Blood Glucose Tolerance Research Articles

Defects of WFS1-mediated peptide hormones secretion contribute to the manifestations of Wolfram syndrome

AimsThe study aims to investigate whether WFS1 is involved in the regulation of the exportation and secretion of other peptide hormones, as well as to elucidate the precise molecular mechanisms underlying WS caused by pathogenic mutations in the WFS1 gene. Materials and methodsThe plasma proteome from the WS patients (n = 2, male) and WFS1-deficient mice (n = 5, male) were analyzed using liquid-chromatography tandem mass spectrometry (LC-MS/MS), while age- and gender-matched healthy individuals and wildtype (WT) mice serve as controls. WFS1-deficient mice were intraperitoneally injected with IGF1 starting from 4 weeks of age. Body weight was monitored every 2 days, fasting blood glucose and glucose tolerance test were performed on the day 30 and day 40 after injection of IGF1, respectively. BiFC (bimolecular fluorescence complementation) and Co-immunoprecipitation (IP) were used to analyze the interaction between WFS1 and peptide hormones. Confocal microscopy was employed to analyze the colocalization of IGF1 with ER and Golgi. Key findingsPeptide hormones are deficient in both the plasma of WS patients and WFS1-deficient mice. WFS1 binds to and mediates the secretion of these peptide hormones, suggesting that WFS1 serves as a general COPII vesicular receptor for sorting peptide hormones. Interestingly, the WFS1 pathogenic mutations significantly disrupt its interaction with these peptide hormones. Furthermore, intraperitoneal administration of IGF1 partially attenuates high blood glucose levels in WFS1-deficient male mice. SignificanceThis study suggests that WS is characterized by defective peptide hormone secretion and proposes administration of these deficient peptide hormones as a promising treatment regimen for WS.

O15 DIFFERENTIAL CARDIAC MACROPHAGE POLARIZATION IS ASSOCIATED WITH BETTER PRECLINICAL MARKERS IN FEMALE SEX VERSUS MALE SEX WITH HYPERTENSION AND METABOLIC SYNDROME

Background: Women compared to men with hypertension (HT) and metabolic syndrome (MS) exhibit better clinical outcomes. In the preclinical model of HT-MS, female mice develop attenuated cardiac remodeling (CRM) compared to male mice (not mediated by sex hormones). Male cardiac macrophages (Mo) from mice are more susceptible to inflammatory stimuli. It is unknown whether subpopulations of cardiac pro-inflammatory Mo and resident repair Mo differ between males and females. Purpose: To characterize, in male and female mice with HT-MS, the cardiac pro-inflammatory cardiac Mo derived from monocytes (CCR2+MHCII+) and the resident repair Mo (CCR2-MHCII+ and CCR2- MHCII-). Methods: 12-week-old male and female C57BL/6N mice were assigned to experimental groups: high-fat diet + L-NAME or control diet. Body weight (BW), systolic (SBP) and diastolic (DBP) blood pressure, glucose and exercise tolerance, cardiac function and cardiac Mo CCR2+MHCII+, CCR2-MHCII+, CCR2- MHCII- were determined. Results: (mean ± SEM, n=11-18 mice/group). Compared with males, females with HT-MS gained less BW (14% vs. 22%, p<0.05), 2), had lower glucose levels (265±13 mg/dL vs 191±14 vs., p<0.001) and covered a greater distance on the treadmill (p<0.05). SBP and DBP was similary increased vs. their controls in both groups. In males but not in females with HT-MS both the LV septum and posterior wall were thicker vs controls (p< 0.001). Left atrium size increased 7.6% in females and 20% in males. In the myocardium, CR2+MHCII+ Mo increased by 58% only in males (p<0.001, F=11.7). The CCR2-MHCII- Mo increased by 75% in HT-MS females vs their controls, (p<0.001,F=18.7) and vs males. The CCR2-MHCII+ Mo decreased by 28.4% only in males (p<0.05, F=3.7). Conclusion: In females with HT-MS protective resident cardiac Mo increased significantly which was associated to less CRM and better exercise performance. Activation of resident cardiac Mo may be an important mechanism for prevention and treatment of CRM by HT and MS.

