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OBJECTIVE: The main objective of this study was to find if thiamine disulfide (TD) lowers blood glucose level and improves insulin resistance (IR) in liver and muscle in rats with chronic type 1 diabetes (T1DM) using euglycemic-hyperinsulinemic clamp technique. METHODS: A total of fifty male Wistar rats were assigned to five groups consisted of: non-diabetic control (NDC), diabetic control (DC), diabetic treated with thiamine disulfide (D-TD), diabetic treated with insulin (D-insulin), and diabetic treated with both TD and insulin (D-insulin+TD). Diabetes was induced by a 60â¯mg/kg dose of streptozotocin. Blood glucose levels, pyruvate tolerance test (PTT), intraperitoneal glucose tolerance test (IPGTT), levels of glycosylated hemoglobin (HbA1c), glucose infusion rate (GIR), liver and serum lipid profiles, liver glycogen stores, liver enzymes ([ALT], [AST]), and serum calcium and magnesium levels. were evaluated. Additionally, gene expression levels of phosphoenolpyruvate carboxykinase (Pepck), forkhead box O1 (Foxo1), and glucose transporter type 4 (Glut4) were assessed in liver and skeletal muscle tissues. RESULTS: Blood glucose level was reduced by TD treatment. In addition, TyG index, HOMA-IR, serum and liver lipid profiles, HbA1c levels, and expressions of Foxo1 and Pepck genes were decreased significantly (P<0.05) in all the treated groups. However, TD did not influence Glut4 gene expression, but GIR as a critical index of IR were 5.0±0.26, 0.29±0.002, 1.5±0.07, 0.9±0.1 and 1.3±0.1â¯mg.min-1Kg-1 in NDC, DC, D-TD, D-insulin and D-insulin+TD respectively. CONCLUSIONS: TD improved IR in the liver primarily by suppressing gluconeogenic pathways, implying the potential use of TD as a therapeutic agent in diabetes.
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Glucemia , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Resistencia a la Insulina , Hígado , Ratas Wistar , Tiamina , Animales , Masculino , Hígado/metabolismo , Hígado/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Ratas , Tiamina/farmacología , Tiamina/administración & dosificación , Transportador de Glucosa de Tipo 4/metabolismo , Insulina/sangre , Transducción de Señal/efectos de los fármacos , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Estreptozocina , Proteína Forkhead Box O1 , Péptidos y Proteínas de Señalización IntracelularRESUMEN
CONTEXT: Relative hypoglycemia (RH) is linked to sympathetic responses that can alter vascular function in individuals with type 2 diabetes. However, less is known about the role of RH on hemodynamics or metabolic insulin sensitivity in prediabetes. OBJECTIVE: Determine if RH alters peripheral endothelial function or central hemodynamics to a greater extent in those with prediabetes (PD) versus normoglycemia (NG). METHODS: Seventy adults with obesity were classified using ADA criteria as PD (n=34 (28F); HbA1c=6.02±0.1%) or NG (n=36 (30F); HbA1c=5.4±0.0%). Brachial artery endothelial function, skeletal muscle capillary perfusion, and aortic waveforms were assessed at 0 and 120min of a euglycemic clamp (40 mU/m2/min, 90 mg/dl). Plasma nitrate/nitrite and endothelin-1 (ET-1) were measured as surrogates of nitric oxide-mediated vasodilation and vasoconstriction, respectively. RH was defined as the drop in glucose (%) from fasting to clamp steady state. RESULTS: There were no differences in age, weight, or VO2max between groups. PD had higher HbA1c (P<0.01) and a greater drop in glucose in response to insulin (14 vs. 8%; P=0.03). Further, heart rate (HR) increased in NG compared to PD (P<0.01), while forward wave (Pf) decreased in PD (P=0.04). Insulin also tended to reduce arterial stiffness (cfPWV) in NG versus PD (P=0.07), despite similar increases in pre-occlusion diameter (P=0.02), blood flow (P=0.02), and lower augmentation index (AIx75) (P≤0.05). CONCLUSION: Compared with NG, insulin-induced RH corresponded with a blunted rise in HR and drop in Pf during insulin infusion in adults with PD, independent of changes in peripheral endothelial function.
