Effects of a single bout of aerobic exercise on short-term low-carbohydrate/high-fat intake-induced postprandial glucose metabolism during an oral glucose tolerance test

Objective

A single bout of exercise can improve acute postprandial glucose metabolism aggravated by short-term low-carbohydrate/high-fat diet (HFD). The purpose of this study was to investigate the effect of a single bout of aerobic exercise on short-term HFD-induced postprandial glucose and incretin metabolism during an oral glucose tolerance test (OGTT).

Materials/Methods

Eleven healthy young men (age [mean ± SE] 27 ± 1 years; body mass index, 22 ± 1 kg/m²) performed three, 3-day interventions in randomized order: (1) a normal diet (ND: ~ 22% fat), (2) an HFD (~ 69% fat) and (3) an HFD with a single bout of aerobic exercise (HFDEx). The exercise (50% peak oxygen consumption; ~ 200 kcal) was performed on the third day in HFDEx. An OGTT was performed after each 3-day dietary intervention.

Results

The incremental area under the curve (iAUC) of plasma glucose levels during the OGTT was significantly higher in the HFD and HFDEx trials than in the ND trial (P = 0.001). In addition, the iAUC of glucagon-like peptide-1 (GLP-1) level was significantly higher in the HFD trial than in the ND and HFDEx trials (P = 0.04). The first-phase insulin secretion indexes were significantly lower in the HFD (P = 0.01 and 0.002) and HFDEx trials (P = 0.05 and 0.008) than in the ND trial.

Conclusion

A single bout of aerobic exercise did not improve the short-term HFD-induced aggravation of postprandial glucose and insulin metabolism during the OGTT. However, it did normalize the increased postprandial GLP-1 level induced by HFD.     

Artemisia scoparia extract attenuates non-alcoholic fatty liver disease in diet-induced obesity mice by enhancing hepatic insulin and AMPK signaling independently of FGF21 pathway

Objective

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease which has no standard treatment. In this regard, we sought to evaluate the effects of extracts of Artemisia santolinaefolia (SANT) and Artemisia scoparia (SCO) on hepatic lipid deposition and cellular signaling in a diet-induced obesity (DIO) animal model.

Materials/Methods

DIO C57/B6J mice were randomly divided into three groups, i.e. HFD, SANT and SCO. Both extracts were incorporated into HFD at a concentration of 0.5% (w/w). Fasting plasma glucose, insulin, adiponectin, and FGF21 concentrations were measured.

Results

At the end of the 4-week intervention, liver tissues were collected for analysis of insulin, AMPK, and FGF21 signaling. SANT and SCO supplementation significantly increased plasma adiponectin levels when compared with the HFD mice (P < 0.001). Fasting insulin levels were significantly lower in the SCO than HFD mice, but not in SANT group. Hepatic H&E staining showed fewer lipid droplets in the SCO group than in the other two groups. Cellular signaling data demonstrated that SCO significantly increased liver IRS-2 content, phosphorylation of IRS-1, IR β, Akt1 and Akt2, AMPK α1 and AMPK activity and significantly reduced PTP 1B abundance when compared with the HFD group. SCO also significantly decreased fatty acid synthase (FAS), HMG-CoA Reductase (HMGR), and Sterol regulatory element-binding protein 1c (SREBP1c), but not Carnitine palmitoyltransferase I (CPT-1) when compared with HFD group. Neither SANT nor SCO significantly altered plasma FGF21 concentrations and liver FGF21 signaling.

Conclusion

This study suggests that SCO may attenuate liver lipid accumulation in DIO mice. Contributing mechanisms were postulated to include promotion of adiponectin expression, inhibition of hepatic lipogenesis, and/or enhanced insulin and AMPK signaling independent of FGF21 pathway.     

Berberine improves insulin resistance in cardiomyocytes via activation of 5′-adenosine monophosphate-activated protein kinase

Objective

Insulin resistance plays an important role in the pathogenesis of diabetic cardiomyopathy. Berberine (BBR) is a plant alkaloid which promotes hypoglycemia via increasing insulin sensitivity in peripheral tissues. Little is known of BBR’s role in regulating glucose metabolism in heart.