Fufang Zhenzhu Tiaozhi (FTZ) capsule ameliorates diabetic kidney disease in mice via inhibiting the SGLT2/glycolysis pathway

Ethnopharmacological relevanceFufang Zhenzhu Tiaozhi (FTZ) capsule is a hospital preparation of a patented traditional Chinese medicine compound. FTZ has been clinically used for nearly 13 years in the treatment of diabetes and glycolipid metabolic diseases. With the significant benefits of SGLT2 inhibitor in patients with diabetic kidney disease (DKD), it provides a research avenue to explore the mechanism of FTZ in treating this disease based on glycolysis pathway. Aim of the studyTo explore the pharmacological characteristics of FTZ in DKD mice and its impact on the glycolysis pathway. Materials and methodsWe induced a DKD model in C57BL/6 mice by injection of streptozotocin (STZ) combined with long-term high-fat diet. We administered three doses of FTZ for 12 weeks of treatment. Kidney function, blood lipid levels, glucose tolerance, and key glycolytic enzymes were evaluated. Renal pathological changes were observed using HE, MASSON, and PAS staining. The potential targets of the active ingredients of FTZ in the glycolysis pathway were predicted using network pharmacology and molecular docking. Validation was performed using immunohistochemistry and Western blotting. ResultsFTZ effectively reduces blood glucose, total cholesterol, triglyceride, low density lipoprotein cholesterol, 24 h proteinuria, serum creatinine, blood urea nitrogen, and increases urinary glucose levels. Glucose tolerance and renal pathological changes were significantly improved by FTZ treatment. Pinusolidic acid, a component of FTZ, shows good binding affinity with three active pockets of SGLT2. WB and immunohistochemistry revealed that FTZ significantly inhibits the expression of SGLT2 and its glycolytic related proteins (GLUT2/PKM2/HK2). Hexokinase, pyruvate kinase, and lactate dehydrogenase in the kidney were also significantly inhibited by FTZ in a dose-dependent manner. ConclusionFTZ may alleviate the progression of DKD by inhibiting the activation of the SGLT2/glycolytic pathway. Our study provides new insights into the clinical application of FTZ in DKD.

High-Protein Mulberry Leaves Improve Glucose and Lipid Metabolism via Activation of the PI3K/Akt/PPARα/CPT-1 Pathway.

High-Protein Mulberry is a novel strain of mulberry. High-Protein Mulberry leaves (HPM) were the subject of this study, which aimed to investigate its efficacy and underlying mechanisms in modulating glucose and lipid metabolism. A six-week intervention using db/db mice was carried out to assess the effects of HPM on serum lipid levels, liver function, and insulin (INS) levels. qRT-PCR and Western Blotting were employed to measure key RNA and protein expressions in the PI3K/Akt and PPARα/CPT-1 pathways. UHPLC-MS and the Kjeldahl method were utilized to analyze the component content and total protein. Additionally, network pharmacology was employed to predict regulatory mechanism differences between HPM and Traditional Mulberry leaves. The results of the study revealed significant improvements in fasting blood glucose, glucose tolerance, and insulin resistance in mice treated with HPM. HPM notably reduced serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and INS, while increasing high-density lipoprotein cholesterol (HDL-C) levels. The treatment also effectively mitigated liver fatty lesions, inflammatory infiltration, and islet atrophy. HPM activation of the PI3K/Akt/PPARα/CPT-1 pathway suggested its pivotal role in the regulation of glucose and lipid metabolism. With its rich composition and pharmacodynamic material basis, HPM displayed a greater number of targets associated with glucose and lipid metabolism pathways, underscoring the need for further research into its potential therapeutic applications.

Blood glucose outcomes of anti-retroviral therapy naïve Ugandan people with HIV with pre-diabetes mellitus initiated on dolutegravir for 48 weeks

