Lower Insulin Levels Research Articles

Casual C peptide index: Predicting the subsequent need for insulin therapy in outpatients with type 2 diabetes under primary care.

BackgroundEvaluation of residual beta cell function is indispensable in patients with type 2 diabetes as it informs not only diagnoses but also appropriate treatment modalities. However, there is a lack of convenient biomarkers for residual beta cell function. Therefore, we evaluated endogenous insulin level as a biomarker in outpatients who were being treated with insulin therapy and in patients who were introduced to insulin therapy after 4 years.MethodsData of 174 outpatients with type 2 diabetes (50% male) whose glycemia was moderately controlled (glycated A1c 7.3% [5.2%–14.8%]) were reviewed. Twenty patients whose estimated glomerular filtration rate was lower than 30 ml/min/1.73 m2 were excluded from the evaluation of endogenous insulin level with both casual C‐peptide index (C‐CPI) and urinary C‐peptide/creatinine ratio (determined at any time, generally 1–2 h after breakfast). Patients were stratified based on the provision of insulin therapy.ResultsC‐CPI and UCPCR were significantly lower in the insulin‐treated patients than in the insulin‐untreated patients (0.9 vs. 2.2, p < 0.0001; 24.7 vs. 75.5, p = 0.0003, respectively). Moreover, C‐CPI were significantly lower in the insulin‐requiring patients for 4 years than in the insulin‐unrequiring patients (1.0 vs. 1.7, p = 0.0184). The multivariate logistic regression analysis revealed that both indicators of insulin secretion influenced the requirement for insulin therapy, but C‐CPI could serve as the most convenient and useful biomarker for not only current insulin therapy requirements (p = 0.0002) but also the subsequent requirement for insulin therapy (p = 0.0008).ConclusionsC‐CPI could be determined easily, and it was found to be a more practical marker for outpatients; therefore, our findings would have critical implications for primary care.

Antioxidant Potential, DNA Damage, Inflammation, Glycemic Control and Lipid Metabolism Alteration: A Mediation Analysis of Islamic Sunnah Intermittent Fasting on Cognitive Function among Older Adults with Mild Cognitive Impairment.

This study aimed to determine the relationship between oxidative stress, DNA damage, inflammation, and metabolic biomarkers as the mediating factor between Islamic Sunnah intermittent fasting (IF) practice and cognitive function among older adults with mild cognitive impairment (MCI). This study was a 36 months prospective cohort study. Community-dwelling older participants recruited through a stratified random sampling method from four states representing Malaysia's central, north-west, northeast and southern regions. Ninety-nine Malay Muslim older adults (n= 99) aged 60 and above with MCI and no known critical illnesses were included in the current analysis. The participants were divided into regularly practicing IF (r-IF), irregularly practicing IF (i-IF) and not practicing IF (n-IF) groups. Fasting venous blood was collected and used to determine the levels of oxidative stress, DNA damage, inflammatory and metabolic biomarkers. Mini-Mental State Examination, Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test, Digit Span and Digit symbol were used to evaluate the cognitive function. Then, the mediation analysis was conducted using a multistep regression model to determine the mediating role of various biomarkers between IF practice and cognitive function. When comparing the r-IF and n-IF groups, higher SOD activity, lower DNA damage (percentage of DNA in tail), lower CRP levels and higher HDL-cholesterol levels established partial mediation while lower insulin levels established complete mediation between IF practice and better cognitive function. Meanwhile, when comparing the r-IF and i-IF groups, higher SOD activity and lower CRP levels completely mediated the effects of IF practice on better cognitive function. It can be concluded that changes in antioxidant function, DNA damage, inflammation and a limited set of metabolic biomarkers (insulin and HDL cholesterol) may mediate improvements in cognitive function among older participants with MCI who practice Islamic Sunnah IF.

