Glucose Homeostasis Markers Research Articles

Coagonist of GLP-1 and Glucagon Receptor Ameliorates Development of Non-Alcoholic Fatty Liver Disease.

Obesity, diabetes and dyslipidemica are the key pathogenic stimulus that enhances progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Coagonist of Glucagon Like- Peptide-1 (GLP-1) Receptor (GLP-1R) and Glucagon Receptor (GCGR) are being evaluated for obesity and diabetes. GLP-1 analogs have shown to reverse diabetes and obesity. Glucagon treatment reduces lipids after acute and chronic treatment. In this study, we have investigated the effect of co-agonist on the prevention of NAFLD induced by long-term feeding of High Fat Diet (HFD). We have used HFD to induce NAFLD after chronic feeding in mice. Co-agonist treatment (150 µg.kg-1, s.c.) was initiated with induction of HFD, which was continued for 40 weeks. Body weight, food intake, glucose homeostasis, lipid profile, inflammatory and fibrotic markers were assessed at the end of treatment. Co-agonist treatment prevented body weight gain, glucose intolerance and insulin resistance. Treatment with co-agonist reduced NEFA, increased FGF21 and adiponectin levels. Co-agonist increased glycerol release and energy expenditure, while decreased respiratory quotient. Co-agonist reduced lipids in circulation and liver. Expression of SREBP-1C, SCD-1, ACC and FAS were decreased, while ACOX1 and CPT1 were increased after co-agonist treatment. Inflammatory cytokine TNF-α and IL-6 in plasma and expression of MCP-1, TGF-ß, MMP-9, TNF-α, TIMP-1, α-SMA, and COL1A1 were decreased after co-agonist treatment. Plasma transaminases, hepatic TBARS, hepatic hydroxyproline and relative liver weight were suppressed after co-agonist treatment. Fat accumulation, inflammation and fibrosis were reduced in histological assessment of liver in co-agonist treated animals. Co-agonist prevented development of HFD-induced NAFLD by ameliorating obesity, diabetes, inflammation and fibrosis.

Different effects of fenofibrate on cardiometabolic risk factors in young women with and without hyperprolactinemia.

Elevated prolactin levels are associated with increased cardiometabolic risk. No previous study has compared the effect of hypolipidemic therapy on plasma levels of lipids and other cardiometabolic risk factors in patients with and without hyperprolactinemia. The study included three age-, weight-, blood pressure- and lipid-matched groups of premenopausal women: 18 women with untreated hyperprolactinemia, 19 women with bromocriptine-treated hyperprolactinemia and 20 drug-naïve women with normal prolactin levels. Because of concomitant atherogenic dyslipidemia, all patients were treated with fenofibrate (200 mg daily) for 12 weeks. Plasma lipids, glucose homeostasis markers, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine and fibrinogen were assessed at baseline and at the end of hypolipidemic treatment. Unlike similar baseline lipid levels, plasma concentrations of the remaining investigated cardiometabolic risk factors were higher in women with elevated prolactin levels than in patients with normal prolactin levels. The impact of fenofibrate on total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels, as well as on uric acid, hsCRP, homocysteine, and fibrinogen was less pronounced in women with untreated hyperprolactinemia than in women with bromocriptine-treated hyperprolactinemia and drug-naïve women with normal prolactin levels. The results of our study indicate that cardiometabolic effects of fenofibrate depend on plasma prolactin levels.

Effect of Vitamin D Treatment on Glucose Homeostasis and Metabolism in Lebanese Older Adults: A Randomized Controlled Trial.

A low serum 25-hydroxyvitamin D [(25(OH) D)] concentration was shown to correlate with higher fasting blood glucose (FBG) and insulin levels. Since age affect insulin sensitivity and the metabolism, we aimed in this randomized controlled trial to investigate the effect of vitamin D supplementation on glucose homeostasis and index of insulin resistance in elderly subjects living in Beirut, Lebanon. Participants (n= 115) deficient in vitamin D were randomly divided into two groups, a group receiving 30,000 IU cholecalciferol/week for a period of 6 months, and a placebo group. The index of insulin resistance HOMA (homeostasis model assessment) was the primary outcome. Glucose homeostasis and metabolic markers were also measured at start of treatment and at 6 months. Vitamin D supplementation led to significant improvements in blood levels of [25(OH) D] (P< 0.0001), and a significant decreased of HOMA, PTH and FBG concentrations (P< 0.0001) in the intervention group compared to placebo. No significant changes were observed in HbA1c levels for both groups. Total cholesterol and LDL cholesterol concentrations have also decreased significantly in the intervention group (P< 0.0001). Short-term supplementation with cholecalciferol improved vitamin D status, and markers of insulin resistance in healthy elder population. This trial was registered at ClinicalTrials.gov; Identifier number#:NCT03478475.