BackgroundThe Uganda ministry of Health recommends frequent blood glucose monitoring for the first six months on dolutegravir, in people with HIV (PWH) having pre-diabetes mellitus (pre-DM). We sought to determine if indeed PWH with pre-diabetes started on dolutegravir had worse blood glucose outcomes at 48 weeks compared to those with normal blood glucose.MethodsIn this matched cohort study, we compared 44 PWH with pre-DM and 88 PWH with normal blood glucose at baseline. The primary outcome was change in mean fasting blood glucose (FBG) from baseline to week 48 and 2-hour blood glucose (2hBG) from baseline to week 36 compared between the two groups.ResultsThere was significant increase in FBG in PWH with normal blood glucose (mean change in FBG(FBG): 3.9 mg/dl, 95% confidence interval (95% CI): (2.2, 5.7), p value (p) = < 0.0001) and decrease in those with pre-DM (FBG: -6.1 mg/dl, 95%CI (-9.1, -3.2), p = < 0.0001) at 48 weeks. 2hBG was significantly lower than at baseline in both groups with the magnitude of reduction larger in those with pre-DM at 12 weeks (adjusted differences in mean drop in 2hBG (a2hBG): -19.69 mg/dl, 95%CI (-30.19, -9.19), p = < 0.0001) and 36 weeks (a2hBG: -19.97 mg/dl, 95%CI (-30.56, -9.39), p = < 0.0001).ConclusionWe demonstrated that Ugandan ART naïve PWH with pre-diabetes at enrollment have consistent improvement in both fasting blood glucose and glucose tolerance over 48 weeks on dolutegravir. Intensified blood glucose monitoring of these patients in the first six months of dolutegravir may be unnecessary.

Impacts of different pancreatic resection ranges on endocrine function in Suncus murinus.

Surgical intervention involving the pancreas can lead to impaired glucose tolerance and other types of endocrine dysfunction. The scope of pancreatectomy and whether it includes the ventral pancreas are the key factors in the development of postoperative diabetes. The ventral and dorsal pancreases are almost separated in Suncus murinus (S. murinus). To investigate the effects of different extents of pancreatic resection on endocrine function in S. murinus. Eight-week-old male S. murinus shrews were randomly divided into three experimental groups according to different pancreatic resection ranges as follows: ventral pancreatectomy (VPx) group; partial pancreatectomy (PPx) group; subtotal pancreatectomy (SPx) group; and a sham-operated group. Postprandial serum insulin, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), and somatostatin (SST) levels, as well as food intake, weight, blood glucose, and glucose tolerance were regularly measured for each animal. S. murinus treated with PPx and SPx suffered from varying degrees of impaired glucose tolerance, but only a small proportion of the SPx group developed diabetes. Only S. murinus in the SPx group showed a significant decrease in food intake accompanied by severe weight loss, as well as a significant increase in postprandial serum GLP-1 levels. Postprandial serum PP levels decreased in both the VPx and PPx groups, but not in the SPx group. Postprandial serum SST levels decreased in both VPx and PPx groups, but the decrease was marginal. Severe weight loss after pancreatectomy may be related to loss of appetite caused by compensatory elevation of GLP-1. PP and GLP-1 may play a role in resisting blood glucose imbalance.

Anti-hyperglycemic effect of Commelina diffusa extracts on diabetic mice model

This study aimed to investigate the blood glucose stabilising effect of extracts from Commelina diffusa Burm.f. on glucose tolerance test and diabetes test in white mice by streptozotocin. The diabetic mice were induced to hyperglycemia by intraperitoneal injection of streptozotocin in a single dose (170 mg/kg). Water extract, 96% ethanol extract, and 50% ethanol extract of C. diffusa were given orally for 7 days and the reference drug glibenclamide was given orally once on the 7th experimental day. The hypoglycemic effect was evaluated by quantifying fasting plasma glucose concentration and glucose tolerance test. The results of 96% ethanol extract of C. diffusa at two oral doses of 0.21 and 0.42 g/kg showed a more typical hypoglycemic effect than the water extract (0.36 and 0.72 g/kg) and 50% ethanol extract (0.49 and 0.98 g/kg) in both fasting blood glucose and glucose tolerance tests. The hypoglycemic effect of 96% ethanol extract of C. diffusa was equivalent to glibenclamide at a dose of 5 mg/kg measured in fasting state and was weaker than glibenclamide in the glucose tolerance test.