Materials/methods

We examined the effect and mechanism of BBR on glucose consumption and glucose uptake in insulin sensitive or insulin resistant rat H9c2 cardiomyocyte cells. H9c2 myoblast cells were differentiated into cardiomyocytes and incubated with insulin for 24 h to induce insulin resistance.

Results

BBR-treatment of H9c2 cells increased glucose consumption and glucose uptake compared to controls. In addition, BBR-treatment attenuated the reduction in glucose consumption and glucose uptake in insulin resistant H9c2 cells. Compound C, an inhibitor of AMP-activated protein kinase (AMPK), abolished the enhancement of glucose consumption and glucose uptake mediated by BBR in both insulin sensitive and insulin resistant H9c2 cells compared to controls.

Conclusion

BBR significantly increased AMPK activity, but had little effect on the activity of protein kinase B (AKT) in insulin resistant H9c2 cells, suggesting that berberine improves insulin resistance in H9c2 cardiomyocytes at least in part via stimulation of AMPK activity.     

Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice

Objective

We recently discovered that leucine deprivation increases hepatic insulin sensitivity via general control nondepressible (GCN) 2/mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways. The goal of the present study was to investigate whether the above effects were leucine specific or were also induced by deficiency of other branched chain amino acids including valine and isoleucine.

Methods

Following depletion of BCAAs, changes in metabolic parameters and the expression of genes and proteins involved in regulation of insulin sensitivity and glucose metabolism were analyzed in mice and cell lines including human HepG2 cells, primary mouse hepatocytes and a mouse myoblast cell line C2C12.

Results

Valine or isoleucine deprivation for 7 days has similar effect on improving insulin sensitivity as leucine, in wild type and insulin-resistant mice models. These effects are possibly mediated by decreased mTOR/S6K1 and increased AMPK signaling pathways, in a GCN2-dependent manner. Similar observations were obtained in in vitro studies. In contrast to leucine withdrawal, valine or isoleucine deprivation for 7 days significantly decreased fed blood glucose levels, possibly due to reduced expression of a key gluconeogenesis gene, glucose-6-phosphatase. Finally, insulin sensitivity was rapidly improved in mice 1 day following maintenance on a diet deficient for any individual BCAAs.

Conclusions

Our results show that while improvement on insulin sensitivity is a general feature of BCAAs depletion, individual BCAAs have specific effects on metabolic pathways, including those that regulate glucose level. These observations provide a conceptual framework for delineating the molecular mechanisms that underlie amino acid regulation of insulin sensitivity.     

The one year exercise and lifestyle intervention program KLAKS: Effects on anthropometric parameters,cardiometabolic risk factors and glycemic control in childhood obesity

Objective

Regular physical exercise within structured lifestyle programs may improve weight status and minimize metabolic risk factors in childhood obesity. The aim of this study was to evaluate the effect of the one-year combined physical exercise/lifestyle program KLAKS on anthropometric and metabolic parameters and glycemic control in childhood obesity.

Materials and Methods

142 overweight/obese (BMI > 90th percentile) candidates (7–18 years) were enrolled, 115 participants completed the program. Anthropometrics and biochemical parameters were obtained at beginning and completion. An oral glucose tolerance test (OGTT) was performed in a subgroup of participants. Course of glucose and insulin levels within OGTT was correlated with several parameters and is reported here for those who completed the program.

Results

The mean standard deviation scores (SDS) decreased significantly for BMI, waist circumference, waist-to-height ratio (WHtR) and percentage body fat (all p ≤ 0.01). Improved metabolic risk markers included mean glucose levels within an OGTT at follow-up compared to baseline (p < 0.0001) and HbA1c (p = 0.05) as well as indications of improvement for gamma-glutamyl-transferase and free fatty acids.

Conclusions

The one-year combined exercise/lifestyle program KLAKS significantly improves markers of obesity and glycemic control. Impaired cardiometabolic risk markers, even subclinical, are also favorably influenced by program participation.     

Prevalence and predictors of postpartum glucose intolerance in Italian women with gestational diabetes mellitus

Aims

To determine the prevalence of both prediabetes and type 2 diabetes mellitus (T2DM) by postpartum oral glucose tolerance test (ppOGTT) in Italian women diagnosed with gestational diabetes mellitus (GDM), and identify antepartum predictors of glucose intolerance.