Supplementation of Lactobacillus plantarum Improves Markers of Metabolic Dysfunction Induced by a High Fat Diet.

Obesity is a prevalent chronic condition in many developed and developing nations that raises the risk for developing heart disease, stroke, and diabetes. Previous studies have shown that consuming particular probiotic strains of Lactobacillus is associated with improvement in the obese and diabetic phenotype; however, the mechanisms of these beneficial effects are not well understood. In this study, C57BL/6J male mice were fed a lard-based high fat diet for 15 weeks with Lactobacillus plantarum supplementation NCIMB8826 (Lp) between weeks 10 and 15 ( n = 10 per group). Systemic metabolic effects of supplementation were analyzed by NMR metabolomics, protein expression assays, gene transcript quantification, and 16S rRNA marker gene sequencing. Body and organ weights were not significantly different with Lp supplementation, and no microbiota community structure changes were observed in the cecum; however, L. plantarum numbers were increased in the treatment group according to culture-based and 16S rRNA gene quantification. Significant differences in metabolite and protein concentrations (serum, liver, and colon), gene expression (ileum and adipose), and cytokines (colon) were observed between groups with increases in the gene expression of tight junction proteins in the ileum and cecum and improvement of some markers of glucose homeostasis in blood and tissue with Lp supplementation. These results indicate Lp supplementation impacts systemic metabolism and immune signaling before phenotypic changes and without large-scale changes to the microbiome. This study supports the notion that Lp is a beneficial probiotic, even in the context of a high fat diet.

Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function.

HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts <350 cells/μL, PI:C ratios were lower than in HIV- controls (p<0.01), suggesting a reduction in intrinsic beta cell stress among this group. By contrast, HIV+ participants on ART had higher fasting glucose (p<0.0001) and lower HOMA%B (p<0.001) compared to HIV- controls. Among the entire HIV+ population, higher HIV RNA correlated with lower fasting glucose (r = -0.57, p<0.001), higher HOMA%B (r = 0.40, p = 0.001), and lower PI:C ratios (r = -0.42, p<0.001), whereas higher CD4 counts correlated with higher PI:C ratios (r = 0.2, p = 0.00499). Our results suggest that HIV seropositivity in the absence of ART does not worsen beta cell function or glucose homeostasis, but immune reconstitution with ART may be associated with worsened beta cell function.

The Effect of Metformin on Serum Gonadotropin Levels in Postmenopausal Women with Diabetes and Prediabetes: A Pilot Study.

Metformin was found to decrease serum levels of prolactin and thyrotropin. The aim of this study was to investigate the effect of this drug on hypothalamic-pituitary-ovarian axis activity in postmenopausal women with recently diagnosed and untreated glucose metabolism abnormalities. The study included three matched groups of postmenopausal women: patients with type 2 diabetes (group A, n=16), women with prediabetes (group B, n=14), and individuals with normal glucose metabolism (group C, n=14). Women with diabetes were then treated with high-dose metformin (3 g daily), while women with prediabetes received moderate doses of this agent (1.7 g daily). Glucose homeostasis markers, as well as serum levels of FSH, LH, thyrotropin, prolactin, estradiol and creatinine were measured at baseline and after 16 weeks of metformin treatment. In both groups of metformin-treated women, the drug improved glucose homeostasis. High-dose metformin treatment reduced circulating levels of FSH and tended to reduce serum levels of LH, and these effects correlated with an improvement in insulin sensitivity. No changes in gonadotropin levels were observed in prediabetic women receiving moderate doses of metformin. Serum levels of thyrotropin, prolactin and estradiol, as well as the estimated glomerular filtration rate remained at a similar level throughout the study. Our study shows that the effect of metformin on hypothalamic-pituitary-ovarian axis activity in postmenopausal women depends on its dose and the magnitude of insulin resistance.

Specific synbiotics in early life protect against diet-induced obesity in adult mice.