UNUSUAL PRESENTATION OF PANCREATIC INSULINOMA:A CASE REPORT

Insulinomas are pancreatic neuroendocrine tumors (PNETs) responsible for inappropriate insulin release, leading to episodes of hypoglycemia. The diagnosis of insulinoma is suspected clinicaly andbiochemically made with low blood glucose, elevated insulin, proinsulin, and C-peptide levels, and confirmed by localizing the tumor ,usually, by non-invasive imaging techniques and for difficult cases invasive modalities could be needed.Herein, we present the case of a 15 years old female who had a 1 year historyof episodic and repetitive neuroglycopenicsymptoms without weight gain, and loss of consciousness resolved with ingestion of sugary foods. Initially a neuro-psychiatric pathology was suspected, the patient was on Sodium Valproate and Antidepressants (SSRIs)with no improvement.After thorough examinations, a pancreatic insulinoma was diagnosed. The patient had a successful resection of the tumor, and her symptoms disappeared entirely.

Long-term impact of maternal dietary intervention on metabolic homeostasis in male offspring in mice

The long-term effect of changes in maternal dietary composition during pregnancy on the offspring's metabolic homeostasis is uncertain. We aimed to investigate the long-term effects of maternal balanced low-fat interventions on metabolic homeostasis of the offspring using a mouse model of gestational obesity induced by a high-fat diet (HFD). Male newborns in the balanced low-fat intervention group had significantly lower serum insulin and higher serum adiponectin levels than those in the HFD group. Changes in maternal dietary composition improved glucose tolerance in pups at 3 and 12 weeks of age. We also performed transcriptomic analysis of the liver in neonatal and 3-week-old pups. Genes in the peroxisome proliferator-activated receptor signaling pathway were significantly down-regulated in neonates in the balanced low-fat intervention group compared with the HFD group. A maternal balanced low-fat diet fully compensated for the detrimental effects of a maternal HFD on glucose metabolism, insulin tolerance, circulating insulin, dyslipidemia, and body weight gain in male offspring by changing the gene expression profile. These data suggest that maternal balanced low-fat intervention is critical for improving the metabolic health of future generations.

A Review of the Relationship between Lentil Serving and Acute Postprandial Blood Glucose Response: Effects of Dietary Fibre, Protein and Carbohydrates.

Pulse consumption has been shown to confer beneficial effects on blood glucose and insulin levels. Lentil consumption, in particular, consistently lowers acute blood glucose and insulin response when compared to starchy control foods. The mechanism by which lentils lower postprandial blood glucose response (PBGR) and insulin levels is unclear; however, evidence suggests that this effect may be linked to macronutrients and/or the amount of lentils consumed. This review attempts to consolidate existing studies that examined lentil consumption and glycemic and/or insulinemic responses and declared information on macronutrient composition and dietary fibre content of the foods tested. Collectively, these studies suggest that consumption of lentils reduces PBGR, with the minimum effective serving being ~110g cooked to reduce PBGR by 20%. Reductions in PBGR show modest-to-strong correlations with protein (45–57 g) and dietary fibre (22–30 g) content, but has weaker correlations with available carbohydrates. Increased lentil serving sizes were found to moderately influence relative reductions in peak blood glucose concentrations and lower the area under the blood glucose curve (BG AUC). However, no clear relationship was identified between serving and relative reductions in the BG AUC, making it challenging to characterize consistent serving–response effects.

The Intricate Crosstalk Between Insulin and Pancreatic Ductal Adenocarcinoma: A Review From Clinical to Molecular.

Increased insulin level (or “hyperinsulinemia”) is a common phenomenon in pancreatic ductal adenocarcinoma (PDA) patients and signals poor clinical outcomes. Insulin is safe in low PDA risk population, while insulin significantly promotes PDA risk in high PDA risk population. The correlation between insulin and PDA is a reciprocal self-reinforcing relationship. On the one hand, pancreatic cancer cells synthesize multiple molecules to cause elevated peripheral insulin resistance, thus enhancing hyperinsulinemia. On the other hand, insulin promotes pancreatic cancer initiation and sustains PDA development by eliciting tumorigenic inflammation, regulating lipid and glucose metabolic reprogram, overcoming apoptosis through the crosstalk with IGF-1, stimulating cancer metastasis, and activating tumor microenvironment formation (inflammation, fibrosis, and angiogenesis). Currently, taking glucose sensitizing agents, including metformin, SGLT-2 inhibitor, and GLP-1 agonist, is an effective way of lowering insulin levels and controlling PDA development at the same time. In the future, new drugs targeting insulin-related signal pathways may pave a novel way for suppressing PDA initiation and progression.