Central Obesity as A Risk Factor For Prediabetes

Central obesity has become a health problem and is associated with the incidence of prediabetes. Prediabetes is characterized by impaired fasting blood glucose (GDPT) or impaired glucose tolerance (TGT) or both without any complaints and symptoms, and is a condition that precedes the occurrence of type 2 diabetes mellitus. This study aims to prove central obesity as a risk factor for prediabetes by calculating the prevalence ratio. The method of this research is observational analysis with a cross-sectional design approach. The respondents of the study were the community around the work area of the Jati Ranggon health center who met the inclusion and exclusion criteria, totaling 1241 people, 523 men and 718 women. The prevalence of central obesity in this study was 39.6%. The prevalence of prediabetes is 18.8%, prediabetes with central obesity is 27.9% and non-central obesity prediabetes is 12.8%. Bivariate analysis with chi-square showed a relationship between age and the incidence of prediabetes (RP=1.62, 95% CI 1.24-2.11 and p= &lt;0.001), hypertension with the incidence of prediabetes (RP=1.58CI 95% 1.22-2.04, p=&lt;0.001), gender with prediabetes (RP=1.47, 95% CI 1.12-1.94, and p=0.005), general obesity with prediabetes (RP=1.87, 95% CI 1.44-2.42 and p=&lt;0.001), smoking with the incidence of prediabetes (RP= 0.54, 95% CI 0.33-0.88 and p=0.013). The results of multivariate analysis with cox regretion showed that the variables that affected prediabetes were central obesity (RP=1.87, CI95% 1.40-2.50, p=&lt;0.001) and general obesity (RP=1.42, CI95% 1.06-1.89, p=0.017). Central obesity is a risk factor for prediabetes with a prevalence ratio of 2.18.

Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine β-Synthase Mediated IL-6/STAT3 Inactivation.

Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine β-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using β-cell lines (MIN6, β-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of β-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.

Communicating cardiovascular health information and improving coordination with primary care: A Childhood Cancer Survivor Study randomized trial.

10011 Background: Childhood cancer survivors are at risk of early cardiovascular disease (CVD). We conducted a survivorship care plan (SCP)-based counseling intervention to improve CVD risk factor control in adult-aged survivors. Methods: Randomized (1:1) trial of survivors at high CVD risk based on history of anthracycline or chest radiotherapy exposures with undertreated hypertension (≥130/80 mmHg), dyslipidemia (LDL ≥160 mg/dL or triglyceride ≥200 mg/dL), and/or glucose intolerance (threshold varied if history of pre-diabetes or diabetes) based on in-home testing. Approximating a survivorship clinic visit, the intervention consisted of a remotely delivered session with an advanced practice provider to review results, a SCP with personalized CVD risk information, and an action plan to help manage CVD risk factors. A remote booster session was provided 4 months later with the action plan updated. Control participants only received a copy of their in-home results with abnormalities noted and written encouragement to follow-up with their primary care provider (PCP). Blood pressure, lipid profile, and glucose tolerance were retested after 1y. For both groups, all participant materials were sent to PCPs throughout the study, and PCP medical records were abstracted at study completion. Logistic regression assessed the odds ratio (OR) for undertreatment at 1y associated with the intervention, adjusting for pre-specified variables (sex, current age, time since cancer, insurance status, recent history of survivorship clinic visit, and undertreated CVD risk factor). Results: Among 644 survivors who completed in-home testing, 347 met inclusion criteria and were randomized (175 intervention; overall 52% male, mean age 40y, 31y since cancer diagnosis); 264 with 1y follow-up (126 intervention). At baseline, rates of hypertension, dyslipidemia, and glucose intolerance were 53%, 52%, and 49%, respectively; 43% had &gt; 1 undertreated condition. Although the intervention achieved &gt; 95% satisfaction, it was not associated with reduced undertreatment vs control (OR 0.9, 95% CI 0.7-1.3). Notably, 48% of intervention and 44% of control participants had less undertreatment after 1y. In secondary analysis, greater internal locus of control was associated with less undertreatment at 1y (OR 0.7, 95% CI 0.6-0.9). The intervention group was more likely than controls to have CVD risk (+10 vs -1%), SCP (+17 vs -2%), and some late effects surveillance plan (+8 vs +2%) documented within PCP records at 1y vs baseline (p &lt; 0.05 for all). Conclusions: While a remotely delivered counseling intervention did not reduce CVD risk factor undertreatment compared with provision of test results alone, both study arms had &gt; 40% reduction in undertreatment. These results suggest that simply providing a formal CVD risk assessment to high-risk cancer survivors and their PCPs may be effective. Clinical trial information: NCT03104543 .