AimsThe metabolic state of human adults is associated with their gut microbiome. The symbiosis between host and microbiome is initiated at birth, and early life microbiome perturbation can disturb health throughout life. Here, we determined how beneficial microbiome interventions in early life affect metabolic health in adulthood.MethodsPostnatal diets were supplemented with either prebiotics (scGOS/lcFOS) or synbiotics (scGOS/lcFOS with Bifidobacterium breve M‐16 V) until post‐natal (PN) day 42 in a well‐established rodent model for nutritional programming. Mice were subsequently challenged with a high‐fat Western‐style diet (WSD) for 8 weeks. Body weight and composition were monitored, as was gut microbiota composition at PN21, 42 and 98. Markers of glucose homeostasis, lipid metabolism and host transcriptomics of 6 target tissues were determined in adulthood (PN98).ResultsEarly life synbiotics protected mice against WSD‐induced excessive fat accumulation throughout life, replicable in 2 independent European animal facilities. Adult insulin sensitivity and dyslipidaemia were improved and most pronounced changes in gene expression were observed in the ileum. We observed subtle changes in faecal microbiota composition, both in early life and in adulthood, including increased abundance of Bifidobacterium. Microbiota transplantation using samples collected from synbiotics‐supplemented adolescent mice at PN42 to age‐matched germ‐free recipients did not transfer the beneficial phenotype, indicating that synbiotics‐modified microbiota at PN42 is not sufficient to transfer long‐lasting protection of metabolic health status.ConclusionTogether, these findings show the potential and importance of timing of synbiotic interventions in early life during crucial microbiota development as a preventive measure to lower the risk of obesity and improve metabolic health throughout life.

Effect of fibrates on glycemic parameters: A systematic review and meta-analysis of randomized placebo-controlled trials

AimsThe aim of this meta-analysis of randomized placebo-controlled clinical trials was to assess the effect of fibrates on glycemic parameters. Materials and methodsOnly randomized placebo-controlled trials investigating the impact of fibrate treatment on glucose homeostasis markers were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (from inception to April 11, 2017). A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters. ResultsThis meta-analysis of data from 22 randomized placebo-controlled clinical trials involving a total of 11,402 subjects showed that fibrate therapy significantly decreased fasting plasma glucose (WMD: −0.28 mmol/L, 95% CI: −0.42, −0.14, p < 0.001), insulin levels (WMD: −3.87 pmol/L, 95% CI: −4.97, −2.78, p < 0.001) and insulin resistance (HOMA-IR, WMD: −1.09, 95% CI: −1.71, −0.47, p = 0.001), but with no effect on HbA1c (WMD: 0.01%, 95% CI: −0.18, 0.19, p = 0.955). All analyses were robust in the leave-one-out sensitivity analysis except for insulin levels that showed a non-significant result (WMD: −0.84 pmol/L, 95% CI: −6.36, 4.68, p = 0.766) following omission of one of the included trials. ConclusionThis meta-analysis has shown that fibrate treatment significantly decreases fasting plasma glucose, insulin levels, and HOMA-IR indicating additional clinical therapeutic benefits.

Effect of Metformin on Hypothalamic-Pituitary-Thyroid Axis Activity in Elderly Antipsychotic-Treated Women With Type 2 Diabetes and Subclinical Hypothyroidism: A Preliminary Study.

Metformin was found to reduce elevated serum thyrotropin levels, and this effect was partially determined by endogenous dopaminergic tone. The aim of this study was to compare the effect of metformin treatment on hypothalamic-pituitary-thyroid axis activity in elderly women with subclinical hypothyroidism treated with antipsychotic agents and not receiving this drug. The study population consisted of 34 elderly women with subclinical hypothyroidism, 16 of whom received antipsychotic drugs. Because of coexistent type 2 diabetes, these women were treated with metformin (2.55-3 g daily). Glucose homeostasis markers as well as serum levels of thyrotropin, free thyroid hormones and prolactin were measured at the beginning of the study and 6 months later. Thirty women completed the study. With the exception of prolactin, baseline serum levels of the assessed hormones were comparable in both study groups. Although metformin reduced serum thyrotropin levels in both groups, this effect was more pronounced in the antipsychotic-treated than in the antipsychotic-naive patients. The effect on serum prolactin was observed only in antipsychotic-treated patients. The impact on serum thyrotropin levels correlated with improvement in insulin sensitivity and with a reduction in prolactin levels. Free thyroxine and free triiodothyronine remained at a similar level throughout the study. The obtained results indicate that metformin reduces serum thyrotropin levels in elderly women, and this effect is particularly pronounced in women with diminished dopaminergic transmission.

