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Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short‐term exercise would raise neuronal insulin signaling and pro‐BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty‐one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m2) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work‐matched continuous (n = 13, 70% HRpeak) or interval (n = 8, 90% HRpeak and 50% HRpeak for 3 min each) sessions over 2‐wks for 60 min/d. Aerobic fitness (VO2peak) and body weight were assessed. After an overnight fast, whole‐body glucose tolerance (total area under the curve, tAUC) and insulin sensitivity (SIis) were determined from a 120 min 75 g OGTT. nEVs were acquired from 0 and 60 min time‐points of the OGTT, and levels of insulin signaling proteins (i.e., p‐IRS‐1, total−/p‐Akt, pERK1/2, pJNK1/2, and pp38) and pro‐BNDF were measured. OGTT stimulatory effects were calculated from protein differences (i.e., OGTT 60‐0 min). Adults were collapsed into a single group as exercise intensity did not affect nEV outcomes. Exercise raised VO2peak (+1.4 ± 2.0 mL/kg/min, p = 0.008) and insulin sensitivity (p = 0.01) as well as decreased weight (−0.4 ± 0.9 kg, p = 0.04) and whole‐body glucose tAUC120min (p = 0.02). Training lowered 0‐min pro‐BDNF (704.1 ± 1019.0 vs. 414.5 ± 533.5, p = 0.04) and increased OGTT‐stimulated tAkt (−51.8 ± 147.2 vs. 95 ± 204.5 a.u., p = 0.01), which was paralleled by reduced pAkt/tAkt at 60 min of the OGTT (1.3 ± 0.2 vs. 1.2 ± 0.1 a.u., p = 0.04). Thus, 2 weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro‐BNDF among adults with prediabetes, thereby potentially lowering ADRD risk. [ABSTRACT FROM AUTHOR]

Ghrelin has effects that range from the maturation of the central nervous system to the regulation of energy balance. The production of ghrelin increases significantly during the first weeks of life. Studies have addressed the metabolic effects of liver-expressed antimicrobial peptide 2 (LEAP2) in inhibiting the effects evoked by ghrelin, mainly in glucose homeostasis, insulin resistance, and lipid metabolism. Despite the known roles of ghrelin in the postnatal development, little is known about the long-term metabolic influences of modulation with the endogenous expressed growth hormone secretagogue receptor (GHSR) inverse agonist LEAP2. This study aimed to evaluate the contribution of GHSR signalling during perinatal phases, to neurodevelopment and energy metabolism in young animals, under inverse antagonism by LEAP2[1–14]. For this, two experimental models were used: (i) LEAP2[1–14] injections in female rats during the pregnancy. (ii) Postnatal modulation of GHSR with LEAP2[1–14]or MK677. Perinatal GHSR modulation by LEAP2[1–14] impacts glucose homeostasis in a sex and phase-dependent manner, despite no effects on body weight gain or food intake. Interestingly, liver PEPCK expression was remarkably impacted by LEAP2 injections. The observed results suggests that perinatal LEAP2 exposure can modulate liver metabolism and systemic glucose homeostasis. In addition, these results, although not expressive, may just be the beginning of the metabolic imbalance that will occur in adulthood. [ABSTRACT FROM AUTHOR]

Identifying specific markers of adipose stem and progenitor cells (ASPCs) in vivo is crucial for understanding the biology of white adipose tissues (WAT). PDGFRα‐positive perivascular stromal cells represent the best candidates for ASPCs. This cell lineage differentiates into myofibroblasts that contribute to the impairment of WAT function. However, ASPC marker protein(s) that are functionally crucial for maintaining WAT homeostasis are unknown. We previously identified Meflin as a marker of mesenchymal stem cells (MSCs) in bone marrow and tissue‐resident perivascular fibroblasts in various tissues. We also demonstrated that Meflin maintains the undifferentiated status of MSCs/fibroblasts. Here, we show that Meflin is expressed in WAT ASPCs. A lineage‐tracing experiment showed that Meflin+ ASPCs proliferate in the WAT of obese mice induced by a high‐fat diet (HFD), while some of them differentiate into myofibroblasts or mature adipocytes. Meflin knockout mice fed an HFD exhibited a significant fibrotic response as well as increases in adipocyte cell size and the number of crown‐like structures in WAT, accompanied by impaired glucose tolerance. These data suggested that Meflin expressed by ASPCs may have a role in reducing disease progression associated with WAT dysfunction. [ABSTRACT FROM AUTHOR]