Potential of FGF21 in type 2 diabetes mellitus treatment based on untargeted metabolomics

Fibroblast growth factor 21 (FGF21) has promise for treating diabetes and its associated comorbidities. It has been found to reduce blood glucose in mice and humans; however, its underlying mechanism is not known. Here, the metabolic function of FGF21 in diabetes was investigated. Diabetic db/db mice received intraperitoneal injections of FGF21 for 28 days, the serum of each mouse was collected, and their metabolites were analyzed by untargeted metabolomics using UHPLC-MS/MS. It was found that FGF21 reduced blood glucose and oral glucose tolerance without causing hypoglycemia. Moreover, administration of FGF21 reduced the levels of TG and LDL levels while increasing those of HDL and adiponectin. Importantly, the levels of 45 metabolites, including amino acids and lipids, were significantly altered, suggesting their potential as biomarkers. We speculated that FGF21 may treat T2DM through the regulation of fatty acid biosynthesis, the TCA cycle, and vitamin digestion and absorption. These findings provide insight into the mechanism of FGF21 in diabetes and suggest its potential for treating diabetes.

Estrogen restores disordered lipid metabolism in visceral fat of prediabetic mice.

Visceral obesity is increasingly prevalent among adolescents and young adults and is commonly recognized as a risk factor for type 2 diabetes. Estrogen [17β-estradiol (E2)] is known to offer protection against obesity via diverse me-chanisms, while its specific effects on visceral adipose tissue (VAT) remain to be fully elucidated. To investigate the impact of E2 on the gene expression profile within VAT of a mouse model of prediabetes. Metabolic parameters were collected, encompassing body weight, weights of visceral and subcutaneous adipose tissues (VAT and SAT), random blood glucose levels, glucose tolerance, insulin tolerance, and overall body composition. The gene expression profiles of VAT were quantified utilizing the Whole Mouse Genome Oligo Microarray and subsequently analyzed through Agilent Feature Extraction software. Functional and pathway analyses were conducted employing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Feeding a high-fat diet (HFD) moderately increased the weights of both VAT and SAT, but this increase was mitigated by the protective effect of endogenous E2. Conversely, ovariectomy (OVX) led to a significant increase in VAT weight and the VAT/SAT weight ratio, and this increase was also reversed with E2 treatment. Notably, OVX diminished the expression of genes involved in lipid metabolism compared to HFD feeding alone, signaling a widespread reduction in lipid metabolic activity, which was completely counteracted by E2 administration. This study provides a comprehensive insight into E2's local and direct protective effects against visceral adiposity in VAT at the gene level. In conclusion, the present study demonstrated that the HFD-induced over-nutritional challenge disrupted the gene expression profile of visceral fat, leading to a universally decreased lipid metabolic status in E2 deficient mice. E2 treatment effectively reversed this condition, shedding light on the mechanistic role and therapeutic potential of E2 in combating visceral obesity.

Endothelin-1 Receptor Antagonism Attenuates Increased Uncoupling Protein-1 in Brown Adipose Tissue of Obese Mice

Endothelin-1 (ET-1) is increased in patients and rodent models with obesity and promotes metabolic syndrome by causing inflammation and adipocyte dysfunction. Recently, our laboratory demonstrated that treatment of obese mice with Atrasentan (Atr) and Bosentan (Bos) significantly improved fasting blood glucose, insulin, and glucose and insulin tolerance; however, the mechanisms are not completely understood. Brown adipocytes express all components of the ET-1 system and are important in limiting adiposity though an increase in uncoupling protein-1 (UCP-1) leading to increased metabolism via thermogenesis. We hypothesized that ET-1 antagonism may improve metabolism in obese mice by regulating UCP-1 in brown adipose. Mice were fed either normal (NMD) or high fat diet (HFD) for 10 week and treated with either vehicle, Atr, or Bos for the final two weeks. HFD significantly increased ET-1 and tumor necrosis factor alpha expression in brown adipose tissue compared to NMD controls with no significant effect of either ET-1 receptor antagonists. Interestingly, brown adipose expression of UCP-1 was significantly increased in HFD fed mice compared to NMD, an effect that was significantly attenuated in mice treated with atrasentan and bosentan. These data suggest that ET-1 modulates brown adipose tissue function in obesity, a potential contributor to obesity induced cardio metabolic risk. This work was supported by National Institutes of Health grant 5T32HL105324-14. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