Response of Growth Hormones and Cortisol to One Session of Moderate-Intensity Endurance Exercise in Patients with Type 2 Diabetes: A Quasi-experimental Study.

Background: Therapeutic interventions for diabetes are one of the main components of treatment and having proper physical activity in these patients is important from different physical, psychological, and social aspects. The benefits of exercise in these people include improved cardiovascular health and increased self-confidence, contributing to maintaining proper weight, controlling blood pressure, lowering blood lipids, and lowering insulin levels. The objective of this study was to assess the baseline levels of growth hormones and cortisol and the response of these 2 hormones to 1 session of moderate-intensity exercise in type 2 diabetic patients and to compare them with healthy individuals. Methods: This was a quasi-experimental and applied study, with a pretest and posttest design and with 1 control group. Participants included 12 healthy people without diabetes and 12 patients with type 2 diabetes aged over 30 years who were referred to the Diabetes Clinic of Tohid hospital, Kurdistan, Iran. After describing the objectives and hypothesis of the study and the implementation method, informed consent was obtained from all participants. SPSS Version 22 software was used for data analysis and coding. The Shapiro-Wilk normality test was used to assess data distribution. A paired t test, an independent t test, the Wilcoxon test, and the Mann-Whitney U test were used to compare outcomes between the 2 groups before and after the intervention. Results: A total of 24 individuals were included: 5 men and 7 women were included in the diabetic group and 7 men and 5 women were included in the healthy group. The mean duration of diabetes in the diabetic group was 7.82 years. The results showed that there was no reason for rejecting a relationship between 1 session of moderate-intensity exercise and increased growth hormone secretion in healthy individuals (p=0.010), but the relationship between this factor and increased growth hormone secretion in the diabetic participants could be strongly rejected (p=0.900). Also, 1 session of the moderate-intensity exercise was not significantly correlated with cortisol secretion in healthy and diabetic participants (p>0.05). Conclusion: This study revealed that baseline growth hormone levels in healthy participants were higher than those of diabetic participants and 1 session of moderate-intensity exercise significantly increased the growth hormone secretion but did not significantly increase the cortisol secretion.

Artemisia scoparia and Metabolic Health: Untapped Potential of an Ancient Remedy for Modern Use.

Botanicals have a long history of medicinal use for a multitude of ailments, and many modern pharmaceuticals were originally isolated from plants or derived from phytochemicals. Among these, artemisinin, first isolated from Artemisia annua, is the foundation for standard anti-malarial therapies. Plants of the genus Artemisia are among the most common herbal remedies across Asia and Central Europe. The species Artemisia scoparia (SCOPA) is widely used in traditional folk medicine for various liver diseases and inflammatory conditions, as well as for infections, fever, pain, cancer, and diabetes. Modern in vivo and in vitro studies have now investigated SCOPA’s effects on these pathologies and its ability to mitigate hepatotoxicity, oxidative stress, obesity, diabetes, and other disease states. This review focuses on the effects of SCOPA that are particularly relevant to metabolic health. Indeed, in recent years, an ethanolic extract of SCOPA has been shown to enhance differentiation of cultured adipocytes and to share some properties of thiazolidinediones (TZDs), a class of insulin-sensitizing agonists of the adipogenic transcription factor PPARγ. In a mouse model of diet-induced obesity, SCOPA diet supplementation lowered fasting insulin and glucose levels, while inducing metabolically favorable changes in adipose tissue and liver. These observations are consistent with many lines of evidence from various tissues and cell types known to contribute to metabolic homeostasis, including immune cells, hepatocytes, and pancreatic beta-cells. Compounds belonging to several classes of phytochemicals have been implicated in these effects, and we provide an overview of these bioactives. The ongoing global epidemics of obesity and metabolic disease clearly require novel therapeutic approaches. While the mechanisms involved in SCOPA’s effects on metabolic, anti-inflammatory, and oxidative stress pathways are not fully characterized, current data support further investigation of this plant and its bioactives as potential therapeutic agents in obesity-related metabolic dysfunction and many other conditions.