Methods

Retrospective study of 454 Caucasian women that underwent a 75 g OGTT between 6 and 12 weeks postpartum in Calabria (Southern Italy) between 2004 and 2012. Prediabetes and T2DM were diagnosed according to the American Diabetes Association (ADA) criteria. Data were examined by univariate analysis and multiple regression analysis.

Results

290 women (63.9%) were normal, 146 (32.1%) had prediabetes (85 impaired fasting glycemia; 61 impaired glucose tolerance), and 18 (4.0%) had T2DM. Of the continuous variables, pre-pregnancy body mass index (BMI), age at pregnancy, fasting plasma glucose (FPG) at gravid OGTT, and week at diagnosis of GDM were associated with prediabetes and T2DM, whereas the parity was associated with T2DM only. For categorical traits, pre-pregnancy BMI ≥25 and previous diagnosis of polycystic ovary syndrome (PCOS) emerged as the strongest predictors of prediabetes whereas the strongest predictors of T2DM were FPG ≥100 mg/dl (5.6 mmol/l) at GDM diagnosis and pre-pregnancy BMI ≥25. Moreover, FPG at GDM screening was a good predictor of T2DM after receiver-operating-characteristic analysis.

Conclusions

Our findings confirm the high prevalence of glucose intolerance in the early postpartum period in women with previous GDM. PCOS emerges as a new strong antepartum predictor of prediabetes.     

Liraglutide enhances glucose transporter 4 translocation via regulation of AMP-activated protein kinase signaling pathways in mouse skeletal muscle cells

Objective

Liraglutide is an anti-diabetic drug and human glucagon-like peptide-1 (GLP-1) analog that primarily functions in the pancreas. However, its extra-pancreatic functions are not clear. Skeletal muscle tissue is an important determinant of blood glucose and cells take in approximately 80% of dietary glucose via glucose transporter 4 (GLUT4) on the plasma membrane. Insulin and muscle contraction are two physiological stimuli of GLUT4 translocation to the cell membrane from intracellular storage compartments, but the signaling mechanisms that mediate these processes are different. AMP-activated protein kinase (AMPK) and Akt are the key signal molecules mediating the effects of muscle contraction and insulin, respectively, on GLUT4 translocation. Here, we investigate the effect of liraglutide on GLUT4 translocation and the roles of AMPK and Akt in this mechanism in skeletal muscle cells by stably expressing GLUT4myc with an exofacial myc-epitope C₂C₁₂-GLUT4myc.

Materials/Methods

The cell surface GLUT4myc levels were determined by an antibody-coupled colorimetric assay. The phosphorylation levels of AMPK, Akt, AS160, TBC1D1, and GLUT4 were determined by western blotting. The cAMP levels were measured by an ELISA kit. siRNA was transfected with Lipofectamine 2000. Analysis of variance (ANOVA) was used for data analysis.

Results

Liraglutide stimulated GLUT4 translocation in C₂C₁₂-GLUT4myc myotubes. Liraglutide increased the intracellular cAMP levels and the phosphorylation of AMPK, AS160, and TBC1D1. Akt phosphorylation and GLUT4 expression were not affected. Inhibition of AMPK by siRNA or Compound C reduced liraglutide-induced GLUT4 translocation.

Conclusion

Our results suggest that liraglutide may induce GLUT4 translocation by activation of AMPK in muscle cells.     

Thyroid hormone improves the mechanical performance of the post-infarcted diabetic myocardium: A response associated with up-regulation of Akt/mTOR and AMPK activation

Objective

Thyroid hormone (TH) is shown to be protective against cardiac and pancreatic injury. Thus, this study explored the potential effects of TH treatment on the functional status of the postinfarcted diabetic myocardium. Diabetic patients have worse prognosis after acute myocardial infarction (AMI).

Materials/Methods

AMI was induced by left coronary ligation in rats previously treated with 35 mg/kg streptozotocin (STZ), (DM-AMI). TH treatment was initiated at 2 weeks after AMI and continued for 6 weeks (DM-AMI + TH), while sham-operated animals served as control (DM-SHAM).