HbA1c or fructosamine on evaluating glucose intolerance in children with beta- thalassemia

BackgroundBeta-thalassemia major (β-TM) patients are more likely to experience blood glucose intolerance and to date; the blood markers that could evaluate this are debatable. So, this study aimed to assess the roles of glycated hemoglobin A1c (HbA1c) and fructosamine in evaluating glucose intolerance in children with β-TM and figuring out role of insulin resistance in these patients.MethodsOne hundred children diagnosed with β-TM and 100 age and sex-matched controls were enrolled. Fasting plasma glucose (FPG), 2-h post-prandial blood glucose (2-h PG), HbA1c, fructosamine, fasting insulin level (FINS), insulin resistance index (HOMA-IR), and insulin sensitivity index (HOMA-IS) were evaluated.ResultsFPG and 2-h PG revealed glucose intolerance in 51 patients (51%), 19 of them had diabetes mellitus. HbA1c, fructosamine, FINS, and HOMA-IR showed a high statistically significant increase in patients compared to controls, (P < 0.001). Results revealed fructosamine was more specific in detecting prediabetes state and more sensitive in identifying diabetes mellitus in our patients when compared to HbA1c.ConclusionsDespite controversies on HbA1c in children with β-TM, it is still valuable in glucose intolerance detection. Fructosamine showed more sensitivity and specificity. Furthermore, insulin resistance was prevalent in children with β-TM highlighting the necessity of regular glycemic state evaluation.ImpactGlucose intolerance is a common complication in beta thalassemia patients.Conflicting data was reported about the role of HbA1c and fructosamine in evaluating glucose intolerance in thalassemic patients.Fructosamine does not yet have a threshold that may be used to distinguish between patients who have diabetes mellitus and those who do not.Fructosamine was more specific in detecting blood glucose intolerance compared to HbA1c and was more sensitive for diagnosing diabetes mellitus.Insulin resistance was common in patients with beta-thalassemia and often present before the onset of overt diabetes.

Fish oil alleviates diabetes-induced aortic endothelial dysfunction and injuries in mice

Diabetes mellitus (DM)-induced endothelial dysfunction (DED) contributes to macrovascular complications of DM, resulting in high mortality. Fish oil (FO) is a dietary source of omega-3 polyunsaturated fatty acids, with little known for its action on DED. Thus, the objective of the current study was to investigate the effect of FO on aortic DED using a mouse model of DM. To this end, C57BL/6 J male mice (n = 8/each group) were intraperitoneally injected with streptozotocin (50 mg/kg/day, 5 days), following feeding with a high-fat diet containing FO for 24 weeks, with fasting blood glucose levels and glucose tolerance monitored. At the end of the procedure, aortic rings were harvested and evaluated for the contraction and relaxation in response to phenylephrine and acetylcholine respectively. Aortic pathological injuries were assessed by hematoxylin and eosin, and Masson's trichrome staining. Aortic expression of proinflammatory, oxidative stress and profibrotic markers were determined by qRT-PCR and immunohistochemical staining. The diabetic mice developed impaired glucose tolerance, abnormal endothelial dependent aortic contraction and relaxation, thickened tunica media, and increased accumulation of fibrosis in the aortas. These effects were remarkably reversed by FO supplementation. Further investigation revealed that FO inhibited aortic mRNA expression of Tnf-α, Il-6, Il-1β and Vcam-1 as markers for inflammation, Nox1, Nox2, Nox4 and Nos2 as markers for oxidative stress, as well as Acta 2, Col1a1, Col3 and Ccn2 as markers for fibrosis. Moreover, FO decreased the aortic protein expression of TNF-α, 4-HNE and COL1, all of which were increased under the diabetic condition. The present study may provide a molecular basis for the application of FO in prevention of macrovascular complications of DM.

Sulforaphane Ameliorates High-Fat-Diet-Induced Metabolic Abnormalities in Young and Middle-Aged Obese Male Mice.