Effect of lidocaine infusion compared to dexmedetomidine infusion on proinflammatory cytokines and stress response in pelvi–abdominal cancer surgeries: a randomized clinical trial

Background &amp; Objectives: Stress response to extensive surgeries in cancer patients results in an imbalance between the pro-inflammatory and anti-inflammatory cytokines, besides activating an inflammatory cascade. We investigated the comparative effects of intravenous infusion of dexmedetomidine and lidocaine on proinflammatory cytokines and the stress reaction.&#x0D; Methodology: A prospective randomized double blind trial was performed in National Cancer Institute. 54 patients scheduled for pelvi–abdominal cancer surgery under general anesthesia were randomly allocated to three equal groups. Lidocaine group: patients received 1.5 mg/kg loading dose of lidocaine followed by 1.5 mg/kg/h infusion; Dexmedetomidine group: received a loading dose of dexmedetomidine 1 µg/kg followed by infusion of 0.5 µg/kg/h; or Saline group: received 50 ml of normal saline followed by infusion at a rate of 10 ml/h till the end of the surgery. The primary outcome was a postoperative target level of IL–6 after 24 h.&#x0D; Results: Immediate and 24 h postoperative IL–6 and TNFα were significantly lower in both dexmedetomidine and lidocaine groups compared to the control group (P &lt; 0.001). Dexmedetomidine group had a significantly lower IL–6 and TNFα levels compared to lidocaine group at immediate postoperative and 24 h postoperative period (P &lt; 0.001). Dexmedetomidine and lidocaine groups had a significantly lower lactate and insulin levels compared to the control group immediately postoperatively as well as 24 h postoperatively (P &lt; 0.001). The dexmedetomidine group had a significantly lower lactate levels compared to the lidocaine group immediately postoperatively only. The lidocaine group had lower insulin level than the control group regarding immediate postoperative period only.&#x0D; Conclusion: Intraoperative infusion of dexmedetomidine or lidocaine, both attenuate the postoperative levels of proinflammatory cytokines and stress response in patients undergoing pelvi–abdominal cancer surgeries.&#x0D; Clinical trial registration: The study was registered at clinicaltrials.gov (NCT 04148599).&#x0D; Key words: Lidocaine; Dexmedetomidine; Interleukins; Tumor necrosis factor-α; Stress response; Pelvi–abdominal cancer; Surgery&#x0D; Abbreviations: TNF - Tumor necrosis factor; IL – Interleukins;&#x0D; Citation: Hassan MM, Saleh RG, Abdalla NO, Radwan NH, Abdelghfar EM. Effect of lidocaine infusion compared to dexmedetomidine infusion on proinflammatory cytokines and stress response in pelvi–abdominal cancer surgeries: a randomized clinical trial. Anaesth. pain intensive care 2021;26 (1):44-52.&#x0D; DOI: 10.35975/apic.v26i1.1765&#x0D; Received: February 15, 2021, Reviewed: December 02, 2021, Accepted: December 05, 2021

The Association Between Physical Activity and Insulin Level Under Different Levels of Lipid Indices and Serum Uric Acid.

ObjectivesInsulin resistance (IR) has been shown to play important role in the pathogenesis of type 2 diabetes mellitus (T2DM). There is an intricate interplay between IR, dyslipidemia, and serum uric acid (SUA) in people with and without diabetes. Physical activity has a positive impact on insulin sensitivity in insulin-resistant populations. However, the effect of different intensities of physical activity on insulin levels under different lipid indices and SUA levels is unclear.MethodsTo explore the association between physical activity and insulin, we enrolled 12,982 participants aged above 18 years from the National Health and Nutrition Examination Survey (NHANES) conducted between 2009 and 2018. Next, we conducted multivariate logistic regression analyses, generated fitted smoothing curves, and visualized the data using generalized additive models.ResultsIncreased intensities of physical activity can significantly reduce insulin levels. The association between physical activity and insulin persisted even after adjusting for confounding factors, with β value (95% CI) = −17.10 (−21.64, −12.56) in moderate group, β value (95% CI) = −28.60 (−33.08, −24.11) in high group, respectively. High-intensity physical activity significantly lowered insulin levels in the lower and higher SUA tertiles, and three tertiles of LDL-c, HDL-c, and TG. Moreover, the link between physical activity and insulin was stronger in male individuals.ConclusionThis study shows that physical activity can significantly lower insulin levels, and high-intensity physical activity still has additional potential benefits for insulin levels, even in the condition of dyslipidemia and hyperuricemia.