Results

TH treatment increased cardiac mass, improved wall stress and favorably changed cardiac geometry. TH significantly increased echocardiographic left ventricular ejection fraction (LVEF%): [54.2 (6.5) for DM-AMI + TH vs 37 (2.0) for DM-AMI, p < 0.05]. TH treatment resulted in significantly increased insulin and decreased glucose levels in serum. The ratios of phosphorylated (p)-Akt/total Akt and p-mTOR/total mTOR were increased 2.0 fold and 2.7 fold in DM-AMI + TH vs DM-AMI respectively, p < 0.05. Furthermore, the ratio of p-AMPK/total AMPK was found to be increased 1.6 fold in DM-AMI + TH vs DM-AMI, p < 0.05.

Conclusion

TH treatment improved the mechanical performance of the post-infarcted myocardium in rats with STZ-induced diabetes, an effect which was associated with Akt/mTOR and AMPK activation.     

The utility of urinary myo-inositol as a marker of glucose intolerance

Objective

The most common screening tests for glucose intolerance are fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Because it reflects the current status of hyperglycemia, urinary myo-inositol (UMI) may be useful. We evaluated UMI as a screening tool for glucose intolerance.

Design and methods

A cross-sectional, community-based population study of 1057 Japanese residents. 173 with an FPG level between 5.5 and 6.9 mmol/L and an HbA1c under 6.5% had an oral glucose tolerance test. We measured UMI level before (fasting UMI) and 2 h after (2 h-UMI) glucose ingestion. Δ-UMI was defined as the difference between fasting UMI and 2 h-UMI.

Results

Δ-UMI, 2 h-UMI and HbA1c levels significantly increased as glucose intolerance worsened. Δ-UMI level was significantly positively correlated with 2 h-UMI level (r = 0.896, p < 0.001). Using cutoff levels from receiver operating characteristic (ROC) analyses, the sensitivity of Δ-UMI (82.1%) and 2 h-UMI (79.3%) were higher than that of HbA1c (48.3%). The area under the ROC curve values for Δ-UMI (0.903) and 2 h-UMI (0.891) were higher than that for HbA1c (0.785).

Conclusions

2 h-UMI is useful as a non-invasive screening of glucose intolerance.     

Higher insulin and glucagon-like peptide-1 (GLP-1) levels in healthy,young South Asians as compared to Caucasians during an oral glucose tolerance test

Objective

Higher insulin levels during an oral glucose test (OGTT) have been shown in South Asians. We aimed to investigate if this increased insulin response causes reactive hypoglycemia later on, and if an increased glucagon-like-peptide-1 (GLP-1) response, which could contribute to the hyperinsulinemia, is present in this ethnic group.

Methods

A prolonged, 6-h, 75-g OGTT was performed in healthy, young Caucasian (n = 10) and South Asian (n = 8) men. The glucose, insulin and GLP-1 response was measured and indices of insulin sensitivity and beta-cell activity were calculated.

Results

Age (Caucasians (CAU) 21.5 ± 0.7 years vs South Asians (SA) 21.4 ± 0.7 years (mean ± SEM)) and body mass index (CAU 22.7 ± 0.7 kg/m² vs SA 22.1 ± 0.8 kg/m²) were comparable between the two groups. South Asian men were more insulin resistant, as indicated by a comparable glucose but significantly higher insulin response, and a significantly lower Matsuda index (CAU 8.7(8.6) vs SA 3.2(19.2), median(IQR)). South Asians showed a higher GLP-1 response, as reflected by a higher area under the curve for GLP-1 (CAU 851 ± 99.8 mmol/l vs SA 1235 ± 155.0 mmol/L). During the whole 6-h period, no reactive hypoglycemia was observed.

Conclusion

Healthy, young South Asian men have higher insulin levels during an OGTT as compared to Caucasians. This does not, however, lead to reactive hypoglycemia. The hyperinsulinemia is accompanied by increased levels of GLP-1. Whether this is an adaptive response to facilitate hyperinsulinemia to overcome insulin resistance or reflects a GLP-1 resistant state has yet to be elucidated.     

Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines

Aims/Hypothesis

Irisin is a novel, myocyte secreted, hormone that has been proposed to mediate the beneficial effects of exercise on metabolism. Irisin is expressed, at lower levels, in human brains and knock-down of the precursor of irisin, FNDC5, decreases neural differentiation of mouse embryonic stem cells. No previous studies have evaluated whether irisin may directly regulate hippocampal neurogenesis in mouse hippocampal neuronal (HN) cells.

Methods

Hippocampal neurogenesis and irisin signaling were studied in vitro using mouse H19-7 HN cell lines.

Results

We observed that cell proliferation is regulated by irisin in a dose-dependent manner in mouse H19-7 HN cells. Specifically, physiological concentrations of irisin, 5 to 10 nmol/L, had no effect on cell proliferation when compared to control. By contrast, pharmacological concentrations of irisin, 50 to 100 nmol/L, increased cell proliferation when compared to control. Similar to these results regarding irisin's effects on cell proliferation, we also observed that only pharmacological concentrations of irisin increased STAT3, but not AMPK and/or ERK, activation. Finally, we observed that irisin did not activate either microtubule-associated protein 2, a specific neurite outgrowth marker, or Synapsin, a specific synaptogenesis marker in mouse H19-7 HN cells.

Conclusions/Interpretations

Our data suggest that irisin, in pharmacological concentrations, increases cell proliferation in mouse H19-7 HN cells via STAT3, but not AMPK and/or ERK, signaling pathways. By contrast, neither physiological nor pharmacological concentrations of irisin alter markers of hippocampal neurogenesis in mouse H19-7 HN cell lines.     

Adiponectin stimulates Rho-mediated actin cytoskeleton remodeling and glucose uptake via APPL1 in primary cardiomyocytes

Objective

Adiponectin is known to confer its cardioprotective effects in obesity and type 2 diabetes, mainly by regulating glucose and fatty acid metabolism in cardiomyocytes. Dynamic actin cytoskeleton remodeling is involved in regulation of multiple biological functions, including glucose uptake. Here we investigated in neonatal cardiomyocytes whether adiponectin induced actin cytoskeleton remodeling and if this played a role in adiponectin-stimulated glucose uptake.

Materials/methods

Primary cardiomyocytes were treated with full-length and globular adiponectin (fAd and gAd, respectively).

Results

Both fAd and gAd increased RhoA activity, phosphorylation of the Rho/ROCK signaling target cofilin and actin polymerization to form filamentous actin as determined by rhodamine–phallodin immunofluorescence and quantitative analysis of filamentous to globular actin ratio. Scanning electron microscopy also demonstrated structural remodeling. Adiponectin stimulated glucose uptake, was significantly abrogated in the presence of inhibitors of actin cytoskeleton remodeling (cytochalasin D) and Rho/ROCK signaling (C3 transferase, Y27632). We showed that adiponectin increased colocalization of actin and APPL1 and that actin remodeling, phosphorylation of AMPK, p38MAPK and cofilin, glucose uptake and oxidation were all attenuated after siRNA-mediated knockdown of APPL1.

Conclusion

We show that adiponectin mediates Rho/ROCK-dependent actin cytoskeleton remodeling to increase glucose uptake and metabolism via APPL1 signaling.     

Association of GLP-1 secretion with anti-hyperlipidemic effect of ginsenosides in high-fat diet fed rats

Objective

Ginsenosides, major bioactive constituents in Panax ginseng, have been shown to exert anti-hyperlipidemia effects. However, the underlying mechanism was not well-elucidated due to the low bioavailability of ginsenosides. Glucagon-like peptide-1 (GLP-1) was considered to be a critical regulator of energy homeostasis. Our previous studies have showed that ginseng total saponins (GTS) exhibited antidiabetic effects partly via modulating GLP-1 release. The aim of this study was to investigate the potential role of GLP-1 in anti-hyperlipidemia effect of GTS in rats fed with high-fat diet.

Material and methods

Male Sprague–Dawley rats were fed with normal diet (CON) or high-fat diet (HFD) for 4 weeks. Then, the HFD rats orally received vehicle (HFD), 150 mg/kg/day (HFD-GL) and 300 mg/kg/day of GTS (HFD-GH) for another 4 weeks, respectively.