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AIMS: Prior studies provided evidence that low-density lipoprotein (LDL)-cholesterol-lowering statins reduce cardiovascular events while conveying an increased risk of type 2 diabetes. The aim of this study was to investigate the association between LDL levels and both insulin sensitivity and insulin secretion in a cohort of 356 adult first-degree relatives of patients with type 2 diabetes. METHODS: Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp and first-phase insulin secretion was measured by both intravenous glucose tolerance test (IVGTT) and OGTT. RESULTS: LDL-cholesterol levels were not independently associated with insulin-stimulated glucose disposal. After adjusting for several potential confounders, LDL-cholesterol concentration exhibited a positive independent association with acute insulin response (AIR) during IVGTT and with the OGTT derived Stumvoll first-phase insulin secretion index. When insulin release was adjusted for the underlying degree of insulin sensitivity, using the disposition index (AIR × insulin-stimulated glucose disposal), ß-cell function was significantly associated with LDL-cholesterol levels, even after further adjusting for several potential confounders. CONCLUSIONS: The present results suggest that LDL cholesterol is a positive modulator of insulin secretion. The deterioration in glycemic control observed during treatment with statins might thus be explained by an impairment in insulin secretion due to the cholesterol-lowering effect of statins.
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Diabetes Mellitus Tipo 2 , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Resistencia a la Insulina , Adulto , Humanos , Insulina , Resistencia a la Insulina/fisiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Insulina Regular Humana , Glucosa , Lipoproteínas LDL , GlucemiaRESUMEN
There is interest in the impact that dietary interventions can have on preventing the transition from insulin resistance to type 2 diabetes, including a suggestion that the bioactive components of cocoa may enhance fasting insulin sensitivity. However, a role for cocoa flavanols (CF) in reducing insulin resistance in the insulin-stimulated state, an important risk factor for cardiovascular disease, is unresolved. This study investigated whether CF consumption improved whole-body insulin-mediated glucose uptake ('M') in females with overweight/obesity, using a randomized, double-blinded, placebo-controlled, parallel-group design. Thirty-two premenopausal females (19-49 years; 27-35 kg·m-2) with elevated HOMA-IR (HOMA-IR >1.5) supplemented their habitual diet with two servings/day of a high-flavanol cocoa drink (HFC; 609 mg CF/serving; n = 16) or low-flavanol cocoa drink (LFC; 13 mg CF/serving; n = 16) for 4 weeks. Assessment of HOMA-IR and 'M' during a 3-h, 60 mIU insulin·m-2·min-1 euglycemic clamp was performed before and after the intervention. Data are the mean (SD). Changes to HOMA-IR (HFC -0.003 (0.57); LFC -0.0402 (0.86)) and 'M' (HFC 0.99 (7.62); LFC -1.32 (4.88) µmol·kg-1·min-1) after the intervention were not different between groups. Four weeks' consumption of ~1.2 g CF/day did not improve indices of fasting insulin sensitivity or insulin-mediated glucose uptake. A recommendation for dietary supplementation with cocoa flavanols to improve glycemic control is therefore not established.
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Cacao , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Femenino , Sobrepeso , Flavonoles/farmacología , Obesidad , Insulina , Polifenoles , Suplementos Dietéticos , Glucosa , Método Doble CiegoRESUMEN
The results of the studies on the pattern of insulin sensitivity (IS) are contradictory in patients with GH deficiency (GHD); however, the interference of the GHD onset stage, childhood or adulthood in the IS has not been assessed by euglycemic hyperinsulinemic clamp (EHC), a gold-standard method for the assessment of insulin sensitivity. In a prospective cross-sectional study, we assessed IS and body composition in 17 adults with hypopituitarism without GH replacement, ten with childhood-onset (COGHD) and seven with adulthood-onset (AOGHD) and compared them to paired control groups. COGHD presented higher IS (p = 0.0395) and a similar percentage of fat mass (PFM) to AOGHD. COGHD showed higher IS than the control group (0.0235), despite a higher PFM (0.0022). No differences were found between AODGH and the control group. In AOGHD and the control group, IS was negatively correlated with PFM (rs: −0.8214, p = 0.0234 and rs: −0.3639, p < 0.0344), while this correlation was not observed with COGHD (rs: −0.1152, p = 0.7514). Despite the higher PFM, patients with COGHD were more sensitive to insulin than paired healthy individuals, while patients with AOGHD showed similar IS compared to controls. The lack of GH early in life could modify the metabolic characteristics of tissues related to the glucose metabolism, inducing beneficial effects on IS that persist into adulthood. Thus, the glycometabolic findings in patients with COGHD seems to be not applicable to AOGHD.
