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Abstract Mesopelagic species are unexplored novel low‐trophic sources of essential micronutrients and may contribute to combat malnutrition. In this study, common mesopelagic species from the North Sea including Northern krill (Meganyctiphanes norvegica), glacier lanternfish (Benthosema glaciale), and Muller's pearlside (Maurolicus muelleri) were supplemented in mice feed using a Western diet recipe. The metabolic outcomes were subsequently compared to those of ordinary seafood. Consumption of mesopelagic species induced a large variation in weight gain, in the following order: lanternfish (7.1 g) > krill (14.4 g) > control (19.7 g) > pearlside (22.6 g). The lanternfish‐supplemented diet containing wax esters reduced weight gain and obesity and improved insulin sensitivity. The wax esters from the lanternfish‐supplemented diet were efficiently absorbed, with more than 92% of the fatty alcohols being assimilated. The inclusion of lanternfish and pearlside led to improvements in the fatty acid (FA) composition in the mouse liver, evidenced by increased levels of essential long‐chain polyunsaturated FAs and an increased n‐3/n‐6 ratio (0.7 to 1.45 vs. 0.46 in control group). Notably, no adverse effects were found in mice fed pearlside and lanternfish, although an elevated level of fluoride in femur bone was observed in mice fed a diet supplemented with krill followed by reduced sperm concentration and sperm motility. Collectively, our findings underscore the diverse array of metabolic and physiological effects induced by the consumption of mesopelagic species. Furthermore, these species can be considered as good sources of n‐3 FAs and essential vitamins, suggesting their potential value to human nutrition.

In order to detemine the anti-diabetic effect and potential mechanism of a novel soluble epoxide hydrolas inhibitor (A34) on diabetic mice. Type 1 diabetes mellitus (T1DM) mice were induced by streptozotocin (50 mg/(kg·d) for 5 days, ip.)and the hypoglycemic effect of A34 were evaluated by water and food intake, non-fasting and fasting blood glucose, glucose tolerance and plasma insulin level in diabetic mice after water administration.The underlying mechanism was explored via measuring the expression level of sEH in islets, the morphological change of islets and the concerntration of cytokines INF-γ and IL-4 in plasma. Compared with diabetic model group, the water and food intake(p＜0.01, p＜0.05), blood glucose (p＜0.01), glucose tolerance (p＜0.01) and plasma insulin level (p＜0.05 ) were improved in A34 group. Additionally, A34 could protect pancreatic islet morphology, suppress sEH expression in islet (p＜0.01), reduce the ratio of INF-γ to IL-4 in plasma(p＜0.05 ). These results showed that A34 prevents hyperglycemia and β-cell dysfunction through regulating the dynamic balance of pro-inflammatory and anti-inflammatory cytokines in diabetic mice.

Abstract Background To investigate the association between serum branched chain amino acids (BCAAs), mammalian target of rapamycin (mTOR) levels and the risk of gestational diabetes mellitus (GDM) in pregnant women. Methods 1:1 matched case–control study was conducted including 66 GDM patients and 66 matched healthy pregnant women (± 3 years) in 2019, in China. Fasting bloods of pregnant women were collected in pregnancy at 24 ~ 28 weeks gestation. And the serum levels of valine (Val), leucine (Leu), isoleucine (Ile) and mTOR were determined. Conditional logistic regressions models were used to estimate the associations of BCAAs and mTOR concentrations with the risk of GDM. Results Concentrations of serum Val and mTOR in cases were significantly higher than that in controls (P

Abstract Background The glucose transporter 2 (GLUT2) is constitutively expressed in pancreatic beta cells and hepatocytes of mice. It is the most important receptor in glucose-stimulated insulin release and hepatic glucose transport. The Sema4D is a signalin receptor on cell membranes. The correlation between Sema4D and GLUT2 has not been reported previously. We investigated whether knockdown of Sema4D could exert a hypoglycemic effect based on the increased GLUT2 expression in Sema4D -/- mice hepatocytes. Methods The glucose tolerance test and insulin tolerance test in sema4D -/- and sema4D +/+ mice were compared before and after streptozotocin (STZ) injection; the expression of GLUT2 content on the membrane surface of both groups was verified by Western blot. Then, the levels of insulin and C-peptide in the serum of the two groups of mice after STZ injection were measured by ELISA; the differentially expressed mRNAs in the liver of the two groups of mice were analyzed by transcriptomic analysis; then the differences in the expression of GLUT2, glycogen, insulin and glucagon in the two groups of mice were compared by tissue section staining. Finally, metabolomics analysis was performed to analyze the metabolites differentially expressed in the two groups of mice. Key findings First, Sema4D -/- male mice exhibited significantly greater glucose tolerance than wild-type mice in a hyperglycemic environment. Secondly, Sema4D -/- mice had more retained GLUT2 in liver membranes after STZ injection according to an immunofluorescence assay. After STZ injection, Sema4D -/- male mice did not exhibit fasting hyperinsulinemia like wild-type mice. Finally, analysis of metabolomic and immunohistochemical data also revealed that Sema4D -/- mice produce hypoglycemic effects by enhancing the pentose phosphate pathway, but not glycogen synthesis. Conclusions Thus, Sema4D may play an important role in the regulation of glucose homeostasis by affecting GLUT2 synthesis.

Abstract Method Twenty inactive males (BMI 27.67 ± 0.88 kg/m2, age 49.15 ± 2.58 years) participated in an eight-week were randomly assigned to one of three intervention groups (combined (CT), resistance (RT), and aerobic (AT)) exercise modalities to assess within-subject and between group changes in glycolipid profile. Data were analyzed using repeated measures ANCOVA. Result Pre-post mean values of body fat percentage (%BF), area under the curve (AUC), low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol (TC) decreased in all three groups. The main effect of exercise modality on the AUC (F (2, 26) = 10.577, P = 0.001, η2 = 0.569) was significant. Post-hoc analyses revealed that the RT group (-30.653 ± 6.766, p = 0.001) with 11.53% and the CT group (M = -0.896, SE = 3.347, P = 0.015) with 3.79% exhibited significantly greater reductions in AUC compared to the AT group. LDL levels showed significant different between groups (F (2, 26) = 6.33, p = 0.009, η2 = 0.442), specially significantly 3.7% lowered in AT (MD = 4.783, SE = 1.563, P = 0.002) and 3.79% lower in CT (MD = 4.57, SE = 1.284, P = 0.008) groups compared to the RT group. AT significantly reduced TC by 17.716 ± 5.705 mg/dL (p = 0.02) compared to RT, representing a 7.97% decrease. Conclusion Exercise type significantly influences lipid profiles and glycemic control. Notably, both aerobic and combined training demonstrated a superior ability to modulate the lipid profile, and resistance training and combined training were more effective in reducing the AUC. Trial registration May, 31st 2024. Registration no: PACTR202405463745521 “Retrospectively registered”.

Abstract Aim Pancreatic reconstruction after pancreaticoduodenectomy (PD) that leaves a small remnant pancreas is often difficult. Pancreatic fistula is a major complication after PD, and fistulas are rare in patients with hard pancreas. However, the clinical impact of non‐reconstructed small remnant after PD with hard pancreas is unknown. Methods We included all patients who underwent PD for pancreatic tumor without pancreatic reconstruction in two institutions supervised by one surgeon between January 2004 and March 2021. Their short‐ or long‐term outcome after surgery was retrospectively analyzed. Results PD was performed in 774 patients, of whom 16 patients were without reconstruction (2.1%) with negative margins at the pancreatic stump. Pancreatic transection was performed above or to the left of the superior mesenteric artery, with a median remnant pancreas length of 3.7 cm (range, 1.3–10.0). A major complication (≥ Clavien–Dindo Grade IIIa) occurred in one patient (6%). Fistula of grade B occurred in one patient (6%). After a median follow‐up of 44 months (95%CI, 10.6–77.3), insulin administration was unnecessary in 11 patients. Conclusion The preservation of a small pancreatic remnant without reconstruction after PD can be performed safely and may enable the keeping of pancreatic endocrine function for some selected patients with hard pancreas.

