Template to improve glycemic control without reducing adiposity or dietary fat.
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ABSTRACT:
SUBMITTER: Krishnapuram R
PROVIDER: S-EPMC3093976 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Studies indicate that modulating enterocyte metabolism might affect whole body glucose homeostasis and the development of diet-induced obesity (DIO). We tested whether enhancing enterocyte fatty acid oxidation (FAO) could protect mice from DIO and impaired glycemic control. To this end, we used mice expressing a mutant form of carnitine palmitoyltransferase-1a (CPT1mt), insensitive to inhibition by malonyl-CoA, in their enterocytes (iCPT1mt) and fed them low-fat control diet (CD) or high-fat diet (HFD) chronically. CPT1mt expression led to an upregulation of FAO in the enterocytes. On CD, iCPT1mt mice had impaired glycemic control and showed concomitant activation of lipogenesis, glycolysis and gluconeogenesis in their enterocytes. On HFD, both iCPT1mt and control mice developed DIO, but iCPT1mt mice showed improved glycemic control and reduced visceral fat mass. Together these data indicate that modulating enterocyte metabolism in iCPT1mt mice affects glycemic control in a body weight-independent, but dietary fat-dependent manner.
| S-EPMC6050244 | biostudies-literature
Project description:There is considerable interest in dietary and other approaches to maintaining blood glucose concentrations within the normal range and minimizing exposure to postprandial hyperglycemic excursions. The accepted marker to evaluate the sustained maintenance of normal blood glucose concentrations is glycated hemoglobin A1c (HbA1c). However, although this is used in clinical practice to monitor glycemic control in patients with diabetes, it has a number of drawbacks as a marker of efficacy of dietary interventions that might beneficially affect glycemic control in people without diabetes. Other markers that reflect shorter-term glycemic exposures have been studied and proposed, but consensus on the use and relevance of these markers is lacking. We have carried out a systematic search for studies that have tested the responsiveness of 6 possible alternatives to HbA1c as markers of sustained variation in glycemic exposures and thus their potential applicability for use in dietary intervention trials in subjects without diabetes: 1,5-anhydroglucitol (1,5-AG), dicarbonyl stress, fructosamine, glycated albumin (GA), advanced glycated end products (AGEs), and metabolomic profiles. The results suggest that GA may be the most promising for this purpose, but values may be confounded by effects of fat mass. 1,5-AG and fructosamine are probably not sensitive enough to the range of variation in glycemic exposures observed in healthy individuals. Use of measures based on dicarbonyls, AGEs, or metabolomic profiles would require further research into possible specific molecular species of interest. At present, none of the markers considered here is sufficiently validated and sensitive for routine use in substantiating the effects of sustained variation in dietary glycemic exposures in people without diabetes.
| S-EPMC7490172 | biostudies-literature
Project description:Purpose: Obesity is a global health issue. To investigate if protein and fat contents of the diets had effects on energy balance via the canonical hunger signaling pathways in the hypothalamus, RNAseq was performed on RNA extracted from the hypothalami of mice exposed to the different diets. A suggested mechanism by which animals may avoid obesity is by burning off excess energy via upregulation of white adipose tissue (WAT) browning. To investigate if protein and fat content of the diet had effects on energy balance via the browning related signaling pathways in the WAT, RNAseq was performed on RNA extracted from the subcutaneous WAT (sWAT) and epididymal WAT (eWAT) of mice exposed to the different diets. Methods: C57BL/6 male mice were used in this work. All mice were fed a standard diet with 10% fat and 20% protein (D12450B, Research Diets Ltd) for 2 weeks as the baseline period. Following 2 weeks of baseline monitoring (at age 12 weeks), all mice were randomly allocated to different groups and switched to the experimental diets for 12 weeks. After 12 weeks all mice were sacrificed and dissected. Methods: In total, mice were fed on 4 diet series, each series consisting of 6 different diets (total = 24 diets). In the first two series (Series 1: D14071601–D14071606 and series 2: D14071607 – D14071612) we fixed the level of fat by energy, and varied the protein content. The protein source was casein. The balance was made up by carbohydrate (roughly equal mix of corn starch and maltodextrose). The source of fat was a mix of cocoa butter, coconut oil, menhaden oil, palm oil and sunflower oil. This mix was designed to match the balance of saturated, mono-unsaturated and polyunsaturated fats (ratio 47.5: 36.8: 15.8) and the n-6: n-3 ratio (14.7: 1) in the typical western diet. The proportions of the different fat constituents and hence fatty acid distributions did not change as the total fat content changed. Sucrose and cellulose were both fixed 5% by energy and weight respectively, and all diets were supplemented with a standard vitamin and mineral mix. In the second two series of diets (series 3: D14071613 – D14071618 and series 4: D14071619 – D14071624) we fixed the level of protein by energy and then allowed the fat content to vary. In these diets the sucrose, cellulose and vitamin and mineral contents were the same as the