with T2DM. Methods: The study included 80 patients with T2DM taking oral antidiabetic drugs. The patients were randomized to receive antidiabetic drugs alone or with different regimens of Vitamin D3 for 3 months. Vitamin D3-treated patients were supplemented by either daily oral 4000 IU Vitamin D3, weekly oral 50,000 IU Vitamin D3, or a single parenteral dose of 300,000 IU Vitamin D3. In addition to the assessment of patient characteristics, laboratory measurements of serum creatinine, blood urea, total and ionized calcium, serum phosphorus, fasting blood glucose, fasting serum insulin, homeostasis model assessment of insulin resistance, hemoglobin A1c, and 25(OH) Vitamin D levels were measured at the beginning and after 3 months. Results: After 3 months, the increased Vitamin D levels resulting from the daily and weekly oral doses of Vitamin D3 caused a significant decrease in metabolic parameters, whereas the parenteral dose demonstrated a non-significant decrease. Conclusion: Oral daily and weekly doses of Vitamin D3 could improve glucose homeostasis equally in patients with T2DM and better than a single parenteral dose of Vitamin D3.

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The Role of Sexual Hormones on the Enteroinsular Axis

Endocrine Reviews ◽

10.1210/er.2019-00004 ◽

2019 ◽

Vol 40 (4) ◽

pp. 1152-1162 ◽

Cited By ~ 2

Author(s):

Sandra Handgraaf ◽

Jacques Philippe

Keyword(s):

Sex Hormones ◽

Glucose Homeostasis ◽

Fine Tuning ◽

Protective Effects ◽

Enteroinsular Axis ◽

Sexual Hormones ◽

The Impact ◽

Potential Therapeutics

AbstractSex steroid estrogens, androgens, and progesterone, produced by the gonads, which have long been considered as endocrine glands, are implicated in sexual differentiation, puberty, and reproduction. However, the impact of sex hormones goes beyond these effects through their role on energy metabolism. Indeed, sex hormones are important physiological regulators of glucose homeostasis and, in particular, of the enteroinsular axis. In this review, we describe the roles of estrogens, androgens, and progesterone on glucose homeostasis through their effects on pancreatic α- and β-cells, as well as on enteroendocrine L-cells, and their implications in hormonal biosynthesis and secretion. The analysis of their mechanisms of action with the dissection of the receptors implicated in the several protective effects could provide some new aspects of the fine-tuning of hormonal secretion under the influence of the sex. This knowledge paves the way to the understanding of transgender physiology and new potential therapeutics in the field of type 2 diabetes.

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