Abstract Background Cardiovascular disease is a leading cause of death worldwide. Rates of cardiovascular disease vary both across the lifespan and between sexes. While multiple factors, including adverse life experiences, impact the development and progression of cardiovascular disease, the potential interactions of biological sex and stress history on the aged heart are unknown. To this end, we examined sex- and stress-specific impacts on left ventricular hypertrophy (VH) after aging. We hypothesized that early-life chronic stress exposure impacts behavioral and physiologic responses that predict cardiac remodeling in a sex-specific manner. Methods Histological analysis was conducted on hearts of male and female rats previously exposed to chronic variable stress during the late adolescent period (postnatal days 43–62). These animals were challenged with a forced swim test and a glucose tolerance test before aging to 15 months and again being challenged. Predictive analyses were then used to isolate factors that relate to cardiac remodeling among these groups. Results Early-life chronic stress impacted cardiac remodeling in a sex-specific manner. Among rats with a history of chronic stress, females had increased concentric VH. However, there were few associations within the female groups among individual behavioral and physiologic parameters and cardiac remodeling. While males as a group did not have VH after chronic stress, they exhibited multiple individual associations with cardiac susceptibility. Passive coping in young males and active coping in aged males related to VH in a stress history-dependent manner. Moreover, baseline corticosterone positively correlated with VH in unstressed males, while chronically-stressed males had positive correlations between VH and visceral adiposity. Conclusions These results indicate that females as a group are uniquely susceptible to the effects of early-life stress on cardiac remodeling later in life. Conversely, males have more individual differences in vulnerability, where susceptibility to cardiac remodeling relates to endocrine, metabolic, and behavioral measures depending on stress history. These results ultimately support a framework for assessing cardiovascular risk based on biological sex and prior adverse experiences.

Patients with gain-of-function mutations of Dyrk1b have higher fasting blood glucose (FBG) levels. However, the role of Dyrk1b in glucose metabolism is not fully elucidated. Herein, we found that hepatic Dyrk1b overexpression in mice impaired systemic glucose tolerance and hepatic insulin signaling. Dyrk1b overexpression in vitro attenuated insulin signaling in a kinase activity-dependent manner, and its kinase activity was required for its effect on systemic glucose homeostasis and hepatic insulin signaling in vivo. Dyrk1b ablation improved systemic glucose tolerance and hepatic insulin signaling in mice. Quantitative proteomic analyses showed that Dyrk1b downregulated WW domain-binding protein 2 (Wbp2) protein abundance. Mechanistically, Dyrk1b enhanced Wbp2 ubiquitylation and proteasomal degradation. Restoration of hepatic Wbp2 partially rescued the impaired glucose homeostasis in Dyrk1b overexpression mice. In addition, Dyrk1b inhibition with AZ191 moderately improved systemic glucose homeostasis. Our study uncovers that hepatic Dyrk1b impairs systemic glucose homeostasis via its modulation of Wbp2 expression in a kinase activity-dependent manner.

Excess accumulation of visceral fat induces insulin resistance in skeletal muscle and impairs glucose tolerance. Although weight loss improves glucose tolerance by reducing visceral fat mass, the effects of the speed of weight loss on glucose metabolism are unclear. This study compared the effects of long-term energy restriction–induced weight loss and short-term fasting–induced weight loss on glucose tolerance in rats fed a high-fat diet. After 2 weeks of high-fat diet feeding, male Wistar rats were subjected to either 30% calorie restriction for 2 weeks (CR) or 3-day fasting (FAST). After the intervention period, body weight and intra-abdominal fat mass decreased to a similar extent in both weight-loss groups. The maximum insulin-stimulated glucose uptake and GLUT-4 content in the epitrochlearis muscle were significantly higher in the FAST group than in both control rats fed ad libitum (CON) and the CR group, with no significant differences between the CON and CR groups. Blood glucose levels during the oral glucose tolerance test (OGTT) were similar in the CON and CR groups, but insulin levels were significantly lower in the CR group than in the CON group, indicating improved insulin resistance in the CR group. However, compared to the CON and CR groups, plasma glucose and insulin levels were significantly higher and lower, respectively, in the FAST group during the OGTT. These findings suggest that rapid weight loss through short-term fasting, in contrast to long-term energy restriction, may impair glucose tolerance by reducing insulin secretion capacity.

This study aims to determine the antidiabetic activity of n-hexane and ethanol extracts of Nypa fruticans leaf sheaths. The ethanol extract, with the most active antidiabetic properties from the n-hexane extract, was characterized using GC-MS. The total phenol, total flavonoid, and antioxidant properties were determined, and then the ethanol extract was fractionated. An antidiabetic activity test was carried out using the glucose tolerance method in male Swiss Webster mice. The results showed that subfraction A (the effect of fractionation of ethanol extract) was the most capable of reducing blood sugar levels, namely 247.67 mg/dL in 30 min (the activity is 98.67% compared to glibenclamide). The ethanol extract can reduce blood glucose levels by 203.34 mg/dL at 30 min (81.01% compared to glibenclamide). The results of total phenolic and total flavonoid content tests for the ethanol extract were obtained at 18.0349 mg gallic acid equivalents/g and 2.8309 mg quercetin equivalents/g, respectively. On the other hand, the IC50 antioxidant activity of the extract is 417.4399 ppm. Characterization using GC-MS on the extract showed that the dominant phytoconstituent in the extract is 4-methoxy-6-(2-propenyl)-1,3-benzodioxole, with a composition of 63.45%.

Background: Antenatal iron deficiency and anaemia are associated with gestational hypertension and diabetes mellitus, but so are elevated iron stores and haemoglobin. In South Africa, pregnant women receive routine iron supplementation regardless of iron status. Aim: This study aimed to assess associations of antenatal iron status and anaemia with blood pressure in pregnant women in urban South Africa. Secondary to this, associations with heart rate, fasting glucose and glucose tolerance were also investigated. Setting: Johannesburg, South Africa. Methods: A total of 250 pregnant women, aged 27 (24–32) years, were recruited using consecutive sampling. The authors measured biomarkers of iron status and anaemia at 18 and ± 22 weeks’, blood pressure and heart rate at ± 36 weeks’, and fasting glucose and glucose tolerance between 24 and 28 weeks’ gestation. Associations were determined using multivariable regression models adjusted for confounders. Results: The odds of prehypertension in late pregnancy among women with anaemia at ± 22 weeks’ gestation were three times higher than among women without anaemia (odds ratio [OR]: 3.01, 95% confidence interval [CI]: 1.22, 7.42). Participants with anaemia at ± 22 weeks’ gestation had 2.15 times higher odds of having elevated mean arterial pressure than women without anaemia (OR: 2.15, 95% CI: 1.01, 4.60). Conclusion: Anaemia at mid-pregnancy could be a predictor of hypertensive disorders in pregnancy. The cause of antenatal anaemia may need further investigation apart from iron deficiency. The effective management of anaemia in pregnant women living in urban South Africa remains a challenge. Contribution: This study provides evidence about the health impact of pregnant women regarding antenatal supplementation practices in South Africa.

Objectives: To analyze the impact of exercise under hypoxic exposure versus normoxic exposure on blood glucose level, insulin level, and insulin sensitivity in people at risk of Type 2 diabetes mellitus (T2DM). Materials and Methods: We systematically performed electronic searching on PubMed, Web of Science, ProQuest, and Scopus. Primary studies that met the inclusion criteria were analyzed using Revman 5.4.1. Results: Nine randomized controlled trials were included in this meta-analysis. We found that physical exercise under hypoxic exposure had no significant effect on improving blood glucose levels, insulin levels, and insulin sensitivity in the elderly and sedentary people compared to normoxic condition. However, physical exercise during hypoxic exposure had a significant effect on lowering blood glucose levels in overweight/obese individuals (pooled Standardized Mean Difference = 0.29; 95% confidence interval = 0.01–0.57; P = 0.04). Conclusions: Exercising under hypoxic exposure can be an alternative strategy for reducing blood glucose levels in overweight/obese people. Nevertheless, in other populations at risk of T2DM, exercising in hypoxic conditions gives similar results to normoxic conditions.