The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism.

Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the treatment of metabolically driven diseases. We previously identified the deubiquitinase OTUB1 as substrate for the cellular oxygen sensor factor-inhibiting HIF (FIH) with regulatory effects on cellular energy metabolism, but the physiological relevance of OTUB1 is unclear. Here, we report that the induced global deletion of OTUB1 in adult mice (Otub1 iKO) elevated energy expenditure, reduced age-dependent body weight gain, facilitated blood glucose clearance and lowered basal plasma insulin levels. The respiratory exchange ratio was maintained, indicating an unaltered nutrient oxidation. In addition, Otub1 deletion in cells enhanced AKT activity, leading to a larger cell size, higher ATP levels and reduced AMPK phosphorylation. AKT is an integral part of insulin-mediated signaling and Otub1 iKO mice presented with increased AKT phosphorylation following acute insulin administration combined with insulin hypersensitivity. We conclude that OTUB1 is an important regulator of metabolic homeostasis.

Association between Frequency of Toothbrushing and Metabolic Syndrome among Adolescents: A 5-Year Follow-Up Study.

This study longitudinally examines the relationship between the frequency of toothbrushing and the development of selected components of metabolic syndrome (MetS), along with the potential role of salivary biomarkers in this relationship. In 2014, 6317 12-year-old children underwent health examinations (T1), of which, 348 children participated in the second stage of data collection in 2019 (T2). The association between the change in the metabolic status during the 5-year follow-up examination (between T1 and T2) and frequency of toothbrushing was assessed using multinomial logistic regression analyses. At T2, healthy adolescents had significantly higher odds of toothbrushing twice or more daily compared with adolescents with components of MetS (OR = 1.99, 95% CI 1.15–3.45). Adolescents who were healthy at T1 but developed components of MetS at T2, had significantly higher frequencies of dining-out compared with adolescents with components of MetS at both T1 and T2 (OR = 0.09, 95% CI 0.02 to 0.49). Adolescents who were ‘healthy’ at both T1 and T2 had significantly (p < 0.05) lower levels of C-reactive protein (T2), insulin (T1 and T2), interleukin-6 (T1) and adiponectin (T1) compared with adolescents who had components of MetS. Toothbrushing and frequency of dining-out were associated with the presence of MetS components.

A haplotype in the dipeptidyl peptidase 4 gene impacts glycemic-related traits of Brazilian older adults.

Dipeptidyl peptidase 4 (DPP4) regulates various physiological pathways and has a pivotal role in glucose homeostasis. The objective of this study was to verify the association of a haplotype constituted by two single nucleotide polymorphisms (rs2268894 and rs6741949) in the DPP4 gene with type 2 diabetes mellitus (T2DM) and fasting glycemia-related variables in a sample of Brazilian older adults, taking serum levels and enzymatic activity of DPP4 into account. Clinical, biochemical, and anthropometric characteristics as well as DPP4 serum levels and enzymatic activity were determined in 800 elderly (≥60 years old) individuals. Assessment of polymorphic sites was performed by real-time PCR whereas haplotypes were inferred from genotypic frequencies. Statistical analyses compared measures and proportions according to T2DM diagnosis and DPP4 haplotypic groups. The most common haplotype consisted of the T-rs2268894/G-rs6741949 string, which was 20% more frequent among non-diabetics. Considering non-diabetic patients alone, carriers of the T/G haplotype had significantly lower levels of blood glucose, insulin, HOMA-IR index, and DPP4 activity. Among diabetic patients, the T/G haplotype was associated with lower DPP4 levels whereas glycemic scores were not affected by allelic variants. Our results suggested that the genetic architecture of DPP4 affects the glycemic profile and DPP4 serum levels and activity among elderly individuals according to the presence or absence of T2DM, with a possible implication of the T/G haplotype to the risk of T2DM onset.

