Measuring acylcarnitine concentrations in insulin resistant and insulin deficient mouse tissue models
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
TISSUE(S): Muscle
DISEASE(S): Diabetes
PROVIDER: ST000517 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:Abscisic acid (ABA), a plant hormone, has recently been shown to play a role in glycemia regulation in mammals, by stimulating insulin-independent glucose uptake and metabolism in skeletal muscle. The aim of this study was to test whether ABA could improve glycemic control in a murine model of type 1 diabetes (T1D). Mice were rendered diabetic with streptozotocin and the effect of ABA administration, alone or with insulin, was tested on glycemia. Diabetic mice treated with a single oral dose of ABA and low-dose subcutaneous insulin showed a significantly reduced glycemia profile compared with controls treated with insulin alone. In diabetic mice treated for four weeks with ABA, the effect of low-dose insulin on the glycemia profile after glucose load was significantly improved, and transcription both of the insulin receptor, and of glycolytic enzymes in muscle, was increased. Moreover, a significantly increased transcription and protein expression of AMPK, PGC1-α, and GLUT4 was observed in the skeletal muscle from diabetic mice treated with ABA, compared with untreated controls. ABA supplementation in conjunction with insulin holds the promise of reducing the dose of insulin required in T1D, reducing the risk of hypoglycemia, and improving muscle insulin sensitivity and glucose consumption.
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Project description:PurposeTo investigate the potential role of gut microbiota in obesity-induced insulin resistance (IR).MethodsFour-week-old male C57BL/6 wild-type mice (n = 6) and whole-body SH2 domain-containing adaptor protein (LNK)-deficient in C57BL/6 genetic backgrounds mice (n = 7) were fed with a high-fat diet (HFD, 60% calories from fat) for 16 weeks. The gut microbiota of 13 mice feces samples was analyzed by using a 16 s rRNA sequencing analysis.ResultsThe structure and composition of the gut microbiota community of WT mice were significantly different from those in the LNK-/- group. The abundance of the lipopolysaccharide (LPS)-producing genus Proteobacteria was increased in WT mice, while some short-chain fatty acid (SCFA)-producing genera in WT groups were significantly lower than in LNK-/- groups (p < 0.05).ConclusionsThe structure and composition of the intestinal microbiota community of obese WT mice were significantly different from those in the LNK-/- group. The abnormality of the gut microbial structure and composition might interfere with glucolipid metabolism and exacerbate obesity-induced IR by increasing LPS-producing genera while reducing SCFA-producing probiotics.
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Project description:The two insulin receptor (IR) isoforms IR-A and IR-B are responsible for the pleiotropic actions of insulin and insulin-like growth factors. Consequently, changes in IR isoform expression and in the bioavailability of their ligands will impact on IR-mediated functions. Although alteration of IR isoform expression has been linked to insulin resistance, knowledge of IR isoform expression and mechanisms underlying tissue/cell-type-specific changes in metabolic disease are lacking. Using mouse models of obesity/diabetes and measuring the mRNA of the IR isoforms and mRNA/protein levels of total IR, we provide a data set of IR isoform expression pattern that documents changes in a tissue-dependent manner. Combining tissue fractionation and a new in situ mRNA hybridization technology to visualize the IR isoforms at cellular resolution, we explored the mechanism underlying the change in IR isoform expression in perigonadal adipose tissue, which is mainly caused by tissue remodelling, rather than by a shift in IR alternative splicing in a particular cell type, e.g. adipocytes.
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Project description:BackgroundIncreased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance.MethodsWe conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT.ResultsMifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ± 32.9 vs 42.8 ± 23.9; P = 0.002) and reduced adipo-IR (49.9 ± 45.9 vs 65.5 ± 43.8; P = 0.004), and HIRI (50.2 ± 38.7 vs 70.0 ± 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity.ConclusionShort-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.
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Project description:Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.
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