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Type 2 diabetes (T2D) and hypertension (HTN) are common risk factors of cardiovascular diseases (CVD) characterized by chronic low-grade systemic inflammation and impaired endothelial function. This study aimed to assess whether levels of non-enzymatic, lipoxygenase (LOX)- and cytochrome P450 (CYP)-derived arachidonic acid (ARA) metabolites, which are known regulators of vascular homeostasis, are affected by HTN and T2D. For this objective, 17 plasma level derivatives of ARA were quantitated by chromatography coupled with mass spectrometry in 44 patients (12 healthy, 8 HTN, 7 T2D, and 17 HTN + T2D). Effects of hyperglycemic and hyperinsulinemic clamps on ARA metabolite levels were assessed in seven healthy subjects. No significant differences in the plasma levels of ARA metabolites were observed for T2D patients compared with healthy volunteers. HTN was associated with an alteration of ARA metabolite correlation patterns with increased 20-, 19-, 15-, and 8-hydroxyeicosatrienoic acid (HETE). A decrease of 20-HETE was also observed during both hyperglycemic and hyperinsulinemic clamps. Additional experiments are needed to assess whether the modulation of HETE metabolites in HTN may be of interest. Furthermore, although not affected by T2D, it remains to investigate whether the decrease of 20-HETE observed during clamps may be related to the regulation of glucose tolerance and insulin signaling.
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The aim of this experiment was to test whether insulin potentiates the effects of two abomasally infused amino acids (AA), leucine and methionine (LM), on mammary extraction efficiency of energetic and nitrogenous nutrients. Six lactating Holstein cows (155 ± 9 DIM) were ruminally-cannulated and had the right carotid artery subcutaneously transposed. Cows were fed a 20% metabolizable protein-restricted diet and abomasally infused with water (8 L/d) or AA (Met 26 g/d, Leu 70 g/d) for 8 h/d, for 7 days. On the last day of each period, cows were intravenously infused with saline (0.9% NaCl, 110 mL/h) or subjected to 8 h hyperinsulinemic clamp (IC) alongside abomasal infusions. For IC, insulin was infused at 1 µg/kg/h. Normoglycemia was maintained by varying glucose (50% w/v in water) infusion rate based on coccygeal vein glucose concentration. Carotid arterial and subcutaneous abdominal (mammary) vein blood samples were collected at 0, 1, 2, 4, and 6 h from the start of infusions. Milk weights and samples for baseline measurements of production were taken on day 5 PM, day 6 AM and PM, and day 7 AM of the experimental period. A final milk weight and sample was taken immediately after abomasal and intravenous infusions on day 7 PM for assessing the interaction between insulin and the infused AA. The experiment had an incompletely replicated Latin square design with a 2 × 2 factorial arrangement of treatments (abomasal and intravenous infusion). Baseline milk production when cows were only receiving abomasal infusions was largely unaffected by LM, but milk protein yield tended to be decreased. On day 7, LM tended to positively increase milk fat and de novo fatty acid content, and IC tended to decrease milk protein content. Both milk urea nitrogen and plasma urea nitrogen were decreased by IC. Circulating AA concentrations in plasma were decreased by both LM and IC, but mammary extraction efficiency was affected by neither. Infusion of LM had no effect on any energy metabolite analyzed. Circulating non-esterified fatty acid concentration was decreased by IC, with no effect on mammary extraction efficiency. Mammary extraction efficiency of both acetate and ß-hydroxybutyrate were decreased by IC. Overall, while both circulating concentrations of energy metabolites and amino acids were decreased in response to treatments, this was not due to improved mammary extraction efficiency.
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Aminoácidos , Lactancia , Aminoácidos/metabolismo , Aminoácidos/farmacología , Animales , Bovinos , Dieta/veterinaria , Ácidos Grasos/metabolismo , Femenino , Glucosa/metabolismo , Insulina/metabolismo , Lactancia/fisiología , Leucina/metabolismo , Leucina/farmacología , Glándulas Mamarias Animales , Metionina/farmacología , Proteínas de la Leche/metabolismo , Proteínas de la Leche/farmacología , Nitrógeno , Urea , Agua/metabolismo , Agua/farmacologíaRESUMEN
Skeletal muscle is highly plastic and dynamically regulated by the body's physical demands. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to 8 weeks of supervised exercise training in volunteers with a range of insulin sensitivities. We studied 13 sedentary participants and performed euglycemic hyperinsulinemic clamps with basal vastus lateralis muscle biopsies and peak aerobic activity (VO2 peak) tests before and after training. We extracted DNA from the muscle biopsies and performed global methylation using Illumina's Methylation EPIC 850K BeadChip. Training significantly increased peak aerobic capacity and insulin-stimulated glucose disposal. Fasting serum insulin and insulin levels during the steady state of the clamp were significantly lower post-training. Insulin clearance rates during the clamp increased following the training. We identified 13 increased and 90 decreased differentially methylated cytosines (DMCs) in response to 8 weeks of training. Of the 13 increased DMCs, 2 were within the following genes, FSTL3, and RP11-624M8.1. Of the 90 decreased DMCs, 9 were within the genes CNGA1, FCGR2A, KIF21A, MEIS1, NT5DC1, OR4D1, PRPF4B, SLC26A7, and ZNF280C. Moreover, pathway analysis showed an enrichment in metabolic and actin-cytoskeleton pathways for the decreased DMCs, and for the increased DMCs, an enrichment in signal-dependent regulation of myogenesis, NOTCH2 activation and transmission, and SMAD2/3: SMAD4 transcriptional activity pathways. Our findings showed that 8 weeks of exercise training alters skeletal muscle DNA methylation of specific genes and pathways in people with varying degrees of insulin sensitivity.