Epidemiological studies have shown that abnormalities of glucose metabolism are involved in leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). However, the physiological significance of this association is unclear. In the present study, we investigated the effect of LRRK2 on high‐fat diet (HFD)‐induced glucose intolerance using Lrrk2‐knockout (KO) mice. We found for the first time that HFD‐fed KO mice display improved glucose tolerance compared with their wild‐type (WT) counterparts. In addition, high serum insulin and leptin, as well as low serum adiponectin resulting from HFD in WT mice were improved in KO mice. Using western blotting, we found that Lrrk2 is highly expressed in adipose tissues compared with other insulin‐related tissues that are thought to be important in glucose tolerance, including skeletal muscle, liver, and pancreas. Lrrk2 expression and phosphorylation of its kinase substrates Rab8a and Rab10 were significantly elevated after HFD treatment in WT mice. In cell culture experiments, treatment with a LRRK2 kinase inhibitor stimulated insulin‐dependent membrane translocation of glucose transporter 4 (Glut4) and glucose uptake in mouse 3T3‐L1 adipocytes. We conclude that increased LRRK2 kinase activity in adipose tissue exacerbates glucose tolerance by suppressing Rab8‐ and Rab10‐mediated GLUT4 membrane translocation.

Suboptimal nutrition is a leading cause of cardiometabolic disease and mortality. Biological sex is a variable that influences individual responses to dietary components and may modulate the impact of diet on metabolic health and disease risk. This review describes findings of studies reporting how biological sex may associate with or affect metabolic outcomes or disease risk in response to varying dietary macronutrient content, Mediterranean diet, Western diet, and medical very low-calorie diet. Although few dietary interventions have been specifically designed to identify sex–diet interactions, future studies improving understanding how sex influences dietary responses could inform precision nutrition interventions for disease prevention and management.

The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.

Background. The enzymatic cofactor coenzyme Q10 (CoQ10) is involved in the synthesis of adenosine triphosphate in mitochondria. The CoQ10 biosynthesis declines when using statin drugs.Objective: systematization of the impact of coenzyme Q10 on chronic, sluggish systemic inflammation leading to the development of atherosclerosis, liver and pancreas pathologies, and neurodegeneration.Material and methods. Systematic computer analysis of 16,788 publications on CoQ10 found by the query “coenzyme Q10 OR ubiquinone” in PubMed/MEDLINE database of biomedical publications was carried out. Current methods of topological and metric data analysis developed at the scientific school of Academician of the Russian Academy of Sciences Yu.I. Zhuravlev were used.Results. CoQ10 is involved in the regulation of inflammation and exhibits lipid-lowering, hepatoprotective, nephroprotective, anti-asthenic, cardioprotective, and neuroprotective effects. CoQ10 favorably affects carbohydrate metabolism and a wide range of neurological diseases.Conclusion. CoQ10 supplementation improves glycemic control in insulin resistance, kidney function, and is useful in the treatment of migraine and neurodegenerative pathologies (Parkinson’s disease, etc.).

Background This study investigated the risk of cause-specific mortality according to glucose tolerance status in elderly South Koreans. Methods A total of 1,292,264 individuals aged ≥65 years who received health examinations in 2009 were identified from the National Health Information Database. Participants were classified as normal glucose tolerance, impaired fasting glucose, newly-diagnosed diabetes, early diabetes (oral hypoglycemic agents ≤2), or advanced diabetes (oral hypoglycemic agents ≥3 or insulin). The risk of system-specific and disease-specific deaths was estimated using multivariate Cox proportional hazards analysis. Results During a median follow-up of 8.41 years, 257,356 deaths were recorded. Diabetes was associated with significantly higher risk of all-cause mortality (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.57 to 1.60); death due to circulatory (HR, 1.49; 95% CI, 1.46 to 1.52), respiratory (HR, 1.51; 95% CI, 1.47 to 1.55), and genitourinary systems (HR, 2.22; 95% CI, 2.10 to 2.35); and neoplasms (HR, 1.30; 95% CI, 1.28 to 1.32). Diabetes was also associated with a significantly higher risk of death due to ischemic heart disease (HR, 1.70; 95% CI, 1.63 to 1.76), cerebrovascular disease (HR, 1.46; 95% CI, 1.41 to 1.50), pneumonia (HR, 1.69; 95% CI, 1.63 to 1.76), and acute or chronic kidney disease (HR, 2.23; 95% CI, 2.09 to 2.38). There was a stepwise increase in the risk of death across the glucose spectrum (P for trend

With aging populations in many countries, including Japan, efforts to mitigate the aging-related decline in physical function have gained importance not only for improving individual quality of life but also for mitigating the effects of this loss of function on society. Impaired glucose tolerance, muscle weakness, and cognitive decline are well-known effects of aging. These interrelated factors can create a vicious cycle because impaired glucose tolerance can accelerate muscle weakness and cognitive decline. Unmodulated 40 Hz (u40Hz) stimulation is imperceptible to the human ear and has been reported to improve cognitive function in humans and mice. However, research on the effects of u40Hz stimulation is still limited. This study aimed to report the effects of u40Hz stimulation on glucose tolerance and muscle strength in senescence-accelerated prone (SAMP)-10 mice, a model of accelerated aging. SAMP-10 mice underwent five weeks of u40Hz stimulation followed by glucose-tolerance tests, cognitive and behavioral assessments, and frailty evaluations. In comparison with the control group, the u40Hz-stimulation group showed mitigation of age-related decline in glucose tolerance, a better frailty index (FI), and notably preserved muscle strength. Microarray analysis of stimulated muscle tissue revealed significant upregulation of β-oxidation genes and genes functioning downstream of peroxisome proliferator-activated receptor gamma, and significant downregulation of clock genes. These findings indicate the beneficial effects of u40Hz stimulation on glucose tolerance, muscle strength, and cognitive function, warranting further research in this area.

Intermittent fasting has drawn significant interest in the clinical research community due to its potential to address metabolic complications such as obesity and type 2 diabetes mellitus. Various intermittent fasting regimens include alternate-day fasting (24 h of fasting followed by 24 h of eating), time-restricted fasting (fasting for 14 h and eating within a 10 h window), and the 5:2 diet (fasting for two days and eating normally for the other five days). Intermittent fasting is associated with a reduced risk of type 2 diabetes mellitus-related complications and can slow their progression. The increasing global prevalence of type 2 diabetes mellitus highlights the importance of early management. Since prediabetes is a precursor to type 2 diabetes mellitus, understanding its progression is essential. However, the long-term effects of intermittent fasting on prediabetes are not yet well understood. Therefore, this review aims to comprehensively compile existing knowledge on the therapeutic effects of intermittent fasting in managing type 2 diabetes mellitus and prediabetes.

The impaired function of the serotonin transporter (SERT) in humans has been linked to a higher risk of obesity and type 2 diabetes, especially as people age. Consuming a “Western diet” (WD), which is high in saturated fats, cholesterol, and sugars, can induce metabolic syndrome. Previous research indicated that mice carrying a targeted inactivation of the Sert gene (knockout, KO) and fed a WD display significant metabolic disturbances and behaviors reminiscent of ADHD. These abnormalities might be mediated via a dysfunction in insulin receptor (IR) signaling, which is also associated with adult ADHD. However, the impact of Sert deficiency on IR signaling and systemic metabolic changes has not been thoroughly explored. In this study, we conducted a detailed analysis of locomotor behavior in wild-type (WT) and KO mice fed a WD or control diet. We investigated changes in the blood metabolome and examined, via PCR, the expression of insulin receptor A and B isoforms and key regulators of their function in the brain. Twelve-month-old KO mice and their WT littermates were fed a WD for three weeks. Nuclear magnetic resonance spectroscopy analysis of plasma samples showed that KO mice on a WD had higher levels of lipids and lipoproteins and lower levels of glucose, lactate, alanine, valine, and isoleucine compared to other groups. SERT-KO mice on the control diet exhibited increased brain levels of both IR A and B isoforms, accompanied by a modest increase in the negative regulator ENPP. The KO mice also displayed anxiety-like behavior and reduced exploratory activity in an open field test. However, when the KO animals were fed a WD, the aberrant expression levels of IR isoforms in the KO mice and locomotor behavior were ameliorated indicating a complex interaction between genetic and dietary factors that might contribute to ADHD-like symptoms. Overall, our findings suggest that the lack of Sert leads to a unique metabolic phenotype in aged mice, characterized by dysregulated IR-related pathways. These changes are exacerbated by WD in the blood metabolome and are associated with behavioral abnormalities.