The Adiponectin Paradox for All-Cause and Cardiovascular Mortality.

Basic science studies have shown beneficial effects of adiponectin on glucose homeostasis, chronic low-grade inflammation, apoptosis, oxidative stress, and atherosclerotic processes, so this molecule usually has been considered a salutary adipokine. It was therefore quite unexpected that large prospective human studies suggested that adiponectin is simply a marker of glucose homeostasis, with no direct favorable effect on the risk of type 2 diabetes and cardiovascular disease. But even more unforeseen were data addressing the role of adiponectin on the risk of death. In fact, a positive, rather than the expected negative, relationship was reported between adiponectin and mortality rate across many clinical conditions, comprising diabetes. The biology underlying this paradox is unknown. Several explanations have been proposed, including adiponectin resistance and the confounding role of natriuretic peptides. In addition, preliminary genetic evidence speaks in favor of a direct role of adiponectin in increasing the risk of death. However, none of these hypotheses are based on robust data, so further efforts are needed to unravel the elusive role of adiponectin on cardiometabolic health and, most important, its paradoxical association with mortality rate.

Biomarkers of Colorectal Cancer Risk Decrease 6\xa0months After Roux-en-Y Gastric Bypass Surgery

PurposeThe impact of weight loss on obesity-related colorectal cancer (CRC) risk is not well defined. Previous studies have suggested that Roux-en-Y gastric bypass (RYGB) surgery may have an unexpected adverse impact on CRC risk. This study aimed to investigate the impact of RYGB on biomarkers of CRC risk.Materials and methodsRectal mucosal biopsies and blood were obtained from patients undergoing RYGB (n = 22) and non-obese control participants (n = 20) at baseline and at a median of 6.5 months after surgery. Markers of systemic inflammation and glucose homeostasis were measured. Expression of pro-inflammatory genes and proto-oncogenes in the rectal mucosa was quantified using qPCR. Crypt cell proliferation state of the rectal mucosa was assessed by counting mitotic figures in whole micro-dissected crypts.ResultsAt 6.5 months post-surgery, participants had lost 29 kg body mass and showed improvements in markers of glucose homeostasis and in systemic inflammation. Expression of pro-inflammatory genes in the rectal mucosa did not increase and COX-1 expression fell significantly (P = 0.019). The mean number of mitoses per crypt decreased from 6.5 to 4.3 (P = 0.028) after RYGB.ConclusionRYGB in obese adults led to lower rectal crypt cell proliferation, reduced systemic and mucosal markers of inflammation and improvements in glucose regulation. These consistent findings of reduced markers of tumourigenic potential suggest that surgically induced weight loss may lower CRC risk.

Imidacloprid Promotes High Fat Diet-Induced Adiposity in Female C57BL/6J Mice and Enhances Adipogenesis in 3T3-L1 Adipocytes via the AMPKα-Mediated Pathway.

Imidacloprid, a neonicotinoid insecticide, was previously reported to enhance adipogenesis and resulted in insulin resistance in cell culture models. It was also reported to promote high fat diet-induced obesity and insulin resistance in male C57BL/6J mice. Thus, the goal of the present study was to determine the effects of imidacloprid and dietary fat interaction on the development of adiposity and insulin resistance in female C57BL/6J mice. Mice were fed with a low (4% w/w) or high fat (20% w/w) diet containing imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) for 12 weeks. Mice fed with imidacloprid (0.6 mg/kg bw/day) significantly enhanced high fat diet-induced weight gain and adiposity. Treatment with imidacloprid significantly increased serum insulin levels with high fat diet without effects on other markers of glucose homeostasis. AMPKα activation was significantly inhibited by 0.6 and 6 mg imidacloprid/kg bw/day in white adipose tissue. Moreover, AMPKα activation with 5-aminoimidazole-4-carboxamide ribonucleotide abolished the effects of imidacloprid (10 μM) on enhanced adipogenesis in 3T3-L1 adipocytes. N-Acetyl cysteine also partially reversed the effects of imidacloprid on reduced phosphorylation of protein kinase B (AKT) in C2C12 myotubes. These results indicate that imidacloprid may potentiate high fat diet-induced adiposity in female C57BL/6J mice and enhance adipogenesis in 3T3-L1 adipocytes via the AMPKα-mediated pathway. Imidacloprid might also influence glucose homeostasis partially by inducing cellular oxidative stress in C2C12 myotubes.

Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution

ObjectiveDietary protein dilution (PD) has been associated with metabolic advantages such as improved glucose homeostasis and increased energy expenditure. This phenotype involves liver-induced release of FGF21 in response to amino acid insufficiency; however, it has remained unclear whether dietary dilution of specific amino acids (AAs) is also required. Circulating branched chain amino acids (BCAAs) are sensitive to protein intake, elevated in the serum of obese humans and mice and thought to promote insulin resistance. We tested whether replenishment of dietary BCAAs to an AA-diluted (AAD) diet is sufficient to reverse the glucoregulatory benefits of dietary PD. MethodsWe conducted AA profiling of serum from healthy humans and lean and high fat-fed or New Zealand obese (NZO) mice following dietary PD. We fed wildtype and NZO mice one of three amino acid defined diets: control, total AAD, or the same diet with complete levels of BCAAs (AAD + BCAA). We quantified serum AAs and characterized mice in terms of metabolic efficiency, body composition, glucose homeostasis, serum FGF21, and tissue markers of the integrated stress response (ISR) and mTORC1 signaling. ResultsSerum BCAAs, while elevated in serum from hyperphagic NZO, were consistently reduced by dietary PD in humans and murine models. Repletion of dietary BCAAs modestly attenuated insulin sensitivity and metabolic efficiency in wildtype mice but did not restore hyperglycemia in NZO mice. While hepatic markers of the ISR such as P-eIF2α and FGF21 were unabated by dietary BCAA repletion, hepatic and peripheral mTORC1 signaling were fully or partially restored, independent of changes in circulating glucose or insulin. ConclusionsRepletion of BCAAs in dietary PD is sufficient to oppose changes in somatic mTORC1 signaling but does not reverse the hepatic ISR nor induce insulin resistance in type 2 diabetes during dietary PD.

Dissociation of body mass index, excess weight loss and body fat percentage trajectories after 3 years of gastric bypass: relationship with metabolic outcomes

Body weight, body mass index (BMI) and excess weight loss (EWL) are the most frequently used measures to analyse bariatric surgery outcomes. However, these measurements do not provide accurate information on body composition (BC) with body fat (BF), importantly determining the levels of cardiometabolic risk factors. Our aim was to analyse the evolution of BC after Roux-en-Y Gastric Bypass (RYGB) and its influence on the changes of cardiometabolic risk factors in comparison to BMI and EWL. A group of 81 obese Caucasian patients (19 males/62 females) aged 44.9±1.3 years undergoing RYGB between January 2006 and December 2011 was prospectively followed up for a period of 3 years. BC was determined by air-displacement plethysmography. Visceral adiposity, physical activity and cardiometabolic risk factors were measured. BF was markedly (P<0.001) reduced after the first year, increasing progressively during the second and third years after RYGB, following a different trajectory than body weight, BMI and EWL that decreased up to the second year post surgery. Markers of glucose homeostasis decreased during the first month and continued to decrease during the first year (P<0.05), remaining stabilised or slightly increased between the second and third years following RYGB. However, markers of lipid metabolism decreased (P<0.05) markedly during the first 12 months, increasing thereafter in parallel to the changes observed in BC, with the exception of high-density lipoprotein-cholesterol, which increased progressively throughout the whole period analysed. The adverse switch in the changes in BC between the first and the second years after RYGB may underlie the changes observed in cardiometabolic risk factors. Tracking of adiposity during the follow-up of bariatric/metabolic surgery yields clinically relevant information to better identify patients in need of increased lifestyle advice or treatment intensification.

Circulating osteocalcin is unrelated to glucose homoeostasis in adults with type 1 diabetes