Results

Four-week GTS treatment significantly ameliorated hyperlipidemia, decreased body fat, liver weight and improved insulin resistance. It was found that high-dose GTS treatment increased portal GLP-1 level induced by glucose loading, accompanied by increased intestinal GLP-1 content, L-cell number and prohormone convertase 3 mRNA expression. Data from NCI-H716 cells showed that both GTS and ginsenoside Rb1 significantly increased GLP-1 secretion as well as proglucagon mRNA level in NCI-H716 cells supplemented with 10% HFD-rat serum.

Conclusions

Hyperlipidemia and insulin resistance were attenuated effectively in response to GTS treatment. These improvements may be associated with the increased secretion of GLP-1.     

The 5-time point oral glucose tolerance test as a predictor of new-onset diabetes after kidney transplantation

Aims

To evaluate the predictive power of the 5-time point oral glucose tolerance test (OGTT) for new-onset diabetes after kidney transplantation (NODAT).

Methods

We performed a retrospective study of 145 patients without diabetes who received kidney transplantations at our hospital. The 5-time point OGTT was performed before transplantation. The area under a receiver-operating characteristic curve (aROC) was used for evaluating the predictive power of 5-time point OGTT values.

Results

Seventeen patients developed NODAT within 1 year after transplantation. All postload plasma glucose (PPG) levels were higher in patients who developed NODAT than in those who did not; fasting plasma glucose levels were not different. The aROC for the area under the glucose concentration-time curve was significantly greater than that for fasting plasma glucose. Univariate and multivariate analyses showed that each PPG level was an independent risk factor for NODAT. Furthermore, patients with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) could be stratified with a 1-h plasma glucose (1h-PG) cut-off point of 8.4 mmol/L. The incidences of NODAT were 23.5%, 16.7%, 9.1%, and 0% for patients with IGT + 1h-PG ≥8.4 mmol/L,IGT + 1h-PG <8.4 mmol/L, NGT + 1h-PG ≥ 8.4 mmol/L, and NGT + 1h-PG < 8.4 mmol/L, respectively.

Conclusions

The area under the glucose concentration-time curve and each PPG concentration during the 5-time point OGTT are strong predictors of NODAT. A 1h-PG cut-off point of 8.4 mmol/L plus NGT/IGT can be used to identify patients at intermediate and high risk of developing NODAT.     

Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: Role of Nrf2 activation

Background

Oxidative stress-induced vascular endothelial cell injury is a major factor in the pathogenesis of atherosclerosis. Several evidences indicate that ellagic acid (EA), a phenolic compound, contributes to cardiovascular health. This study was to investigate the effects of EA on endothelial dysfunction and atherosclerosis via antioxidant-related mechanisms.

Methods

In animal studies, wild-type (WT) C57BL/6 mice and apolipoprotein E-deficient mice (ApoE^−/−) mice were fed: a high-fat (21%) diet (HFD) or a HFD plus with EA (HFD + EA), for 14 weeks. Vascular reactivity was studied in mice aortas. The effect of EA in human umbilical vein endothelial cells (HAECs) exposed to hypochlorous acid (HOCl) was also investigated.

Results

Compared with animals on HFD alone, EA attenuated atherosclerosis in WT mice. In aortic rings from two mice models, EA significantly improved endothelium-dependent relaxation and attenuated HOCl-induced endothelial dysfunction. Besides, EA significantly improved nitric oxide synthase activity, antioxidant capacity and markers of endothelial dysfunction in plasma. Western blot analysis showed that EA increased NF-E2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) expression in the aortas (P < 0.05). In a separate experiment, EA did not protect against HOCl-induced endothelial dysfunction in arteries obtained from Nrf2 gene knockout mice compared with WT mice. In HAECs, EA prevented HOCl-induced cellular damage and induced HO-1 protein expression, and these effects markedly abolished by the siRNA of Nrf2.

Conclusions

Our results provide further support for the protective effects of dietary EA particularly oxidant-induced endothelial dysfunction and atherosclerosis partly via Nrf2 activation.     