Background: Alkaloid- and polyphenol-rich white mulberry leaf and apple peel extracts have been shown to have potential glucose-lowering effects, benefitting the control of postprandial blood glucose levels. This study aimed to determine the effect of the combination of Malus domestica peel and Morus alba leaf extracts (GLUBLOCTM) on postprandial blood glucose and insulin-lowering effects in healthy adults after a carbohydrate-rich meal or sucrose drink intake. Methods: This study was designed as a randomized, crossover, single-blinded clinical trial. Out of 116 healthy participants, 85 subjects (aged 18–60 years) completed the day 1 and 5 crossover study. On day 1, subjects were supplemented with a placebo or GLUBLOCTM tablet 10 min before the carbohydrate-rich meal (300 g of tomato rice) or sucrose drink intake (75 g of sucrose dissolved in 300 mL water). On day 5, the treatments were crossed over, and the same diet was followed. Postprandial blood glucose and insulin levels were measured on days 1 and 5 (baseline 0, post-meal 30, 60, 90, and 120 min). Differences in iAUC, Cmax, and Tmax were determined between the placebo and GLUBLOCTM-treated cohorts. Results: Significant changes in total iAUC (0–120 min), Cmax, and Tmax of postprandial blood glucose and insulin levels were noticed upon GLUBLOCTM supplementation. The percentage reduction in the iAUC of blood glucose levels was 49.78% (iAUC0–60min) and 43.36% (iAUC0–120min), respectively, compared with the placebo in the sucrose drink intake study. Similarly, there was a 41.13% (iAUC0–60min) and 20.26% (iAUC0–120min) glucose-lowering effect compared with the placebo in the carbohydrate-rich meal intake study. Conclusions: Premeal supplementation with GLUBLOCTM significantly reduced the postprandial surge in blood glucose and insulin levels after a carbohydrate-rich meal or sucrose drink intake over 120 min in healthy individuals. This study proves that GLUBLOCTM can manage steady postprandial blood glucose levels.

To identify body systems subject to epigenetic transformation during in vitro fertilization (IVF), comparative morphological and functional studies were performed on sexually mature offspring of outbred CD1 mice, specific-pathogen-free (SPF), obtained by IVF (experiment) and natural conception (control). The studies included assessment of age-related changes in body weight and composition, energy intake and expenditure, and glucose homeostasis. To level the effects caused by the different number of newborns in the control and in the experiment, the size of the fed litters was halved in the control females. Males obtained using the IVF procedure were superior in body weight compared to control males in all age groups. As was shown by analysis of variance with experiment/control factors, gender, age (7, 10 and 20 weeks), the IVF procedure had a statistically significant and unidirectional effect on body composition. At the same time, IVF offspring outperformed control individuals in relative fat content, but were behind in terms of lean mass. The effect of the interaction of factors was not statistically significant. IVF offspring of both sexes had higher fat to lean mass ratios (FLR). Since adipose tissue contributes significantly less to total energy intake compared to muscle, the main component of lean mass, it is not surprising that at the same level of IVF locomotor activity offspring consumed less food than controls. When converted to one gram of body weight, this difference reached 19 %. One of the consequences of reduced utilization of IVF energy substrates by offspring is a decrease in their tolerance to glucose loading. The integral criterion for the effectiveness of restoring the initial glucose level is the area under the curve (AUC), the value of which was 2.5 (males) and 3.2 (females) times higher in IVF offspring compared to the corresponding control. Thus, the totality of our original and literature data shows an increase in the risk of metabolic disorders in IVF offspring, which is confirmed by epidemiological studies of a relatively young cohort of people born using assisted reproductive technologies.

Abstract Background Biological aging is an important factor leading to the development of pathologies associated with metabolic dysregulation, including type 2 diabetes, cancer, cardiovascular and neurodegenerative diseases. Telomere length, a central feature of aging, has additionally been identified as inversely associated with glucose tolerance and the development of type 2 diabetes. However, the effects of shortened telomeres on body weight and metabolism remain incompletely understood. Here, we studied the metabolic consequences of moderate telomere shortening using second generation loss of telomerase activity in mice. Results Aged male and female G2 Terc-/- mice and controls were characterized with respect to body weight and composition, glucose homeostasis, insulin sensitivity and metabolic activity. This was complemented with molecular and histological analysis of adipose tissue, liver and the intestine as well as microbiota analysis. We show that moderate telomere shortening leads to improved insulin sensitivity and glucose tolerance in aged male and female G2 Terc-/- mice. This is accompanied by reduced fat and lean mass in both sexes. Mechanistically, the metabolic improvement results from reduced dietary lipid uptake in the intestine, characterized by reduced gene expression of fatty acid transporters in enterocytes of the small intestine. Furthermore, G2-Terc-/- mice showed significant alterations in the composition of gut microbiota, potentially contributing to the improved glucose metabolism. Conclusions Our study shows that moderate telomere shortening reduces intestinal lipid absorption, resulting in reduced adiposity and improved glucose metabolism in aged mice. These findings will guide future murine and human aging studies and provide important insights into the age associated development of type 2 diabetes and metabolic syndrome.

The glucose metabolism of poultry draws wide attention as they have nearly twice the fasting blood glucose than that of mammals. To define the relationship between glucose metabolism and breed of chicken, the outcomes from different growth rate chickens showed that Arbor Acres (AA) broilers, a well-known fast-growing breed, had a lower fasting blood glucose concentration and glucose clearance rate when compared to Silky chickens, a Chinese traditional medicinal chicken with black skin and a slow growth rate. Moreover, AA broilers had a relatively slow rise in blood glucose in response to oral glucose solution than the Silky chickens on 21 and 42 d (P

A 12-wk trial was conducted to compare the tolerance of tilapia to high carbohydrate and high lipid diets. Three isonitrogenous and isoenergetic diets, whose carbohydrate and lipid levels were the following: 35.0% and 8% (control), 44.2% and 4% (D1, high carbohydrate), and 25.8% and 12% (D2, high lipid), respectively. Three hundred tilapias (27 ± 0.11 g) were fed the diets for 10 wk (4 replicates per group); 72 fish from the D1 group were continually fed the D1 (D1D1) and 72 fish from the D2 were continually fed the D2 (D2D2) diet for 2 wk (3 replicates each group) to evaluate the tilapia's capacity to tolerate high carbohydrate and high lipid diets, respectively. Another 36 fish from D1 group were continually fed D2 (D1D2) for comparison with D1D1 and D2D2 groups. In phase 1, hepatosomatic index, liver triglycerides (TG), glucose tolerance (GT) and crude protein in the whole body in D1 group were higher than those in D2 group (P

This study investigated the effects of galactose-depleted xyloglucan derived from tamarind seed gum (GXG-TG) on glucose and lipid metabolism in diet-induced obese mice by comparison with intact xyloglucan (TG). Twenty-four male C57BL/6J mice were fed a high-fat diet containing 3 g/100 g of either GXG-TG or TG for 12 weeks. Reduction of postprandial glucose rise was observed in the TG group compared to the control, whereas the GXG-TG group showed intermediate values. Serum cholesterol levels and hepatic mRNA expression of HMG-CoA reductase were significantly lower in the GXG-TG and TG groups compared to the control, while there was no increase in cecal short chain fatty acids in the GXG-TG or TG group. These results indicated that GXG-TG was converted to insoluble dietary fiber and maintained the serum cholesterol-lowering effect, although the blood glucose level-lowering effect was attenuated. TG, although moderately viscous, improved glucose tolerance and lipid metabolism in diet-induced obesity model mice.