AimsTo assess the relationship between total osteocalcin (tOC), undercarboxylated osteocalcin (ucOC) and a range of markers of glucose homeostasis in type 1 diabetes. MethodsOne hundred and eight community-based Caucasian adults (53 males, 55 females) without a history of osteoporosis and with a mean±SD age 39.1±15.1years and median [inter-quartile range] type 1 diabetes duration of 14.3 [6.6–20.4] years participated in a cross-sectional study of bone health. Fasting serum glucose and HbA1c, and serum tOC, ucOC, total adiponectin and procollagen type 1N-terminal propeptide (P1NP) were measured using validated assays, and daily insulin dose and estimated glucose disposal rate (eGDR) were calculated. Multiple linear regression was used to determine independent associates of markers of glucose homoeostasis (HbA1c, fasting serum glucose, daily insulin dose, eGDR and serum total adiponectin). ResultsIn sex-adjusted multivariable regression analyses, ln(serum P1NP) was independently and inversely associated with ln(HbA1c) and ln(serum adiponectin) (P≤0.013). Other associations included those between ln(serum vitamin D) and ln(HbA1c) (inversely), daily insulin dose (inversely) and eGDR (positively) (P≤0.035), as well as an inverse relationship between overweight by waist circumference and ln(serum adiponectin) (P<0.001). Ln(serum tOC) and ln(serum ucOC) were not independently associated with any glucose homoeostasis marker. ConclusionsThese data from well characterized community-based adults with type 1 diabetes do not suggest that there is a role for osteocalcin in the potentially complex interplay between the skeleton and energy homoeostasis in type 1 diabetes.

Alternative Treatment Strategies in Women Poorly Tolerating Moderate Doses of Bromocriptine.

Background: Metformin as well as dopaminergic agents exert a beneficial effect on glucose and lipid metabolism, often impaired in patients with hyperprolactinemia. Objective: The aim of this study was to compare metabolic- and prolactin-lowering effects of low-dose bromocriptine/metformin combination therapy and cabergoline in patients with elevated prolactin levels. Methods: The study included 27 women with hyperprolactinemia and impaired glucose tolerance who were treated with moderate doses of bromocriptine but experienced adverse effects of this treatment. In 12 of these patients bromocriptine was replaced with cabergoline (group A), while the remaining ones continued treatment with bromocriptine, the dose of which was halved, and administered together with metformin (group B). Plasma lipids, glucose homeostasis markers, as well as serum levels of prolactin, thyrotropin and insulin-like growth factor-1 (IGF-1) were assessed before and after 4 months of metformin treatment. Results: Both groups did not differ in baseline levels of plasma glucose and lipids, in insulin sensitivity, as well as in circulating levels of all measured hormones. All patients from group A and 12 patients from group B completed the study. Cabergoline reduced prolactin levels, while no effect on plasma prolactin was found in group B. Neither cabergoline nor bromocriptine plus metformin affected circulating levels of thyrotropin and IGF-1. Both treatment options, particularly low-dose bromocriptine plus metformin, improved glucose and lipid homeostasis. Conclusions: Low-dose bromocriptine combined with metformin may be an interesting alternative to cabergoline in patients with mild hyperprolactinemia and early glucose metabolism abnormalities, in whom moderate doses of bromocriptine are poorly tolerated.

The Exercise-Induced Irisin Is Associated with Improved Levels of Glucose Homeostasis Markers in Pregnant Women Participating in 8-Week Prenatal Group Fitness Program: A Pilot Study.

Background Both exercise and pregnancy influence serum irisin concentration. Aim To determine how the interaction of pregnancy and exercise affects irisin level and whether various patterns of exercise adherence had different effect on irisin concentration. Methods It was a one-group pretest-posttest study among 9 Caucasian nulliparous healthy women in normal pregnancy (age 23 ± 3 years, 21 ± 2 weeks of gestation; mean ± SD) who participated in 8-week group fitness program. Before and after exercise intervention, we determined serum concentrations of irisin and selected parameters of lipid profile and glucose homeostasis markers. Results In active women, irisin slightly decreased with the development of pregnancy. After 8 weeks of exercising, irisin correlated negatively with fasting glucose (R = −0.922; p = 0.001), glycated hemoglobin (R = −0.784; p = 0.012), and insulin concentrations (R = −0.845; p = 0.004). In women exercising below recommended level, we observed a significant drop in irisin concentration, whereas in women exercising at least three times a week this myokine slightly increased (31% difference; 90% confidence limits ±28; a large, clear effect). Conclusions Irisin stimulated by prenatal exercise may improve glucose homeostasis markers in healthy women and compensate for metabolic changes induced by pregnancy. Moreover, the frequency of exercise may regulate the changes in exercise-induced irisin concentration.

Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes.