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BACKGROUND: Functional electrical stimulation-assisted cycle ergometry (FESCE) can deliver active exercise to critically ill patients, including those who are sedated. Aerobic exercise is known to stimulate skeletal muscle glucose uptake. We asked whether FESCE can reduce intravenous insulin requirements and improve insulin sensitivity in intensive care unit (ICU) patients. METHOD: We performed an a priori-planned secondary analysis of data from an outcome-based randomized controlled trial (NCT02864745) of FESCE-based early-mobility program vs standard of care in mechanically ventilated patients. We analyzed glucose profile, glucose intake, and insulin requirements during ICU stay in all enrolled patients. In a nested subgroup, we performed hyperinsulinemic (120 mIU/min/m2 ) euglycemic clamps at days 0, 7, and 180 (n = 30, 23, and 11, respectively). RESULTS: We randomized 150 patients 1:1 to receive intervention or standard of care. Seventeen (23%) patients in each study arm had a history of diabetes. During ICU stay, patients received 137 ± 65 and 137 ± 88 g/day carbohydrate (P = .97), and 31 vs 35 (P = .62) of them required insulin infusion to maintain blood glucose 8.61 ± 2.82 vs 8.73 ± 2.67 mM (P = .75, n = 11,254). In those treated with insulin, median daily dose was 53 IU (interquartile range [IQR], 25-95) vs 62 IU (IQR, 26-96) in the intervention and control arm, respectively (P = .44). In the subgroup of patients undergoing hyperglycemic clamps, insulin sensitivities improved similarly and significantly from acute and protracted critical illness to 6 months after discharge. CONCLUSION: The FESCE-based early-mobility program does not significantly reduce insulin requirements in critically ill patients on mechanical ventilation.
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Enfermedad Crítica , Unidades de Cuidados Intensivos , Estimulación Eléctrica , Ergometría , Estudios de Seguimiento , Humanos , Insulina , Respiración ArtificialRESUMEN
Insulin resistance (IR) is a major metabolic risk factor even before the onset of hyperglycemia. Recently, berberine (BBR) is found to improve hyperglycemia and IR. In this study, we investigated whether BBR could improve IR independent of hyperglycemia. Acute insulin-resistant state was induced in rats by systemic infusion of intralipid (6.6%). BBR was administered via different delivery routes before or after the beginning of a 2-h euglycemic-hyperinsulinemic clamp. At the end of experiment, rats were sacrificed, gastrocnemius muscle was collected for detecting mitochondrial swelling, phosphorylation of Akt and AMPK, as well as the mitochondrial permeability regulator cyclophilin D (CypD) protein expression. We showed that BBR administration markedly ameliorated intralipid-induced IR without affecting blood glucose, which was accompanied by alleviated mitochondrial swelling in skeletal muscle. We used human skeletal muscle cells (HSMCs), AML12 hepatocytes, human umbilical vein endothelial cells, and CypD knockout mice to investigate metabolic and molecular alternations. In either HSMCs or AML12 hepatocytes, BBR (5 µM) abolished palmitate acid (PA)-induced increase of CypD protein levels. In CypD-deficient mice, intralipid-induced IR was greatly attenuated and the beneficial effect of BBR was diminished. Furthermore, we demonstrated that the inhibitory effect of BBR on intralipid-induced IR was mainly mediated by skeletal muscle, but not by intestine, liver, or microvasculature; BBR administration suppressed intralipid-induced upregulation of CypD expression in skeletal muscle. These results suggest that BBR alleviates intralipid-induced IR, which is related to the inhibition of CypD protein expression in skeletal muscle.