Objective: G-protein-coupled receptor (GPCR) kinases (GRKs) abrogate GPCR signaling by promoting receptor desensitization and internalization. Accumulating evidence suggests that GRK2 represents an important regulator of GPCR-mediated effects on systemic glucose metabolism, obesity, and insulin resistance. Despite the key role of the liver in maintaining euglycemia, the potential metabolic relevance of hepatic GRK2 has yet to be examined. Thus, the goal of this study was to explore the potential role of hepatic GRK2 in maintaining glucose homeostasis and other key metabolic functions. Methods: To address this question, we generated mice that showed a ∼90% reduction in GRK2 protein expression selectively in hepatocytes (Hep-GRK2-KO mice) and subjected these mice, together with their control littermates, to systematic metabolic phenotyping studies. Results: We found that Hep-GRK2-KO mice maintained on regular chow did not differ significantly from their control littermates in glycemia, glucose tolerance, insulin sensitivity, in vivo gluconeogenesis, and glucagon-induced hyperglycemia. We obtained similar findings when we analyzed Hep-GRK2-KO mice and control littermates consuming an obesogenic high-fat diet. Likewise, plasma levels of insulin, glucagon, free fatty acids, and ketone bodies remained unaffected by the lack of hepatocyte GRK2. The same was true when we examined the expression levels of key genes regulating hepatic glucose and fatty acid metabolism. Conclusion: In summary, our data suggest that hepatocyte GRK2 is dispensable for systemic glucose homeostasis and other key metabolic functions in both lean and obese mice. This finding suggests that drug development efforts aimed at inhibiting GRK2 to improve impaired glucose homeostasis and insulin sensitivity need to focus on other metabolically important tissues.

Introductionβ-Glucosidase serves as the pivotal rate-limiting enzyme in the cellulose degradation process, facilitating the hydrolysis of cellobiose and cellooligosaccharides into glucose. However, the widespread application of numerous β-glucosidases is hindered by their limited thermostability and low glucose tolerance, particularly in elevated-temperature and high-glucose environments.MethodsThis study presents an analysis of a β-glucosidase gene belonging to the GH1 family, denoted lqbg8, which was isolated from the metagenomic repository of Hehua hot spring located in Tengchong, China. Subsequently, the gene was cloned and heterologously expressed in Escherichia coli BL21(DE3). Post expression, the recombinant β-glucosidase (LQBG8) underwent purification through a Ni affinity chromatography column, thereby enabling the in-depth exploration of its enzymatic properties.ResultsLQBG8 had an optimal temperature of 70°C and an optimum pH of 5.6. LQBG8 retained 100 and 70% of its maximum activity after 2-h incubation periods at 65°C and 70°C, respectively. Moreover, even following exposure to pH ranges of 3.0–10.0 for 24 h, LQBG8 retained approximately 80% of its initial activity. Notably, the enzymatic prowess of LQBG8 remained substantial at glucose concentrations of up to 3 M, with a retention of over 60% relative activity. The kinetic parameters of LQBG8 were characterized using cellobiose as substrate, with Km and Vmax values of 28 ± 1.9 mg/mL and 55 ± 3.2 μmol/min/mg, respectively. Furthermore, the introduction of LQBG8 (at a concentration of 0.03 mg/mL) into a conventional cellulase reaction system led to an impressive 43.7% augmentation in glucose yield from corn stover over a 24-h period. Molecular dynamics simulations offered valuable insights into LQBG8’s thermophilic nature, attributing its robust stability to reduced fluctuations, conformational changes, and heightened structural rigidity in comparison to mesophilic β-glucosidases.DiscussionIn summation, its thermophilic, thermostable, and glucose-tolerant attributes, render LQBG8 ripe for potential applications across diverse domains encompassing food, feed, and the production of lignocellulosic ethanol.

ABSTRACTBrown adipocytes were proposed to reverse metabolic conditions such as obesity and diabetes, which make them potential for therapeutic applications. Brown adipocytes and browning process are capable of thermogenesis, the uncoupling metabolism which allows them to promote balanced energy expenditure, a fundamental mechanism for improving metabolic disorders. Thermogenesis process is not only performed by the thermogenin UCPs within the mitochondria, but instead, is globally regulated within brown and browning adipose tissues, which induces signalling molecules that can be sent to nearby and distant tissues to generate systemic effects on metabolism. This review highlights thermogenesis and describes the crosstalk between different organelles within browning and brown adipocytes, as well as their interorgan axes to regulate whole body metabolism. Finally, browning and thermogenesis activation will also be discussed in terms of physiological conditions, in which, we propose that thermogenesis and functional activities of brown adipocytes should be considered individually in future clinical application.

Abstract Background/Aim Recent research suggests that adenosine receptors (ARs) influence many of the metabolic abnormalities associated with diabetes. A non-xanthine benzylidene indanone derivative 2-(3,4-dihydroxybenzylidene)-4-methoxy-2,3-dihydro-1 H-inden-1-one (2-BI), has shown to exhibit higher affinity at A1/A2A ARs compared to caffeine. Due to its structural similarity to caffeine, and the established antidiabetic effects of caffeine, the current study was initiated to explore the possible antidiabetic effect of 2-BI. Methods The study was designed to assess the antidiabetic effects of several A1 and/or A2A AR antagonists, via intestinal glucose absorption and glucose-lowering effects in fructose-streptozotocin (STZ) induced diabetic rats. Six-week-old male Sprague-Dawley rats were induced with diabetes via fructose and streptozotocin. Rats were treated for 4 weeks with AR antagonists, metformin and pioglitazone, respectively. Non-fasting blood glucose (NFBG) was determined weekly and the oral glucose tolerance test (OGTT) was conducted at the end of the intervention period. Results Dual A1/A2A AR antagonists (caffeine and 2-BI) decreased glucose absorption in the intestinal membrane significantly (p

The metabolic syndrome (MetS), first introduced by Haller in 1975, was sometimes also known as insulin resistance syndrome, syndrome X, and plurimetabolic syndrome. In 1989, it was rechristened by Kaplan as the “Deadly Quartet” based on a consolidation of central obesity, impaired glucose tolerance, dyslipidemia, and systemic hypertension. MetS is positively associated with a pro-inflammatory and pro-thrombotic state, attributed to increased pro-thrombotic and inflammatory marker activity. Moreover, MetS is frequently associated with increased atherosclerotic cardiovascular disease, impaired glucose tolerance, hyperuricemia, obstructive sleep apnea, and chronic kidney disease. Despite concerted endeavors worldwide, the complexity of the pathophysiology of metabolic syndrome still needs to be clearly understood. Currently, therapeutic possibilities are confined to individual therapy for hyperglycemia, hypertension, hypertriglyceridemia, hyperuricemia, regular physical exercise, and a restricted diet. In this review, progress regarding the understanding and pathophysiology of MetS; recent emerging technologies, such as metabolomics and proteomics; the relation of MetS with obesity, diabetes, and cardiovascular diseases; and the association of MetS with COVID-19 are discussed.

This study evaluated the combination interactive effects of G. latifolium leaves and P. nitida seed extracts using a metabolic glucose tolerance test. The plant samples were extracted separately using cold maceration and their acute toxicities were determined. Dose-response glucose tolerant tests of both plants were done using a 2 g/kg glucose load monitored over 0 – 1h. A 41% effect isobologram was used to determine the needed dose combinations according to the principle of Loewe’s additivity model. The glucose tolerant tests of dose pairs of the combined extracts were evaluated and their combination indices were calculated to determine the nature of their interaction. The ED41 of G. latifolium (GL) and P. nitida (PN) were 180 mg/kg and 254 mg/kg respectively. The percentage reductions of GL:PN (50:160); GL:PN (100:90); and GL:PN (150:30) dose pairs were 48.23, 50.76 and 42.99 % respectively. Their combination index were calculated to be 0.91, 0.91 and 0.95 respectively - an indication of synergistic interaction. Findings from this study validate the combined use of G. latifolium leaves and P. nitida seeds in folkloric medicine. However, combining the extracts of G. latifolium: P. nitida in the dose ratios of 50:160, 100:90 and 150:30 mg/kg gave the best dose pairs with synergistic outcome.

Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether postnatal AE exacerbates metabolic deterioration resulting from prenatal AE. Choline is a semi-essential nutrient that has been demonstrated to mitigate the cognitive impairment of prenatal AE. This study investigated how maternal choline supplementation (CS) may modify the metabolic health of offspring with prenatal and postnatal AE (AE/AE). C57BL/6J female mice were fed either a Lieber–DeCarli diet with 1.4% ethanol between embryonic day (E) 9.5 and E17.5 or a control diet. Choline was supplemented with 4 × concentrations versus the control throughout pregnancy. At postnatal week 7, offspring mice were exposed to 1.4% ethanol for females and 3.9% ethanol for males for 4 weeks. AE/AE increased hepatic triglyceride accumulation in male offspring only, which was normalized by prenatal CS. Prenatal CS also improved glucose tolerance compared to AE/AE animals. AE/AE suppressed hepatic gene expression of peroxisome proliferator activated receptor alpha (Ppara) and low-density lipoprotein receptor (Ldlr), which regulate fatty acid catabolism and cholesterol reuptake, respectively, in male offspring. However, these changes were not rectified by prenatal CS. In conclusion, AE/AE led to an increased risk of steatosis and was partially prevented by prenatal CS in male mice.

ABSTRACT Disruption of blood glucose utilization may lead to diabetes mellitus, which has complex genetic and environmental aspects, and free fatty acid receptors (FFARs) may bridge the genetic and dietary aspects. FFAR4 has been identified as a new target for diabetes treatment, and it is essential to investigate how FFAR4 affects glucose homeostasis. FFAR4 knockout mice have been shown to cause severely impaired glucose tolerance under high-fat feeding conditions; however, the findings in FFAR4 knockout mice under chow diet conditions seem to be contradictory. Blood glucose utilization in mice under chow diet conditions is thought to show diurnal rhythmicity. In this study, we aim to investigate the role of FFAR4 in glucose utilization rhythm and explore the possible mechanism. Total Ffar4 and gut-specific Ffar4 knockout mice both showed a clear diurnal rhythm in glucose tolerance. However, deletion of total Ffar4 and gut-specific Ffar4 both deteriorate glucose tolerance at the daily light to dark transition (ZT12) in mice. We show that intestinal FFAR4 deficiency leads to significant changes in fecal microbiota at different ZTs. 16S rRNA sequencing results suggested that Akkermansia muciniphila was the main target of intestinal FFAR4 at ZT12. Akkermansia muciniphila supplementation significantly improved the impaired glucose tolerance at ZT12 in mice with gut-specific Ffar4 deletion and was accompanied by recovery of serum hormone level and transcripts of key genes in glucose metabolism. IMPORTANCE Alterations in the intestinal environment are associated with various diseases, and FFAR4 is abundantly enriched in the intestine, where it has been shown to have the ability to regulate intestinal hormone secretion and intestinal microbiota; here, we confirmed previous reports. Meanwhile, we found that intestinal FFAR4 regulates glucagon-like peptide 1 secretion by decreasing Akkermansia muciniphila abundance and show that such change is associated with the level of glucose utilization at ZT12 in mice. Intestinal FFAR4 deficiency leads to severely impaired glucose tolerance at the ZT12 moment in mice, and Akkermansia muciniphila supplementation ameliorates the abnormal glucose utilization at the ZT12 moment caused by FFAR4 deficiency, which is very similar to the dawn phenomenon in diabetic patients. Collectively, our data suggest that intestinal Ffar4 deteriorates glucose tolerance at the daily light to dark transition by affecting Akkermansia muciniphila.

ObjectivePoor diet quality contributes to metabolic dysfunction. This study aimed to gain a greater understanding of the relationship between dietary macronutrient quality and glucose homeostasis in adults with cystic fibrosis (CF).DesignThis was a cross-sectional study of N = 27 adults with CF with glucose tolerance ranging from normal (n = 9) to prediabetes (n = 6) to being classified as having cystic fibrosis-related diabetes (CFRD, n = 12). Fasted blood was collected for analysis of glucose, insulin, and C-peptide. Insulin resistance was assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA2-IR). Subjects without known CFRD also underwent a 2-h oral glucose tolerance test. Three-day food records were used to assess macronutrient sources. Dietary variables were adjusted for energy intake. Statistical analyses included ANOVA, Spearman correlations, and multiple linear regression.ResultsIndividuals with CFRD consumed less total fat and monounsaturated fatty acids (MUFA) compared to those with normal glucose tolerance (p

Abstract Background Muscle mitochondrial decline is associated with aging‐related muscle weakness and insulin resistance. FoxO transcription factors are targets of insulin action and deletion of FoxOs improves mitochondrial function in diabetes. However, disruptions in proteostasis and autophagy are hallmarks of aging and the effect of chronic inhibition of FoxOs in aged muscle is unknown. This study investigated the role of FoxOs in regulating muscle strength and mitochondrial function with age. Methods We measured muscle strength, cross‐sectional area, muscle fibre‐type, markers of protein synthesis/degradation, central nuclei, glucose/insulin tolerance, and mitochondrial bioenergetics in 4.5‐month (Young) and 22–24‐month‐old (Aged) muscle‐specific FoxO1/3/4 triple KO (TKO) and littermate control (Ctrl) mice. Results Lean mass was increased in Aged TKO compared with both Aged Ctrl and younger groups by 26–33% (P

Abstract Background Green algae contain many polysaccharides. However, there is no information on whether Chaetomorpha linum polysaccharides (CLP) can modulate lipid and glucose metabolism. Material and methods CLP were extracted from chlorella and their components were characterized. Male C57BL/6 mice were randomized and provided with control chow as the control, or high fat diet (HFD) to induce nonalcoholic fatty liver disease (NAFLD). NAFLD mice were treated orally with water as the HFD group or with 50 or 150 mg/kg CLP daily for 10 weeks. The impact of CLP treatment on lipid and glucose metabolism and the PPARα signaling was examined by histology, Western blotting and biochemistry. Results CLP mainly contained arabinogalactan sulfate. Compared with the control, HFD feeding increased body weights, lipid droplet liver deposition and induced hyperlipidemia, liver functional impairment and glucose intolerance in mice. Treatment with CLP, particularly with a higher dose of CLP, limited the HFD-increased body weights and liver lipid droplet deposition, mitigated the HFD-induced hyperlipidemia and improved liver function and glucose tolerance in mice. Mechanistically, feeding with HFD dramatically decreased the expression of liver PPARα, CPT-1, and MCAD, but treatment with CLP enhanced their expression in a trend of dose-dependent in mice. Conclusions These findings indicated that CLP treatment alleviated the gain in body weights, NAFLD, and glucose intolerance in mice after HFD feeding by enhancing the PPARα/CPT-1/MCAD signaling.

Objective: In order to improve the added value of eggplant peel, the best method of phenolic compounds from eggplant peel (EPP), as well as its hypoglycemic impact in vitro and in vivo were studied. Methods: EPP was extracted by ultrasonic-assisted method. The extraction parameters of EPP were optimized by single factor experiments and orthogonal experiment with yield as evaluation index. The inhibitory rate of EPP on α-glucosidase and its effects on body weight, fasting glucose, and glucose tolerance in mice were analyzed to evaluate its hypoglycemic efficacy in vitro and in vivo. Results: The optimal extraction conditions were as follows: Ultrasonic power 540 W, solid-liquid ratio 1:50 g/mL, extraction temperature 50 ℃ and extraction time 50 min. The extraction yield of EPP was 43.21%. The inhibitory rate on α-glucosidase increased with the increase of EPP concentration, and the inhibition rate of α-glucosidase was 45.46% with 1 mg/mL EPP. The body weight, fasting blood glucose and glucose tolerance of diabetic mice could be improved by EPP, and it had a significant hypoglycemic effect on diabetic mice. Conclusion: This study confirmed that EPP had hypoglycemic effect, which laid a theoretical foundation for comprehensive development and utilization of eggplant peel.