New players in high fat diet-induced obesity: LETM1 and CTMP

Objective

Obesity contributes to insulin resistance and is a risk factor for diabetes. C-terminal modulator protein (CTMP) and leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) have been reported to influence the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) signaling pathway via the modulation of PKB activity, a key player for insulin signaling. However, it remains unclear whether CTMP and LETM1 are associated with PI3K/PKB signaling in mouse models of obesity.

Materials/Methods

To address this question, we used two different mouse models of obesity, including high-fat diet (HFD)-induced diabetic mice and genetically modified obese mice (ob/ob mice). The levels of insulin-signaling molecules in these mice were determined by immunohistochemical and Western blot analyses. The involvement of CTMP and LETM1 in PI3K/PKB signaling was investigated in HEK293 cells by transient transfection and adenovirus-mediated infection.

Results

We found that the levels of insulin receptor, phosphorylated PKB, and LETM1 were lower and the level of CTMP was higher in the adipose tissue of obese mice on an HFD compared to lean mice on a chow diet. Similar results were obtained in ob/ob mice. In HEK293 cells, the activation of PKB increased the LETM1 level, and inhibition of PKB increased the CTMP level. The overexpression of CTMP suppressed the insulin-induced increase in PKB phosphorylation, which was abrogated by co-overexpression with LETM1.

Conclusion

These results suggest that CTMP and LETM1 may participate in impaired insulin signaling in the adipose tissue of obese mice, raising the possibility that these parameters may serve as new candidate biomarkers or targets in the development of new therapeutic approaches for diabetes.     

Relationship between whole-body macronutrient oxidative partitioning and pancreatic insulin secretion/β-cell function in non-diabetic humans

Background

Glucose-stimulated insulin secretion correlates inversely with the degree of whole-body insulin sensitivity suggesting a crosstalk between peripheral organs and pancreas. Such sensing mechanism could be mediated by changes in glucose flux (uptake, oxidation or storage) in peripheral tissues that may drive insulin secretion.

Aim

To relate whole-body non-protein respiratory quotient (npRQ), an index of macronutrient oxidative partitioning, with insulin secretion and β-cell function in non-diabetic individuals.

Methods

Macronutrient oxidation was measured after an overnight fast and for 4 h after a 75-g oral glucose tolerance test (OGTT) in 30 participants (15/15 males/females; 35 ± 12 y; 27 ± 4 kg/m²). Furthermore, npRQ was assessed for 24 h in a metabolic chamber. Insulin secretion was estimated by deconvolution of serum C-peptide concentration (fasting and 4-h OGTT) and from 24-h urinary C-peptide excretion corrected for energy intake (metabolic chamber). β-Cell function parameters were obtained by mathematical modeling, while insulin sensitivity was determined by a euglycemic–hyperinsulinemic clamp (120 mU · m^− 2 · min^− 1).

Results

Insulin secretion (from 24-h urinary C-peptide) correlated inversely with 24-h npRQ (r = − 0.61; p = 0.001), even after controlling for insulin sensitivity, energy balance, age and body mass index (r = − 0.52; p = 0.01). In turn, insulin secretion (from serum C-peptide) was not associated with fasting or OGTT npRQ. However, fasting npRQ was positively correlated with rate sensitivity (r = 0.40; p < 0.05) and marginally with glucose sensitivity (r = 0.34; p = 0.08).

Conclusion

Macronutrient oxidative partitioning, specifically glucose oxidation, might play a role on the regulation of insulin secretion. Further studies should aim at identifying the signals linking these processes.     

Negative regulation of glucose metabolism in human myotubes by supraphysiological doses of 17β-estradiol or testosterone

Objective

Exposure of skeletal muscle to high levels of testosterone or estrogen induces insulin resistance, but evidence regarding the direct role of either sex hormone on metabolism is limited. Therefore, the aim of this study was to investigate the direct effect of acute sex hormone exposure on glucose metabolism in skeletal muscle.

Materials/Methods

Differentiated human skeletal myotubes were exposed to either 17β-estradiol or testosterone and metabolic characteristics were assessed. Glucose incorporation into glycogen, glucose oxidation, palmitate oxidation, and phosphorylation of key signaling proteins were determined.