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Berberina/uso terapéutico , Hiperinsulinismo/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina/fisiología , Animales , Línea Celular , Ciclofilinas/metabolismo , Emulsiones , Humanos , Hiperinsulinismo/inducido químicamente , Hiperinsulinismo/metabolismo , Masculino , Ratones , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Fosfolípidos , Ratas Sprague-Dawley , Aceite de SojaRESUMEN
OBJECTIVE: Insulin resistance develops prior to the onset of overt type 2 diabetes, making its early detection vital. Direct accurate evaluation is currently only possible with complex examinations like the stable isotope-based hyperinsulinemic euglycemic clamp (HIEC). Metabolomic profiling enables the detection of thousands of plasma metabolites, providing a tool to identify novel biomarkers in human obesity. DESIGN: Liquid chromatography mass spectrometry-based untargeted plasma metabolomics was applied in 60 participants with obesity with a large range of peripheral insulin sensitivity as determined via a two-step HIEC with stable isotopes [6,6-2H2]glucose and [1,1,2,3,3-2H5]glycerol. This additionally enabled measuring insulin-regulated lipolysis, which combined with metabolomics, to the knowledge of this research group, has not been reported on before. RESULTS: Several plasma metabolites were identified that significantly correlated with glucose and lipid fluxes, led by plasma (gamma-glutamyl)citrulline, followed by betaine, beta-cryptoxanthin, fructosyllysine, octanylcarnitine, sphingomyelin (d18:0/18:0, d19:0/17:0) and thyroxine. Subsequent machine learning analysis showed that a panel of these metabolites derived from a number of metabolic pathways may be used to predict insulin resistance, dominated by non-essential amino acid citrulline and its metabolite gamma-glutamylcitrulline. CONCLUSION: This approach revealed a number of plasma metabolites that correlated reasonably well with glycemic and lipolytic flux parameters, measured using gold standard techniques. These metabolites may be used to predict the rate of glucose disposal in humans with obesity to a similar extend as HOMA, thus providing potential novel biomarkers for insulin resistance.
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BACKGROUND: There is no consensus in the field regarding the optimal method for the expression of metabolic flux data, such as glucose disposal rates during hyperinsulinemic-euglycemic clamp experiments. Several normalization methods are in use today, but their impact on study outcomes is rarely discussed. METHODS: We illustrate this issue using clamp data from 92 lean and 66 obese subjects. Glucose kinetics and insulin sensitivity were determined during hyperinsulinemic-euglycemic clamp studies using [6,6-2H2]glucose. From this single dataset, we calculated 21 expression methods for the glucose disposal rate during hyperinsulinemic conditions. RESULTS AND DISCUSSION: With most normalization methods, the obese subjects demonstrated reduced insulin-stimulated glucose disposal as compared to the lean subjects. However, depending on the normalization method, glucose disposal rates in obese subjects ranged from 26⯱â¯1% to 207⯱â¯10% of glucose disposal rates in lean subjects. We conclude that data normalization methods greatly impacted metabolic flux outcomes in our dataset of lean and obese subjects. There is no compelling evidence to select one method over the other, but we encourage authors in the metabolic arena to think about, and provide a rationale for, the best normalization method for their specific research questions.
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Técnica de Clampeo de la Glucosa/estadística & datos numéricos , Técnica de Clampeo de la Glucosa/normas , Metabolismo/fisiología , Bases de Datos Factuales , Glucosa/metabolismo , Humanos , Resistencia a la Insulina , Cinética , Obesidad/metabolismo , Radiofármacos/farmacocinética , Valores de ReferenciaRESUMEN
ABSTRACT GH is one of the insulin counterregulatory hormones which acts in the opposite way to insulin, increasing the glucose production by the liver and kidneys and decreasing glucose uptake from peripheral tissues, thus being a hyperglycemic hormone. When in excess, as in acromegaly, it induces glucose intolerance and diabetes. As expected, patients with GH deficiency (GHD) have hypoglycemia, especially in early childhood, but as GH is also a lipolytic hormone, these patients are becoming obese with higher percentages of body fat. Although obesity in general is directly related to insulin resistance, in patients with GH secretion disorders this relationship may be altered. In acromegaly there is a decrease in fat mass with worsening insulin sensitivity and mice with isolated GHD are characterized by greater insulin sensitivity despite excess fat mass. In humans with GHD, body composition shows increased body fat and decreased free fat mass, but the results regarding insulin sensitivity are still controversial in these patients. These discrepant results regarding insulin sensitivity in patients with GHD suggest the existence of other variables influencing these results. In the present review, we will try to follow the path of the different researches conducted on this subject, both in animal and human models, with the goal of understanding the current knowledge of insulin sensitivity across the spectrum of GHD. Arch Endocrinol Metab. 2019;63(6):582-91
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Humanos , Animales , Resistencia a la Insulina/fisiología , Transducción de Señal/fisiología , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/fisiología , Glucosa/fisiología , Glucosa/metabolismoRESUMEN