Abstract Background Central nervous system (CNS) control of metabolism plays a pivotal role in maintaining energy balance. In the brain, Glucagon-like peptide 1 (GLP-1), encoded by the proglucagon ‘Gcg’ gene, produced in a distinct population of neurons in the nucleus tractus solitarius (NTS), has been shown to regulate feeding behavior leading to the suppression of appetite. However, neuronal networks that mediate endogenous GLP-1 action in the CNS on feeding and energy balance are not well understood. Results We analyzed the distribution of GLP-1R-expressing neurons and axonal projections of NTS GLP-1-producing neurons in the mouse brain. GLP-1R neurons were found to be broadly distributed in the brain and specific forebrain regions, particularly the hypothalamus, including the arcuate nucleus of the hypothalamus (ARC), a brain region known to regulate energy homeostasis and feeding behavior, that receives dense NTSGcg neuronal projections. The impact of GLP-1 signaling in the ARC GLP-1R-expressing neurons and the impact of activation of ARC GLP-1R on food intake was examined. Application of GLP-1R specific agonist Exendin-4 (Exn-4) enhanced a proportion of the ARC GLP-1R-expressing neurons and pro-opiomelanocortin (POMC) neuronal action potential firing rates. Chemogenetic activation of the ARC GLP-1R neurons by using Cre-dependent hM3Dq AAV in the GLP-1R-ires-Cre mice, established that acute activation of the ARC GLP-1R neurons significantly suppressed food intake but did not have a strong impact on glucose homeostasis. Conclusions These results highlight the importance of central GLP-1 signaling in the ARC that express GLP-1R that upon activation, regulate feeding behavior.

Abstract Aims/Introduction Understanding morning–evening variation in metabolic state is critical for managing metabolic disorders. We aimed to characterize this variation from the viewpoints of insulin secretion and insulin sensitivity, including their relevance to the circadian rhythm. Materials and Methods A total of 14 and 10 people without diabetes were enrolled, and underwent a 75‐g oral glucose tolerance test (OGTT) and hyperinsulinemic‐euglycemic clamp study, respectively. Participants completed the OGTT or hyperinsulinemic‐euglycemic clamp at 08.00 hours and 20.00 hours in random order. Before each study, hair follicles were collected. In mice, phosphorylation levels of protein kinase B were examined in the liver and muscle by western blotting. Results Glucose tolerance was better at 08 .00 hours, which was explained by the higher 1‐h insulin secretion on OGTT and increased skeletal muscle insulin sensitivity on hyperinsulinemic‐euglycemic clamp. Hepatic insulin sensitivity, estimated by the hepatic insulin resistance index on OGTT, was better at 20.00 hours. The 1‐h insulin secretion and hepatic insulin resistance index correlated significantly with Per2 messenger ribonucleic acid expression. The change (evening value – morning value) in the glucose infusion rate correlated significantly with the change in non‐esterified fatty acid, but not with clock gene expressions. The change in non‐esterified fatty acid correlated significantly with E4bp4 messenger ribonucleic acid expression and the change in cortisol. In mice, phosphorylation of protein kinase B was decreased in the liver and increased in muscle in the beginning of the active period as, expected from the human study. Conclusions Glucose metabolism in each tissue differed between the morning and evening, partly reflecting lipid metabolism, clock genes and cortisol levels. Deeper knowledge of these associations might be useful for ameliorating metabolic disorders.

IntroductionThe prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. Strategies to decrease this risk should be strongly encouraged. Lactation has been associated, for the mother, with reduction in future T2DM risk in several studies. The mechanisms behind this phenomenon, however, are poorly understood. The aims of this study were, first, to compare blood glucose levels and markers of insulin resistance (MIR) in early postpartum women with overweight/obesity according to their breastfeeding status and, second, to evaluate whether prolactin (PRL) levels could mediate improvements in these parameters.MethodsThe prospective study followed 95 women older than 18 years from early pregnancy for up to 60 to 180 days postpartum. All participants had a BMI > 25 kg/m2 and a singleton pregnancy. At each visit, questionnaires and clinical and biochemical evaluations were performed. Participants were divided into two groups according to the breastfeeding status as “yes” for exclusive or predominant breastfeeding, and “no” for not breastfeeding.ResultsBreastfeeding women (n = 44) had significantly higher PRL levels [47.8 (29.6–88.2) vs. 20.0 (12.0–33.8), p< 0.001]. They also had significantly lower fasting blood glucose levels [89.0 (8.0) vs. 93.9 (12.6) mg/dl, p = 0.04], triglycerides (TG) [92.2 (37.9) vs. 122.4 (64.4) mg/dl, p = 0.01], TG/HDL ratio [1.8 (0.8) vs. 2.4 (1.6) mg/dl, p = 0.02], TyG index [8.24 (0.4) vs. 8.52 (0.53), p = 0.005], fasting serum insulin [8.9 (6.3–11.6) vs. 11.4 (7.7–17.0), p = 0.048], and HOMA-IR [2.0 (1.3–2.7) vs. 2.6 (1.6–3.9), p = 0.025] in the postpartum period compared to the non-breastfeeding group. Groups were homogeneous in relation to prevalence of GDM, pre-gestational BMI, as well as daily caloric intake, physical activity, and weight loss at postpartum. Linear regression analysis with adjustments for confounders showed a statistically significant association of breastfeeding with fasting blood glucose [−6.37 (−10.91 to −1.83), p = 0.006], HOMA-IR [−0.27 (−0.51 to −0.04), p = 0.024], TyG index [−0.04 (−0.06 to −0.02), p = 0.001], and TG/HDL ratio [−0.25 (−0.48 to −0.01), p = 0.038]. Mediation analysis showed that PRL did not mediate these effects. Sensitivity analyses considering different cutoffs for PRL levels also did not show modification effect in the mediation analyses.ConclusionBreastfeeding was associated with improvement in glucose metabolism and MIR 60 to 180 days after birth in overweight and obese women, even when adjusted for confounders. PRL levels were not found to mediate the association between breastfeeding and improvement in MIR.

AimsThe purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment.MethodsAdults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose

ABSTRACT Preptin is derived from the cleavage of the E‐peptide of pro‐insulin‐like growth factor (IGF)‐II and is an insulin secretagogue. Observational studies have linked elevated circulating preptin to metabolic dysfunction in humans; however, a causal role for preptin in metabolic dysfunction has not been established. Additionally, preptin can promote osteoblast proliferation and differentiation, suggesting a link with skeletal health. We previously described a global preptin knockout (KO) model. In this study, we sought to uncover the impact of preptin KO in mice on the response to a moderately high‐fat diet (HFD) and low‐fat diet (LFD). HFD groups had higher weight and fat mass gain, lower trabecular and cortical bone volume and fracture load, and higher liver triglycerides. In males, preptin deficiency led to lower blood glucose than wild‐type (WT) mice under LFD conditions. This was accompanied by differences in bone microarchitecture, including lower trabecular bone volume fraction, trabecular number, and lower cortical thickness. These differences were absent in female mice, although KO females had a HFD‐driven increase in fat mass and liver triglycerides that was absent in WT mice. Female WT mice had increased glucose‐stimulated insulin secretion under HFD conditions that was absent in female KO mice. Overall, preptin may have a detrimental impact on metabolism and a positive impact on bone health in male mice and may protect against liver fat storage in females while enabling islet compensation under HFD conditions. When we consider that serum preptin levels are elevated in humans of both sexes in pathological states in which insulin levels are elevated, the impact of preptin on comorbidity risk needs to be better understood. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

BackgroundThe purpose of the present study was to investigate the role of oxidative stress, platelet activation, and endocan levels in renal dysfunction in normal glucose tolerance (NGT) patients with 1-h plasma glucose values ≥155 mg/dl (NGT ≥ 155), compared to NGT < 155, impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) newly diagnosed subjects. We enlisted 233 patients subjected to an oral glucose tolerance test (OGTT).Materials and methodsThe serum levels of platelet activation (glycoprotein VI and sP-selectin), oxidative stress biomarkers (8-isoprostane and Nox-2), and endocan were evaluated using an ELISA test.ResultsAmong NGT < 155 patients and the T2DM group, there was a statistically significant increase in 8-isoprostane (p < 0.0001), Nox-2 (p < 0.0001), glycoprotein VI (p < 0.0001), and sP-selectin (p < 0.0001) serum levels. Higher serum endocan levels were found with the worsening of metabolic profile (p < 0.0001); specifically, NGT ≥ 155 patients presented higher serum endocan values when compared to NGT < 155 patients (p < 0.0001). From the multivariate linear regression analysis, 1-h glucose resulted in the major predictor of estimated glomerular filtration rate (e-GFR) justifying 23.6% of its variation (p < 0.0001); 8-isoprostane and Nox-2 added respectively another 6.0% (p < 0.0001) and 3.2% (p = 0.001).ConclusionOur study confirmed the link between 1-h post-load glucose ≥155 mg/dl during OGTT and the possible increased risk for chronic kidney disease (CKD) in newly diagnosed patients. The novelty is that we demonstrated a progressive increase in oxidative stress, platelet activation, and serum endocan levels with the worsening of metabolic profile, which becomes evident early during the progression of CKD.