diets in series 1 and 2. All these diets can be ordered direct from research diets (www.researchdiets.com) using the diet codes provided. Methods: From each diet group, the hypothalami of 8/20 individuals were collected. The left halves of two, and the right halves of another two, were pooled together as one sample, and the same was performed with the other 4 hypothalami, resulting in each diet group having 2 pooled samples of 4 hypothalami (n = 48 samples in total across 24 diets). From each diet group, the sWAT and eWAT of 12/20 individuals were also collected. A small piece from each of six sWAT collections were pooled together as one sample, and the same was performed with the other six eWAT collections. In this way each diet group had one pooled sWAT sample and one pooled eWAT sample (also n = 48 across 24 diets). Methods: The total RNA of the hypothalamus and WAT was isolated using the RNeasy Mini Kit (QIAGEN, 74104) according to manufacturer's protocol. All sequencing was carried out using the Illumina NextSeq 500 sequencer. RNA fragments were sequenced by 75 bp long reads from paired ends (PE 2 x 75 bp, 150 bp per fragment). Quality control checks for raw data FASTQ files were done by using FASTQC (a quality control tool for high throughput sequence data; http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Paired-end reads were mapped to the Mus musculus genome (GRCm38) using Bowtie 2-2.1.0, TopHat-2.0.10, and Samtools-0.1.19; uniquely mapped reads for each gene were counted against the GTF file of GRCm38 provided by Ensembl (release 83) using HTSeq-0.6.1p1 using the strand = reverse; after read count data were obtained from the TopHat-HTSeq pipeline, counts per million (CPM) value for each gene was calculated by using the R package ‘edgeR’ (version 3.12.0, R version 3.2.2) to normalize the count data by the size of the library of each sample. Genes with the CPM value ≥ 1 in at least one of the 24 diets group were retained (Anders et al., 2013). Generalized Linear Modelling (GLM) was applied by R (version 3.2.2). The GLM model used here was: ~p+f+p:f, which regresses gene expression (CPM) against the protein (p) and fat contents (f) of diets, as well as their interaction (p:f). However, when the effect of the interaction was not significant (p value ≥ 0.05), the interaction term was dropped and a revised model (~p+f) was utilized. Results: With TopHat-HTSeq pipeline, reads of each sample were mapped to 46,078 genes. In hypothalamus there were 15,371 genes with the counts per million (CPM) value ≥ 1 in at least one of the 24 diets group; in white adipose tissue there were 18,202 genes with the CPM value ≥ 1 in at least one of the 24 diets group. No major changes in hypothalamic gene expression levels were found in relation to different dietary protein levels at fixed fat contents, however hypothalamic gene expression showed increase in expression of genes in reward pathways in relation to dietary fat, while Agrp and Npy were both downregulated in relation to dietary fat levels. WAT gene expression showed decrease in expression of general thermogenic related genes and WAT browning related genes in relation to both dietary protein and dietary fat, while Tgfb1, Pdk4 and Fgf1 were all upregulated in relation to dietary fat levels. Conclusions: Significant positive associations were evident between the fat levels of the diet and the main hedonic signaling systems linked to food intake. Significant negative associations were found between both protein and fat levels of the diet and WAT browning or general thermogenic signalings linked to energy expenditure.
2018-05-29 | GSE114960 | GEO
Project description:ObjectiveAd36, a human adenovirus, increases adiposity but improves glycemic control in animal models. Similarly, natural Ad36 infection is cross-sectionally associated with greater adiposity and better glycemic control in humans. This study compared longitudinal observations in indices of adiposity (BMI and body fat percentage) and glycemic control (fasting glucose and insulin) in Ad36-infected versus uninfected adults.Research design and methodsBaseline sera from Hispanic men and women (n = 1,400) were screened post hoc for the presence of Ad36-specific antibodies. Indices of adiposity and glycemic control at baseline and at ~10 years past the baseline were compared between seropositive and seronegative subjects, with adjustment for age and sex. In addition to age and sex, indices of glycemic control were adjusted for baseline BMI and were analyzed only for nondiabetic subjects.ResultsSeropositive subjects (14.5%) had greater adiposity at baseline, compared with seronegative subjects. Longitudinally, seropositive subjects showed greater adiposity indices but lower fasting insulin levels. Subgroup analyses revealed that Ad36-seropositivity was associated with better baseline glycemic control and lower fasting insulin levels over time in the normal-weight group (BMI ≤25 kg/m(2)) and longitudinally, with greater adiposity in the overweight (BMI 25-30 kg/m(2)) and obese (BMI >30 kg/m(2)) men. Statistically, the differences between seropositive and seronegative individuals were modest in light of the multiple tests performed.ConclusionsThis study strengthens the plausibility that in humans, Ad36 increases adiposity and attenuates deterioration of glycemic control. Panoptically, the study raises the possibility that certain infections may modulate obesity or diabetes risk. A comprehensive understanding of these under-recognized factors is needed to effectively combat such metabolic disorders.