BACKGROUND: Observational studies have suggested an inverse association between low serum 25-hydroxyvitamin D [25(OH)D] concentrations and development of type 2 diabetes. High-quality trials are required to test the hypothesis that vitamin D is a direct contributor to type 2 diabetes pathogenesis. OBJECTIVE: The purpose of this double-blind randomized placebo-controlled trial was to investigate the effect of vitamin D3 supplementation on insulin resistance (IR) and ß-cell function in people with prediabetes and suboptimal vitamin D status (<50 nmol/L). METHODS: Sixty-six individuals were randomly assigned to receive 3000 IU (75 µg) vitamin D3 or placebo daily for 26 wk. Compliance was monitored by pill count and change in serum 25(OH)D concentration using LC-MS. The primary endpoint was between-group difference in change in IR assessed using a 2-step euglycemic-hyperinsulinemic clamp combined with infusion of tritiated glucose. An oral-glucose-tolerance test was performed pre- and postintervention to calculate indices of ß-cell function. Between-group comparisons were made using ANCOVA. RESULTS: In total, 64 participants completed the study. Baseline serum 25(OH)D concentrations in the vitamin D3 and placebo group were 30.7 and 30.0 nmol/L, with status increasing by 70.5 nmol/L and 5.3 nmol/L, respectively (between-group difference in vitamin D: 65.8 nmol/L; 95% CI: 54.2, 77.3 nmol/L; P < 0.01), after supplementation. There was no difference between groups in measures of whole-body, peripheral, or hepatic IR or in any measure of glycemic control or ß-cell function. CONCLUSION: This study employed a robust assessment of IR and ß-cell function and targeted a high-risk population with low 25(OH)D status at baseline and found that vitamin D3 supplementation had no effect on insulin action in people with prediabetes.This trial was registered on clinicaltrials.gov as NCT01889810.
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Colecalciferol/administración & dosificación , Suplementos Dietéticos , Resistencia a la Insulina , Células Secretoras de Insulina/fisiología , Estado Prediabético/fisiopatología , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Objective: The rs8004664 variation within the FOXN3 gene is significantly and independently associated with fasting blood glucose in humans. We have previously shown that the hyperglycemia risk allele (A) increases FOXN3 expression in primary human hepatocytes; over-expression of human FOXN3 in zebrafish liver increases fasting blood glucose; and heterozygous deletion of the zebrafish ortholog foxn3 decreases fasting blood glucose. Paralleling these model organism findings, we found that rs8004664 A|A homozygotes had blunted glucagon suppression during an oral glucose tolerance test. Here, we test associations between insulin sensitivity and the rs8004664 variation. Research design and methods: 92 participants (49±13 years, body mass index: 32±6 kg/m2, 28 with and 64 without type 2 diabetes mellitus) were genotyped at rs8004664. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp technique. Results: The "A" allele frequency was 59%; the protective (G) allele frequency was 41% (A|A: n=29; G|G: n=12; A|G: n=50). Clamp-measured glucose disposal rate (GDR) was not different by genotype (F=0.046, p=0.96) or by "A" allele carrier (p=0.36). Female G|G homozygotes had better insulin sensitivity compared to female "A" allele carriers (GDR; G|G: 9.9±3.0 vs A|A+A|G: 7.1±3.0 mg/kg fat-free mass+17.7/min; p=0.04). Insulin sensitivity was not different by genotype or by "A" allele carriers. Conclusion: The rs8004664 variation within the FOXN3 gene may modulate insulin sensitivity in women.
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Biomarcadores/análisis , Proteínas de Ciclo Celular/genética , Diabetes Mellitus Tipo 2/genética , Factores de Transcripción Forkhead/genética , Homocigoto , Hiperglucemia/genética , Resistencia a la Insulina/genética , Insulina/metabolismo , Índice de Masa Corporal , Estudios de Casos y Controles , Estudios Transversales , Diabetes Mellitus Tipo 2/patología , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Factores SexualesRESUMEN
Decreased insulin sensitivity in patients with hypopituitarism without GH replacement (pHP-WGHR) remains conflicting in literature. It is known that these patients present a decrease in free fat mass and an increase in fat mass. Typically, these kinds of alterations in body composition are associated with a decrease in insulin sensitivity; however, there is no consensus if this association is found in pHP-WGHR. Thus, we investigated pHP-WGHR regarding insulin sensitivity by euglycemic hyperinsulinemic clamp, the gold standard method, and body composition. In a cross-sectional study, we evaluated 15 pHP-WGHR followed up in a Service of Neuroendocrinology and 15 individuals with normal pituitary function as a control group with similar age, gender and body mass index. Insulin sensitivity was evaluated by euglycemic hyperinsulinemic clamp and homeostatic model assessment insulin resistance (HOMA-IR). Kappa coefficient evaluated the agreement between these two methods. Percentage of fat mass, percentage of free fat mass, fat mass weight and free fat mass weight were assessed by electrical bioimpedance. The pHP-WGHR presented similar insulin sensitivity to control group by euglycemic hyperinsulinemic clamp, both by the M-value, (p = 0.0913) and by the area under the glucose infusion rate curve, (p = 0.0628). These patients showed lower levels of fasting glycemia (p = 0.0128), insulin (p = 0.0007), HOMA-IR (p = 0.009). HOMA-IR shows poor concordance with euglycemic hyperinsulinemic clamp (Kappa = 0.16) in pHP-WGHR, while in the control group the agreement was good (Kappa = 0.53). The pHP-WGHR presented higher values of percentage of fat mass (p = 0.0381) and lower values of percentage of free fat mass (p = 0.0464) and free fat mass weight (0.0421) than the control group. This study demonstrated that the insulin sensitivity evaluated by euglycemic hyperinsulinemic clamp in pHP-WGHR was similar to individuals with normal pituitary function, despite the pHP-WGHR presenting higher fat mass percentage. HOMA-IR was not a good method for assessing insulin sensitivity in pHP-WGHR.