A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY

Aims/hypothesisSystematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum.MethodsWe conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT.ResultsHalf of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17–35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m2 units of BMI, p=2.2 × 10−4, using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 μmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 μmol/l, p=3.1 × 10−5).Conclusions/interpretationThe most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.Graphical abstract

Effects of vitamin C on glucose metabolism during acute Chagas disease

AbstractIntroduction: Chagas disease is characterized by lesions caused by the host immune response, which can influence the glucose metabolism.Objective: To evaluate the action of vitamin C on glucose metabolism during the acute phase of Chagas disease.Methods: Sixty swiss mice were divided into four groups: NW, NC, IW, and IC. NW and NC groups were not infected, whereas IW and IC were intraperitoneally infected with 5.0 × 104 trypomastigotes of T. cruzi QM2 strain. IC and NC groups received 500 mg/day of vitamin C. All groups were treated for 60 days. Blood glucose and weight were measured individually and weekly. Five animals from each group were euthanized on day 15, 30, and 60 for blood and tissues collection.Results: Lower parasitemia (p≤0.05) in the IC group was noticed, but greater damage to the pancreatic tissue. In the 15 days post infection, lower glucose concentrations (p≤0.05) and insulin levels (p≤0.05) were observed in the IC and IW groups regarding NC and NW. The infected groups had decreased body mass 30 days post infection, with significant difference (p≤0.05) in the IW group on the sixtieth day. Significant difference (p≤0.05) for hepatic glycogen was found only on day 60, with a lower concentration in the NC group than the other groups.Conclusion: Vitamin C can control parasitemia, blood glucose and weight 30 days after infection, but a more intense inflammatory process has been observed at the end of acute phase. The use of vitamin C in Chagas disease may have physiological repercussions.

Diammonium Glycyrrhizinate Ameliorates Obesity Through Modulation of Gut Microbiota-Conjugated BAs-FXR Signaling.

Obesity is a worldwide epidemic metabolic disease. Gut microbiota dysbiosis and bile acids (BAs) metabolism disorder are closely related to obesity. Farnesoid X-activated receptor (FXR), served as a link between gut microbiota and BAs, is involved in maintaining metabolic homeostasis and regulating glucose and lipid metabolism. We previously reported that diammonium glycyrrhizinate (DG) could alter gut microbiota and prevent non-alcoholic fatty liver disease. However, it remains ambiguous how DG affects the gut microbiota to regulate host metabolism. In this present study, 16S rRNA Illumina NovaSeq and metabolomic analysis revealed that DG treatment suppressed microbes associated with bile-salt hydrolase (BSH) activity, which, in turn, increased the levels of taurine-conjugated BAs accompanied by inhibition of ileal FXR-FGF15 signaling. As a result, several obesity-related metabolism were improved, like lower serum glucose and insulin levels, increased insulin sensitivity, few hepatic steatosis and resistance to weight gain. Additionally, decreased level of serum lipopolysaccharide was observed, which contributed to a strengthened intestinal barrier. The effect of DG on weight loss was slightly enhanced in the antibiotics-treated obese mice. Collectively, the efficacy of DG in the treatment of obesity might depend on gut microbiota-conjugated BAs-FXR axis. Hence, it will provide a potential novel approach for the treatment of obesity.

Dexamethasone Administration in Mice Leads to Less Body Weight Gain over Time, Lower Serum Glucose, and Higher Insulin Levels Independently of NRF2.

Glucocorticoids are used widely on a long-term basis in autoimmune and inflammatory diseases. Their adverse effects include the development of hyperglycemia and osteoporosis, whose molecular mechanisms have been only partially studied in preclinical models. Both these glucocorticoid-induced pathologies have been shown to be mediated at least in part by oxidative stress. The transcription factor nuclear erythroid factor 2-like 2 (NRF2) is a central regulator of antioxidant and cytoprotective responses. Thus, we hypothesized that NRF2 may play a role in glucocorticoid-induced metabolic disease and osteoporosis. To this end, WT and Nrf2 knockout (Nrf2KO) mice of both genders were treated with 2 mg/kg dexamethasone or vehicle 3 times per week for 13 weeks. Dexamethasone treatment led to less weight gain during the treatment period without affecting food consumption, as well as to lower glucose levels and high insulin levels compared to vehicle-treated mice. Dexamethasone also reduced cortical bone volume and density. All these effects of dexamethasone were similar between male and female mice, as well as between WT and Nrf2KO mice. Hepatic NRF2 signaling and gluconeogenic gene expression were not affected by dexamethasone. A 2-day dexamethasone treatment was also sufficient to increase insulin levels without affecting body weight and glucose levels. Hence, dexamethasone induces hyperinsulinemia, which potentially leads to decreased glucose levels, as well as osteoporosis, both independently of NRF2.