Numerous studies suggest that rapamycin treatment promotes insulin resistance, implying that rapamycin could have negative effects on patients with, or at risk for, type 2 diabetes (T2D). New evidence, however, indicates that rapamycin treatment produces some benefits to energy metabolism, even in the context of T2D. Here, we survey 5 mouse models of T2D (KK, KK-Ay, NONcNZO10, BKS-db/db, TALLYHO) to quantify effects of rapamycin on well-recognized markers of glucose homeostasis within a wide range of T2D environments. Interestingly, dietary rapamycin treatment did not exacerbate impaired glucose or insulin tolerance, or elevate circulating lipids as T2D progressed. In fact, rapamycin increased insulin sensitivity and reduced weight gain in 3 models, and decreased hyperinsulinemia in 2 models. A key covariate of this genetically-based, differential response was pancreatic insulin content (PIC): Models with low PIC exhibited more beneficial effects than models with high PIC. However, a minimal PIC threshold may exist, below which hypoinsulinemic hyperglycemia develops, as it did in TALLYHO. Our results, along with other studies, indicate that beneficial or detrimental metabolic effects of rapamycin treatment, in a diabetic or pre-diabetic context, are driven by the interaction of rapamycin with the individual model's pancreatic physiology.

Ethnic Differences in Glucose Homeostasis Markers between the Kyushu-Okinawa Population Study and the Framingham Offspring Study.

We compared markers of glucose homeostasis and their association with diabetes and impaired fasting glucose (IFG) in Fukuoka, Japanese subjects (n = 1108) and age-, gender- and menopausal status-matched participants in the Framingham Offspring Study (n = 1096). The markers examined included fasting glucose, insulin, adiponectin, and glycated albumin, as well as body mass index (BMI), use of medications, and history of diabetes. The results showed that IFG prevalence in Japanese men (15.9%) and women (7.4%) were 50% less than those observed in Framingham men (34.5%) and women (21.4%) (P < 0.001). However, the diabetes prevalence in Japanese men at 13.3% was twice as high (P < 0.01) as the rate in Framingham men at 6.5%, while these rates were similar in women. Median insulin levels in Japanese men (4.6 μIU/mL) and women (4.3 μIU/mL) were about 50% lower (P < 0.001) than those in Framingham men (10.8 μIU/mL) and women (9.9 μIU/mL), as were insulin resistance values (P < 0.001). These population differences were also observed after subjects were stratified by glucose levels. In conclusion, our data indicate that there is significantly less IFG, lower insulin levels, and insulin resistance, but higher diabetes prevalence in Fukuoka men than in Framingham men, indicating that insulin deficiency may be an important cause of diabetes in Japan.

Effects of Periconception Cadmium and Mercury Co-Administration to Mice on Indices of Chronic Diseases in Male Offspring at Maturity.

Background:Long-term exposure to the heavy metals cadmium (Cd) and mercury (Hg) is known to increase the risk of chronic diseases. However, to our knowledge, exposure to Cd and Hg beginning at the periconception period has not been studied to date.Objective:We examined the effect of Cd and Hg that were co-administered during early development on indices of chronic diseases in adult male mice.Methods:Adult female CD1 mice were subcutaneously administered a combination of cadmium chloride (CdCl2) and methylmercury (II) chloride (CH3HgCl) (0, 0.125, 0.5, or 2.0 mg/kg body weight each) 4 days before and 4 days after conception (8 days total). Indices of anxiety-like behavior, glucose homeostasis, endocrine and molecular markers of insulin resistance, and organ weights were examined in adult male offspring.Results:Increased anxiety-like behavior, impaired glucose homeostasis, and higher body weight and abdominal adipose tissue weight were observed in male offspring of treated females compared with controls. Significantly increased serum leptin and insulin concentrations and impaired insulin tolerance in the male offspring of dams treated with 2.0 mg/kg body weight of Cd and Hg suggested insulin resistance. Altered mRNA abundance for genes associated with glucose and lipid homeostasis (GLUT4, IRS1, FASN, ACACA, FATP2, CD36, and G6PC) in liver and abdominal adipose tissues as well as increased IRS1 phosphorylation in liver (Ser 307) provided further evidence of insulin resistance.Conclusions:Results suggest that the co-administration of Cd and Hg to female mice during the early development of their offspring (the periconception period) was associated with anxiety-like behavior, altered glucose metabolism, and insulin resistance in male offspring at adulthood.Citation:Camsari C, Folger JK, McGee D, Bursian SJ, Wang H, Knott JG, Smith GW. 2017. Effects of periconception cadmium and mercury co-administration to mice on indices of chronic diseases in male offspring at maturity. Environ Health Perspect 125:643–650; http://dx.doi.org/10.1289/EHP481