Type 2 diabetes (T2D) is still a fast-growing health problem globally. It is evident that chronic insulin resistance (IR) and progressive loss of β-cell mass and function are key features of T2D etiology. Obesity is a leading pathogenic factor for developing IR. The aim of the present study was to determine whether sulforaphane (SFN), a natural compound derived from cruciferous vegetables, can prevent (prevention approach) or treat (treatment approach) obesity and IR in mouse models. We show that dietary intake of SFN (0.5 g/kg of HFD) for 20 weeks suppressed high-fat diet (HFD)-induced fat accumulation by 6.04% and improved insulin sensitivity by 23.66% in young male mice. Similarly, dietary provision of SFN (0.25 g/kg) significantly improved blood lipid profile, glucose tolerance, and insulin sensitivity of the middle-aged male mice while it had little effects on body composition as compared with the HFD group. In the treatment study, oral administration of SFN (40 mg/kg) induced weight loss and improved insulin sensitivity and plasma lipid profile in the diet-induced-obesity (DIO) male mice. In all three studies, the metabolic effects of SFN administration were not associated with changes in food intake. In vitro, SFN increased glucose uptake in C2C12 myotubes and increased fatty acid and pyruvate oxidation in primary human skeletal muscle cells. Our results suggest that SFN may be a naturally occurring insulin-sensitizing agent that is capable of improving the metabolic processes in HFD-induced obesity and IR and thereby may be a promising compound for T2D prevention.

Ghrelin regulates the endoplasmic reticulum stress signalling pathway in gestational diabetes mellitus

ObjectiveWe aimed to investigate the effects and mechanisms of the ghrelin-regulated endoplasmic reticulum stress (ERS) signalling pathway in gestational diabetes mellitus (GDM). MethodsPregnant female C57BL/6 mice were randomly divided into a normal group, GDM group (high-fat diet + STZ), GDM + ghrelin group (acyl ghrelin), and GDM + ghrelin + ghrelin inhibitor group ([D-lys3]-GHRP-6). We measured body weight, the intake of water and food, glucose, cholesterol, triglyceride and fasting insulin levels in each group. HE staining was used to observe the morphological changes in the pancreas. The TUNEL method was used to detect the apoptosis rate of islet cells. qPCR and Western boltting were performed to detect the relative expression levels of PERK, ATF6, IREIα, GRP78, CHOP and caspase-12, which are related to the ERS signalling pathway in the pancreas. Then, NIT-1 cells were cultured to verify whether ghrelin regulates ERS under high-glucose or tunicamycin conditions. ResultsCompared with the GDM group, the GDM + ghrelin group showed improved physical conditions and significantly decreased the fasting blood glucose, glucose tolerance, cholesterol, triglyceride and fasting insulin levels. Damaged islet areas were inhibited by ghrelin in the GDM group. The GDM + ghrelin group showed reduced β-cell apoptosis compared to the GDM and GDM + ghrelin + ghrelin inhibitor groups. ERS-associated factors (PERK, ATF6, IREIα, GRP78, CHOP and caspase-12) mRNA and protein levels were obviously lower in the GDM + ghrelin group than in the GDM group, while expression levels were restored in the inhibitor group. Ghrelin treatment improved the high-glucose or tunicamycin-induced apoptosis, increased insulin levels and upregulation of GRP78, CHOP and caspase-12 in NIT-1 cells. ConclusionGhrelin suppressed ERS signalling and apoptosis in GDM mice and in NIT-1 cells. This study established a link between ghrelin and GDM, and the targeting of ERS with ghrelin represents a promising therapeutic strategy for GDM.

Xiasangju alleviate metabolic syndrome by enhancing noradrenaline biosynthesis and activating brown adipose tissue.