Objective: Obesity in laboratory rodents is generally induced by feeding them a high fat diet (HFD). This model does not permit separation of the impact of the HFD from the resultant obesity on metabolic defects such as impaired glucose homeostasis. In Brandt's voles we have previously shown that exposure to long photoperiod (LD: 16L: 8D) induces obesity even when they are fed a low fat diet. We show here that these voles are largely resistant to HFD. This model therefore permits some separation of the effects of HFD and obesity on glucose homeostasis. The objective was therefore to use this model to assess if glucose homeostasis is more related to diet or obesity Methods: Male voles, which were 35 days old and born in LD, were exposed to SD and a low fat diet for 70 days. We then randomly separated the animals into 4 groups for another 63 days: SL (short day and low fat diet: n = 19) group; SH (short day and high-fat diet, n = 20) group; LL (long day and low-fat diet, n = 20) group; LH (long day and high-fat diet, n = 18) group. Glucose tolerance tests (GTT) were performed after treatment for 56 days, and body compositions of the voles were quantified at the end by dissection. Results: Consistent with our previous work LD voles were more obese than SD voles. Although total body weight was independent of dietary fat content, HFD did have an effect on fat storage. Photoperiod induced obesity had no effect on glucose homeostasis, and the fat content in both the liver and muscle. In contrast, HFD induced adiposity was linked with elevated fat deposition in muscle (but not in liver) and led to impaired glucose tolerance. Conclusions: The contrasting effects of diet and photoperiod were consistent with the predictions of the ‘lipotoxicity hypothesis’. This may contribute to our understanding of why some human individuals are able to be obese yet remain metabolically healthy.

IntroductionGestational diabetes (GDM) is associated with negative outcomes in mothers and their offspring, including greater risks of macrosomia at birth and the development of metabolic disorders. While these outcomes are well-established, the mechanisms by which this increased metabolic vulnerability is conferred on the offspring are comparatively lacking. One proposed mechanism is that maternal glycemic dysregulation alters the development of the hypothalamic regions related to metabolism and energy balance.MethodsTo investigate this possibility, in this study, we first examined the effects of STZ-induced maternal glucose intolerance on the offspring on pregnancy day (PD) 19, and, in a second experiment, in early adulthood (postnatal day (PND) 60). Whether effects would be influenced by sex, or exposure of offspring to a high-fat diet was also investigated. The impact of maternal STZ treatment on POMC neuron number in the ARC of offspring at both time points was also examined.ResultsAs expected, STZ administration on PD 7 decreased maternal glucose tolerance, and increased risk for macrosomia, and loss of pups at birth. Offspring of STZ-treated mothers were also more vulnerable to developing metabolic impairments in adulthood. These were accompanied by sex-specific effects of maternal STZ treatment in the offspring, including fewer POMC neurons in the ARC of female but not male infants in late pregnancy and a higher number of POMC neurons in the ARC of both male and female adult offspring of STZ-treated dams, which was exacerbated in females exposed to a high-fat diet after weaning.DiscussionThis work suggests that maternal hyperglycemia induced by STZ treatment, in combination with early-life exposure to an obesogenic diet, leads to adult metabolic alterations that correlate with the increased hypothalamic expression of POMC, showing that maternal glycemic dysregulation can impact the development of hypothalamic circuits regulating energy state with a stronger impact on female offspring.

Exercise is a first-line therapy recommended for patients with type 2 diabetes (T2D). Although moderate to vigorous exercise (e.g. 150 min/wk) is often advised alongside diet and/or behavior modification, exercise is an independent treatment that can prevent, delay or reverse T2D. Habitual exercise, consisting of aerobic, resistance or their combination, fosters improved short- and long-term glycemic control. Recent work also shows high-intensity interval training is successful at lowering blood glucose, as is breaking up sedentary behavior with short-bouts of light to vigorous movement (e.g. up to 3min). Interestingly, performing afternoon compared with morning as well as post-meal versus pre-meal exercise may yield slightly better glycemic benefit. Despite these efficacious benefits of exercise for T2D care, optimal exercise recommendations remain unclear when considering, dietary, medication, and/or other behaviors.

As a crucial enzyme for cellulose degradation, β-glucosidase finds extensive applications in food, feed, and bioethanol production; however, its potential is often limited by inadequate thermal stability and glucose tolerance. In this study, a functional gene (lq-bg5) for a GH1 family β-glucosidase was obtained from the metagenomic DNA of a hot spring sediment sample and heterologously expressed in E. coli and the recombinant enzyme was purified and characterized. The optimal temperature and pH of LQ-BG5 were 55 °C and 4.6, respectively. The relative residual activity of LQ-BG5 exceeded 90% at 55 °C for 9 h and 60 °C for 6 h and remained above 100% after incubation at pH 5.0–10.0 for 12 h. More importantly, LQ-BG5 demonstrated exceptional glucose tolerance with more than 40% activity remaining even at high glucose concentrations of 3000 mM. Thus, LQ-BG5 represents a thermophilic β-glucosidase exhibiting excellent thermal stability and remarkable glucose tolerance, making it highly promising for lignocellulose development and utilization.

One of the major global health and welfare issues is the treatment of obesity and associated metabolic disorders, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease. Obesity, caused by the excessive accumulation of triglycerides in adipose tissues, induces adipocyte dysfunction, followed by inflammation, in adipose tissues and lipotoxicity in nonadipose tissues. Several studies have shown that obesity and glucose homeostasis are influenced by sphingolipid mediators, including ceramide and sphingosine 1-phosphate (S1P). Cellular accumulation of ceramide impairs pancreatic β-cell survival, confers insulin resistance in the liver and the skeletal muscle, and deteriorates adipose tissue inflammation via unknown molecular mechanisms. The roles of S1P are more complicated, because there are five cell-surface S1P receptors (S1PRs: S1P1–5) which have altered functions, different cellular expression patterns, and inapparent intracellular targets. Recent findings, including those by our group, support the notable concept that the pharmacological activation of S1P1 or S1P3 improves obesity and associated metabolic disorders, whereas that of S1P2 has the opposite effect. In addition, the regulation of S1P production by sphingosine kinase (SphK) is an essential factor affecting glucose homeostasis. This review summarizes the current knowledge on SphK/S1P/S1PR signaling in and against obesity, insulin resistance, and associated disorders.

Obesity-resistant (non-responder, NR) phenotypes that exhibit reduced susceptibility to developing obesity despite being exposed to high dietary fat are crucial in exploring the metabolic responses that protect against obesity. Although several efforts have been made to study them in mice and humans, the individual protective mechanisms are poorly understood. In this exploratory study, we used a polygenic C57BL/6J mouse model of diet-induced obesity to show that NR mice developed healthier fat/lean body mass ratios (0.43 ± 0.05) versus the obesity-prone (super-responder, SR) phenotypes (0.69 ± 0.07, p < 0.0001) by upregulating gene expression networks that promote the accumulation of type 2a, fast-twitch, oxidative muscle tissues. This was achieved in part by a metabolic adaptation in the form of blood glucose sparing, thus aggravating glucose tolerance. Resistance to obesity in NR mice was associated with 4.9-fold upregulated mitoferrin 1 (Slc25a37), an essential mitochondrial iron importer. SR mice also showed fecal volatile metabolite signatures of enhanced short-chain fatty acid metabolism, including increases in detrimental methyl formate and ethyl propionate, and these effects were reversed in NR mice. Continued research into obesity-resistant phenotypes can offer valuable insights into the underlying mechanisms of obesity and metabolic health, potentially leading to more personalized and effective approaches for managing weight and related health issues.