| S-EPMC3579356 | biostudies-literature
Project description:BACKGROUND/OBJECTIVE:Poor dietary quality, measured by the Healthy Eating Index 2010 (HEI-2010), is associated with risk of gestational diabetes mellitus (GDM) and type 2 diabetes. The aim was to investigate the association between dietary quality and glycemic control in women with GDM. MATERIALS AND METHODS:The study included 1220 women with GDM. Dietary quality was calculated by HEI-2010 score from a Food Frequency Questionnaire administered shortly after GDM diagnosis; higher scores indicate higher dietary quality. Subsequent glycemic control was defined as ?80% of all capillary glucose measurements meeting recommended clinical targets below 95?mg/dL for fasting, and below 140?mg/dL 1-hour glucose after meals. RESULTS:As compared with Quartile 1 of HEI-2010 score, Quartiles 2, 3, and 4 showed increased adjusted odds of overall optimal glycemic control (odds ratio [95% confidence interval] 1.90 [1.34-2.70], 1.77 [1.25-2.52], and 1.55 [1.09-2.20], respectively). Increased odds of glycemic control were observed in Quartiles 2, 3, and 4 as compared with Quartile 1 of HEI-2010 score for 1-hour postbreakfast and 1-hour postdinner. Mean capillary glucose was lower in Quartiles 2, 3, and 4 of HEI-2010 score when compared with Quartile 1 for 1-hour postdinner (p?=?0.03). CONCLUSIONS:Clinicians should be aware that even a small improvement in diet quality may be beneficial for the achievement of improved glycemic control in women with GDM. TRIAL REGISTRATION:Clinical Trials.gov number, NCT01344278.
| S-EPMC6390645 | biostudies-literature
Project description:BackgroundAlthough there is some evidence of positive associations between both the glycemic index (GI) and glycemic load (GL) with cancer risk, the relationships with lung cancer risk remain largely unexplored. We evaluated the associations between GI and GL with lung cancer.MethodsThe analyses were performed using data from a population-based case-control study recruited between 1999 and 2004 in Los Angeles County. Dietary factors were collected from 593 incident lung cancer cases and 1026 controls using a modified food frequency questionnaire. GI and GL were estimated using a food composition table. Adjusted odds ratios (ORs) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression adjusting for potential confounders.ResultsDietary GI was positively associated with lung cancer (OR for upper vs. lower tertile = 1.62; 95 % CI: 1.17, 2.25). For histologic subtypes, positive associations were observed between GI and adenocarcinoma (OR for upper vs. lower tertile = 1.82; 95 % CI: 1.22, 2.70) and small cell carcinoma (OR for upper vs. lower tertile = 2.68; 95 % CI: 1.25, 5.74). No clear association between GL and lung cancer was observed.ConclusionThese findings suggest that high dietary GI was associated with increased lung cancer risk, and the positive associations were observed for both lung adenocarcinoma and small cell lung carcinoma. Replication in an independent dataset is merited for a broader interpretation of our results.
| S-EPMC7734880 | biostudies-literature
Project description:The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.
| S-EPMC9018739 | biostudies-literature
Project description:Type 2 diabetes (T2DM) and pre-diabetes have become a major public health problem in China. We examined whether a higher dietary glycemic index (GI) or glycemic load (GL) was associated with a less favorable glucose homeostasis among Chinese adults and whether these associations were modified by their genetic predisposition or whether combined effects exist with their cereal fiber intake. Multivariable regression analyses were performed in 3918 adults aged 23-69 years for whom three 24-hour dietary recalls and information on glucose homeostasis, genetic background and potential confounders was available. Adults in the highest GI (GL) tertile had an approximately 9% (5%) higher fasting plasma glucose, 11% (3%) higher glycated haemoglobin, 12% (7%) higher insulin level, and 28% (22%) higher hepatic insulin resistance compared to those in the lowest tertile (adjusted pfor-trend ≤ 0.04). Moreover, a higher dietary GI or GL was associated with higher odds of pre-diabetes (pfor-trend = 0.03). These associations were more pronounced among persons with a high T2DM genetic risk score (pfor-interaction ≤ 0.06) or a low cereal fiber intake (pfor-interaction ≤ 0.05). In conclusion, our study indicates that the dietary GI or GL is of relevance for glucose homeostasis among Chinese adults, particularly among individuals genetically predisposed to T2DM.
| S-EPMC5428428 | biostudies-literature
Project description:Compare differences in glycated proteome between good and poorly controlled T1D human plasma
2020-01-09 | PXD015101 | Pride
Project description:Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus often produce nausea, vomiting, and in some patients, undesired anorexia. Notably, these behavioral effects are caused by direct central GLP-1R activation. Herein, we describe the creation of a GLP-1R agonist conjugate with modified brain penetrance that enhances GLP-1R-mediated glycemic control without inducing vomiting. Covalent attachment of the GLP-1R agonist exendin-4 (Ex4) to dicyanocobinamide (Cbi), a corrin ring containing precursor of vitamin B12, produces a "corrinated" Ex4 construct (Cbi-Ex4). Data collected in the musk shrew (Suncus murinus), an emetic mammal, reveal beneficial effects of Cbi-Ex4 relative to Ex4, as evidenced by improvements in glycemic responses in glucose tolerance tests and a profound reduction of emetic events. Our findings highlight the potential for clinical use of Cbi-Ex4 for millions of patients seeking improved glycemic control without common side effects (e.g., emesis) characteristic of current GLP-1 therapeutics.
| S-EPMC7376604 | biostudies-literature