Fibroblast Growth Factor 21 (FGF21) Administration Sex-Specifically Affects Blood Insulin Levels and Liver Steatosis in Obese Ay Mice.

FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the Ay mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese Ay males and females. Ay mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of Fgf21 and Ucp1 in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of Cpt1 and Irs1 only in males. Thus, FGF21’s beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.

In vivo metabolic effects after acute activation of skeletal muscle Gs signaling

ObjectiveThe goal of this study was to determine the glucometabolic effects of acute activation of Gs signaling in skeletal muscle (SKM) in vivo and its contribution to whole-body glucose homeostasis. MethodsTo address this question, we studied mice that express a Gs-coupled designer G protein-coupled receptor (Gs-DREADD or GsD) selectively in skeletal muscle. We also identified two Gs-coupled GPCRs that are endogenously expressed by SKM at relatively high levels (β2-adrenergic receptor and CRF2 receptor) and studied the acute metabolic effects of activating these receptors in vivo by highly selective agonists (clenbuterol and urocortin 2 (UCN2), respectively). ResultsAcute stimulation of GsD signaling in SKM impaired glucose tolerance in lean and obese mice by decreasing glucose uptake selectively into SKM. The acute metabolic effects following agonist activation of β2-adrenergic and, potentially, CRF2 receptors appear primarily mediated by altered insulin release. Clenbuterol injection improved glucose tolerance by increasing insulin secretion in lean mice. In SKM, clenbuterol stimulated glycogen breakdown. UCN2 injection resulted in decreased glucose tolerance associated with lower plasma insulin levels. The acute metabolic effects of UCN2 were not mediated by SKM Gs signaling. ConclusionsSelective activation of Gs signaling in SKM causes an acute increase in blood glucose levels. However, acute in vivo stimulation of endogenous Gs-coupled receptors enriched in SKM has only a limited impact on whole-body glucose homeostasis, most likely due to the fact that these receptors are also expressed by pancreatic islets where they modulate insulin release.

The association between physical activity and brain integrity is partly mediated by cardiovascular mechanisms

AbstractBackgroundPhysical activity (PA) has been associated with decreased risk of dementia, but the mechanisms underlying this association remain to be determined. One hypothesis is that PA might reduce cardiovascular risk factors (CVRFs), which in turn would benefit brain health. Our objective was to assess the role of CVRFs in the association between PA and neuroimaging markers of brain integrity.MethodBaseline data of 134 cognitively unimpaired older adults (mean age: 69) from the Age‐Well cohort were analyzed. They underwent a PA questionnaire, CVRFs collection (systolic blood pressure, body mass index [BMI], current smoker status, HDL‐cholesterol, total cholesterol, and insulin), and multimodal neuroimaging (structural and diffusion MRI, FDG‐ ]and Florbetapir‐PET). A global measure of brain integrity was obtained for each neuroimaging modality by extracting the averaged signal across the whole gray matter (GM), or white matter for diffusion. Correlations were first conducted to assess the association between PA, CVRFs, and each neuroimaging modality. Multiple regression and mediation analyses were then performed to test whether the associations found between PA and neuroimaging were mediated by CVRFs.ResultHigher PA was associated with higher global GM volume and FDG metabolism, but not with amyloid deposition or white matter integrity. Higher PA was also associated with lower insulin levels and BMI, but not with the other CVRFs. Lower insulin and BMI were related to higher GM volume, but not to FDG metabolism. Adjusting for insulin and BMI (separately), the association between PA and FDG metabolism remained unchanged while the association with GM volume did not. When adding insulin and BMI in the same model, BMI was the only significant predictor of GM volume. This was confirmed by a mediation analysis.ConclusionPA is specifically associated with greater brain volume and FDG metabolism in older adults. While the association between PA and FDG metabolism appears to be independent from CVRFs, the link with GM volume is mediated by changes in BMI and insulin, with BMI driving the effects. Our results suggest that maintenance of a healthy BMI through PA could help preventing disturbed insulin metabolism usually observed in aging, thus promoting brain health.