Results

Treatment of myotubes with either 17β-estradiol or testosterone decreased glucose incorporation into glycogen. Exposure of myotubes to 17β-estradiol reduced glucose oxidation under basal and insulin-stimulated conditions. However, testosterone treatment enhanced basal palmitate oxidation and prevented insulin action on glucose and palmitate oxidation. Acute stimulation of myotubes with testosterone reduced phosphorylation of S6K1 and p38 MAPK. Exposure of myotubes to either 17β-estradiol or testosterone augmented phosphorylation GSK3β^Ser9 and PKCδ^Thr505, two negative regulators of glycogen synthesis. Treatment of myotubes with a PKC specific inhibitor (GFX) restored the effect of either sex hormone on glycogen synthesis. PKCδ silencing restored glucose incorporation into glycogen to baseline in response to 17β-estradiol, but not testosterone treatment.

Conclusion

An acute exposure to supraphysiological doses of either 17β-estradiol or testosterone regulates glucose metabolism, possibly via PKC signaling pathways. Furthermore, testosterone treatment elicits additional alterations in serine/threonine kinase signaling, including the ribosomal protein S6K1 and p38 MAPK.     

Fasting plasma glucose to avoid a full OGTT in the diagnosis of gestational diabetes

Aims

To evaluate the performance of fasting plasma glucose (FPG) in determining the need for a full oral glucose tolerance test (OGTT) to diagnose gestational diabetes (GDM) by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria.

Methods

A multicenter cohort study of 4926 pregnant women 20 years or older consecutively enrolled in prenatal care clinics of the Brazilian National Health Service from 1991 to 1995. All women underwent a single 2 h 75 g OGTT by weeks 24–28 of pregnancy and were followed to detect adverse pregnancy outcomes.

Results

A FPG cut-off value of 80 mg/dl indicated that only 38.7% of all women needed to undergo a complete OGTT, while detecting 96.9% of all GDM cases. When the 85 mg/dl cut-off was used, the corresponding percentages were 18.7% and 92.5%, respectively. The fraction of women labeled with GDM who had adverse pregnancy outcomes was nearly identical when using FPG strategies and universal full testing.

Conclusions

Using a FPG cut-off to diagnose GDM and to determine the need for post-load OGTT measurements is a valid strategy to diagnose GDM by IADPSG criteria. This approach may improve feasibility of applying IADPSG diagnostic criteria by reducing costs and increasing convenience.     

Evaluation of performance of A1c and FPG tests for screening newly diagnosed diabetes defined by an OGTT among tuberculosis patients—A study from India

Aim

The methods used for diagnosis of diabetes have limitations particularly in situations associated with stress hyperglycemia. Aim of this study was to evaluate the performance of A₁c and fasting plasma glucose (FPG) tests for screening newly diagnosed diabetes (NDD) defined by OGTT among tuberculosis (TB) cases in India.

Methods

A total of 983 subjects aged ≥18 years with TB were selected from 7 TB units – 4 urban, 2 rural and 1 semi-urban areas of Tamil Nadu, India, during August 2010–March 2011. Screening for diabetes was carried out by 2-h 75 g OGTT. Classification of glucose intolerance status was based on WHO criteria. HbA₁c was measured by high performance liquid chromatography using Bio-Rad turbo machine. HbA₁c ≥ 47.5 mmol/mol was used for diagnosis of diabetes. FPG was estimated by glucose-oxidase method. Known cases of subjects with diabetes were excluded and final analysis was done using data of 779 individuals. The performance of A₁c and FPG tests was evaluated against the results of OGTT using receiver operating characteristic curve analysis.

Results

Prevalence of NDD was 10.8%. The areas under the curve (AUC) were 0.754 [95% confidence interval (CI) 0.68–0.83] (p < 0.001) for A₁c and 0.662 (95% CI 0.58–0.74) for FPG (p < 0.001) in NDD subjects. The HbA₁c cut-off point of ≥47.5 mmol/mol gave a sensitivity of 59.1% and specificity of 91.7%, and the respective values were 34.8% and 97.5% for FPG in subjects with NDD.

Conclusion

HbA₁c performed better than FPG as a screening tool for newly diagnosed diabetes among subjects with TB.