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Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5-deficient (C5def, B10.D2-Hc0 H2d H2-T18c/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5def mice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5def mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5def mice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the C5 gene, whole genome sequencing revealed an intronic 31-bp deletion in the Insr gene in the B10.D2-Hc0 H2d H2-T18c/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5cont and C5def mice, indicating an insulin-sensitizing function of C5.
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Complemento C5/deficiencia , Complemento C5/genética , Intolerancia a la Glucosa/genética , Enfermedades por Deficiencia de Complemento Hereditario/patología , Adenoviridae/genética , Animales , Complemento C5/fisiología , Modelos Animales de Enfermedad , Metabolismo Energético/genética , Metabolismo Energético/inmunología , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Enfermedades por Deficiencia de Complemento Hereditario/genética , Resistencia a la Insulina/genética , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Endogámicos NOD , Ratones Transgénicos , Transducción de Señal/genética , Transducción GenéticaRESUMEN
BACKGROUND AND AIM: The metabolic syndrome (MetS) is a pathological condition comprised of abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. It has become a major threat globally, resulting in rapidly increasing rates of diabetes, coronary heart disease, and stroke. The polyphenol resveratrol (RES) is believed to improve glucose homeostasis and insulin resistance by activating sirtuin, which acetylates and coactivates downstream targets and affects glucose and lipid homeostasis in the liver, insulin secretion in the pancreas, and glucose uptake in skeletal muscle. We studied the effects of RES on insulin resistance, glucose homeostasis, and concomitant effects on adipose tissue metabolism and fecal microbiota in insulin-resistant subjects with the MetS. METHODS: A total of 28 obese men with the MetS were studied during a 35-day stay in the Rockefeller University Hospital metabolic unit. Subjects were randomized to receive RES 1 g orally twice daily or placebo while kept weight stable and consuming a western-style diet. At baseline, and after 30 days of RES or placebo administration, subjects underwent testing that included a euglycemic, hyperinsulinemic clamp, 2-h oral glucose tolerance test (GTT), resting energy expenditure, daily blood pressure monitoring, abdominal adipose tissue biopsy, and fecal and blood collections. RESULTS: RES induced no changes in insulin resistance but reduced the 120-min time point and the area under the curve for glucose concentration in the 2-h GTT. In post-hoc analysis, Caucasian subjects showed a significant improvement in insulin sensitivity and glucose homeostasis after GTT, whereas non-Caucasians showed no similar effects. Levels of fasting plasma RES and its primary metabolite dihydroresveratrol were variable and did not explain the racial differences in glucose homeostasis. RES administration to Caucasian subjects leads to an increase in several taxa including Akkermansia muciniphila. CONCLUSIONS: RES 2 g administered orally to obese men with MetS and insulin resistance marginally altered glucose homeostasis. However, in a small group of Caucasians, insulin resistance and glucose homeostasis improved. No concomitant changes in adipose tissue metabolism occurred, but fecal microbiota showed RES-induced changes. RELEVANCE FOR PATIENTS: The MetS increases the risk of diabetes, heart disease, and stroke. A major component of the syndrome is insulin resistance, resulting in systemic inflammation and hyperinsulinemia. The primary treatment consists of lifestyle changes, improved diet, and increased physical activity. This is often unsuccessful. In this study, RES was well tolerated. In Caucasian men, it significantly improved insulin sensitivity and glucose homeostasis. Similar results were found in studies that consisted exclusively of Caucasian men. However, RES presents a novel addition to the current treatment of the MetS and its sequelae.