Metabolic syndrome (MetS) is a clinical condition associated with multiple metabolic risk factors leading to type 2 diabetes mellitus and other metabolic diseases. Recent evidence suggests that modulating adipose tissue to adaptive thermogenesis may offer therapeutic potential for MetS. Xiasangju (XSJ) is a marketed drug and dietary supplement used for the treatment of metabolic disease with anti-inflammatory activity. This study investigated the therapeutic effects of XSJ and the underlying mechanisms affecting the activation of brown adipose tissue (BAT) in MetS. The results revealed that XSJ ameliorated MetS by enhancing glucose and lipid metabolism, leading to reduced body weight and abdominal circumference, decreased adipose tissue and liver index, and improved blood glucose tolerance. XSJ administration stimulated catecholamine biosynthesis, increasing noradrenaline (NA) levels and activating NA-mediated proteins in BAT. Thus, BAT enhanced thermogenesis and oxidative phosphorylation (OXPHOS). Moreover, XSJ induced changes in gut microbiota composition, with an increase in Oscillibacter abundance and a decrease in Bilophila, Candidatus Stoquefichus, Holdemania, Parasutterella and Rothia. XSJ upregulated the proteins associated with intestinal tight junctions corresponding with lower serum lipopolysaccharide (LPS), tumor necrosis factor α (TNF-α) monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) levels to maintain NA signaling transport. In summary, XSJ may alleviate MetS by promoting thermogenesis in BAT to ultimately boost energy metabolism through increasing NA biosynthesis, strengthening intestinal barrier integrity and reducing low-grade inflammation. These findings suggest XSJ has potential as a natural therapeutic agent for the treatment of MetS.

Application of Clinical Blood Metabogram to Type 2 Diabetes Mellitus.

The clinical blood metabogram (CBM) was developed to match a tailored analysis of the blood metabolome to the time, cost, and reproducibility constraints of clinical laboratory testing. By analyzing the main blood metabolite groups, CBM offers clinically relevant information about the intake of low-molecular substances into the organism, humoral regulation, liver function, amino acid level, and the lipid and carbohydrate metabolism. The purpose of this work was to investigate the relevance of using the CBM in patients with diabetes mellitus. For this, a CBM was obtained for 18 healthy individuals, 12 individuals with prediabetes, and 64 individuals with type 2 diabetes mellitus, separated into groups according to fasting blood glucose and oral glucose tolerance tests. The results showed that the CBM reveals diabetes-associated metabolic alterations in the blood, including changes in the levels of carbohydrates, ketone bodies, eicosanoids, phospholipids, and amino acids, which are consistent with the scientific data available to date. The CBM enabled the separation of diabetic patients according to their metabolic metabotypes, providing both a general overview of their metabolic alterations and detailing their individual metabolic characteristics. It was concluded that the CBM is a precise and clinically applicable test for assessing an individual's metabolic status in diabetes mellitus for diagnostic and treatment purposes.

Social jet lag impairs exercise volume and attenuates physiological and metabolic adaptations to voluntary exercise training.

Social jet lag (SJL) is a misalignment between sleep and wake times on workdays and free days. SJL leads to chronic circadian rhythm disruption and may affect nearly 70% of the general population, leading to increased risk for cardiometabolic diseases. This study investigated the effects of SJL on metabolic health, exercise performance, and exercise-induced skeletal muscle adaptations in mice. Ten-week-old C57BL/6J mice (n = 40) were allocated to four groups: control sedentary (CON-SED), control exercise (CON-EX), social jet lag sedentary (SJL-SED), and social jet lag exercise (SJL-EX). CON mice were housed under a 12:12-h light-dark cycle. SJL was simulated by implementing a 4-h phase delay for 3 days to simulate "weekends," followed by a 4-h phase advance back to "weekdays," for 6 wk. EX mice had free access to a running wheel. Graded exercise tests (GXTs) and glucose tolerance tests (GTTs) were performed at baseline and after intervention to monitor the effects of exercise and social jet lag on cardiorespiratory and metabolic health, respectively. SJL led to alterations in activity and running patterns and clock gene expression in skeletal muscle and decreased average running distance (P < 0.05). SJL-SED mice gained significantly more weight compared with CON-SED and SJL-EX mice (P < 0.01). SJL impaired fasting blood glucose and glucose tolerance compared with CON mice (P < 0.05), which was partially restored by exercise in SJL-EX mice. SJL also blunted improvements in exercise performance and mitochondrial content in the quadriceps. These data suggest that SJL blunted some cardiometabolic adaptations to exercise and that proper circadian hygiene is necessary for maintaining health and performance.NEW & NOTEWORTHY In mice, disrupting circadian rhythms with social jet lag for 6 wk caused significant weight gain, higher fasting blood glucose, and impaired glucose tolerance compared with control. Voluntary exercise in mice experiencing social jet lag prevented weight gain, though the mice still experienced increased fasting blood glucose and impaired exercise performance compared with trained mice not experiencing social jet lag. Social jet lag seems to be a potent circadian rhythm disruptor that impacts exercise-induced training adaptations.