RESUMEN
OBJECTIVE: To evaluate the correlation between subrogate index for the evaluation of insulin resistance with the M value obtained with the euglycemic-hyperinsulinemic clamp as well as their sensitivity, specificity, and positive and negative predictive values. METHOD: The euglycemic-hyperinsulinemic clamp was performed in subjects having both normal fasting glucose and glycated hemoglobin concentrations. HOMA-IR, QUICKI, HOMA2%S, TyG, TyG*body mass index (BMI) and triglyceride/HDL indexes were calculated. Correlations coefficients were estimated between indexes results and the M-value adjusted by fat-free mass. Areas under the ROC curve were constructed to evaluate overall performance, sensitivity, specificity and predictive values of the subrogate indexes. RESULTS: 57 subjects, 68.4% women, with a mean age of 32.9 ± 11 years-old were included. The subrogate index with the best correlation with the M value was HOMA2%S (r = 0.428), HOMA-IR had the greatest area under the ROC curve (0.683; 95 % confidence interval: 0.503-0.864) and TyG*BMI the best sensitivity (98.2 %) and specificity (51.1 %). CONCLUSIONS: The surrogated indexes for the evaluation of insulin resistance show a significant correlation with the M value obtained with the gold standard. Additional studies are required to determine cut-off values in Mexican population.
OBJETIVO: Evaluar la correlación entre índices subrogados de resistencia a la insulina y el valor M obtenido mediante pinza euglucémica-hiperinsulinémica, así como su sensibilidad, especificidad y valores predictivos positivo y negativo, en mexicanos sin diabetes. MÉTODO: Se realizó una pinza euglucémica-hiperinsulinémica en individuos con glucosa en ayuno y hemoglobina glucosilada normales. Se estimaron los índices HOMA-IR, QUICKI, HOMA2%S, TyG, TyG*índice de masa corporal (IMC) y triglicéridos/colesterol ligado a lipoproteínas de alta densidad. Se estimaron coeficientes de correlación de Pearson entre los resultados y el valor M ajustado por masa libre de grasa. Se construyeron curvas ROC para evaluar su desempeño y se estimaron la sensibilidad, la especificidad y los valores predictivos de los índices. RESULTADOS: Se incluyeron 57 individuos, el 68.4 % mujeres, de 32.9 ± 11 años, con IMC de 26.5 ± 3.9 kg/m2. El índice subrogado con mejor correlación con el valor M fue HOMA2%S (r = 0.428), con la mayor área bajo la curva ROC (0.683; intervalo de confianza del 95 %: 0.503-0.864) HOMA-IR, y con mejor sensibilidad (92.8 %) y especificidad (51.1 %) TyG*IMC. CONCLUSIONES: Los índices subrogados para estimar la resistencia a la insulina muestran una correlación significativa con el valor M obtenido con el método de referencia. Se requieren más estudios para determinar puntos de corte en población mexicana.
Asunto(s)
Glucemia/metabolismo , Índice de Masa Corporal , Hemoglobina Glucada/metabolismo , Resistencia a la Insulina/fisiología , Adulto , Anciano , Estudios Transversales , Ayuno , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Lipoproteínas HDL/metabolismo , Masculino , México , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Sensibilidad y Especificidad , Triglicéridos/metabolismo , Adulto JovenRESUMEN
PURPOSE: The diagnosis of polycystic ovary syndrome (PCOS) is based on a combination of various clinical phenotypes in each patient. However, insulin resistance (IR) and dysmetabolism are not included in the diagnostic criteria of PCOS. Therefore, the definition of PCOS is controversial. The objective of this study is to investigate whether some PCOS phenotypes can be predicted by a circulating biomarker related to IR and metabolic dysfunction in PCOS women. METHODS: One hundred and seventeen women with PCOS and 95 healthy women were recruited for this study. All individuals were assessed by the phenotypic and metabolic characteristics related to PCOS. A euglycemic-hyperinsulinemic clamp was performed to assess insulin sensitivity. Circulating irisin concentrations were determined with ELISA. RESULTS: In our PCOS cohort, 65.8% of individuals were found to have hyperandrogenism. 83.8% had chronic oligoanovulation, and 80.3% of subjects showed polycystic ovaries. According to the diagnostic criteria of PCOS, 30.8% of PCOS subjects were diagnosed with the classic phenotype. In addition, 65.8% of PCOS women had insulin resistance. Serum irisin levels were significantly higher in PCOS women compared with healthy women. However, PCOS women with a normoandrogenic phenotype had similar circulating irisin levels as healthy women. PCOS women with the normoandrogenic phenotype had a low homeostasis model assessment of insulin resistance (HOMA-IR) and higher M-values than PCOS women with other phenotypes. Circulating irisin levels were associated with hyperandrogenism, but not with oligoanovulation or PCO morphology. CONCLUSIONS: Circulating irisin may allow physicians to establish which women merit screening by a biomarker for PCOS.