Purpose: Growth hormone (GH) is a central regulator of β-cell proliferation, insulin secretion and sensitivity. Aim of this study was to investigate the effect of GH insensitivity on pancreatic β-cell histomorphology and consequences for metabolism in vivo. Methods: Pancreata from pigs with growth hormone receptor deficiency (GHR-KO, n = 12) were analyzed by unbiased quantitative stereology in comparison to wild-type controls (WT, n = 12) at 3 and 7–8.5 months of age. In vivo secretion capacity for insulin and glucose tolerance were assessed by intravenous glucose tolerance tests (ivGTTs) in GHR-KO (n = 3) and WT (n = 3) pigs of the respective age groups. Results: Unbiased quantitative stereological analyses revealed a significant reduction in total β-cell volume (83% and 73% reduction in young and adult GHR-KO vs. age-matched WT pigs; p < 0.0001) and volume density of β-cells in the pancreas of GHR-KO pigs (42% and 39% reduction in young and adult GHR-KO pigs; p = 0.0018). GHR-KO pigs displayed a significant, age-dependent increase in the proportion of isolated β-cells in the pancreas (28% in young and 97% in adult GHR-KO vs. age-matched WT pigs; p = 0.0009). Despite reduced insulin secretion in ivGTTs, GHR-KO pigs maintained normal glucose tolerance. Conclusion: GH insensitivity in GHR-KO pigs leads to decreased β-cell volume and volume proportion of β-cells in the pancreas, causing a reduced insulin secretion capacity. The increased proportion of isolated β-cells in the pancreas of GHR-KO pigs highlights the dependency on GH stimulation for proper β-cell maturation. Preserved glucose tolerance accomplished with decreased insulin secretion indicates enhanced sensitivity for insulin in GH insensitivity. [ABSTRACT FROM AUTHOR]

Context Housing temperature is a critical regulator of mouse metabolism and thermoneutral housing can improve model translation to humans. However, the impact of housing temperature on the ability of wheel running exercise training to rescue the detrimental effect of diet-induced obese mice is currently not fully understood. Objective To investigate how housing temperature affects muscle metabolism in obese mice with regard to calcium handling and exercise training (ET) adaptations in skeletal muscle, and benefits of ET on adiposity and glucometabolic parameters. Methods Lean or obese female mice were housed at standard ambient temperature (22 °C) or thermoneutrality (30 °C) with/without access to running wheels. The metabolic phenotype was investigated using glucose tolerance tests, indirect calorimetry, and body composition. Molecular muscle adaptations were measured using immunoblotting, qPCR, and spectrophotometric/fluorescent assays. Results Obese female mice housed at 22 °C showed lower adiposity, lower circulating insulin levels, improved glucose tolerance, and elevated basal metabolic rate compared to 30 °C housing. Mice exposed to voluntary wheel running exhibited a larger fat loss and higher metabolic rate at 22 °C housing compared to thermoneutrality. In obese female mice, glucose tolerance improved after ET independent of housing temperature. Independent of diet and training, 22 °C housing increased skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity. Additionally, housing at 22 °C elevated the induction of training-responsive muscle proteins in obese mice. Conclusion Our findings highlight that housing temperature significantly influences adiposity, insulin sensitivity, muscle physiology, and exercise adaptations in diet-induced obese female mice. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Background: There are several reports on the safety and feasibility of pancreatoduodenectomy (PD) without reconstruction of the small remnant pancreas. However, a few studies have explored central pancreatectomy (CP) for non-reconstructed small remnant pancreases after PD. This study presents a case of CP without pancreatic reconstruction after PD. Case presentation: A 58-year-old man with cerebral palsy underwent PD for distal cholangiocarcinoma. Three years postoperatively, a 12-mm tumor was detected in the remnant pancreatic body and diagnosed as a pancreatic neuroendocrine neoplasm. Surgical resection was performed, because the tumor was enlarged and chemotherapy resistant. The afferent loop with pancreatojejunostomy anastomosis was dissected, and CP, including pancreatojejunostomy anastomosis, was performed. Given the remnant pancreas was hard and atrophic, the pancreatic tail was transected using a stapler without reconstructing the small remnant pancreas. The patient experienced no postoperative complications including postoperative pancreatic fistula, and the endocrine function of the pancreas was preserved. Conclusions: We present a case of remnant pancreatic CP that did not require reconstruction after PD. Preservation of the small remnant pancreas without reconstruction during CP may be feasible to maintain endocrine function in select patients after PD. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ghrelin is an appetite-stimulating hormone secreted from the gastric mucosa in the fasting state, and secretion decreases in response to food intake. After sleeve gastrectomy (SG), plasma concentrations of ghrelin decrease markedly. Whether this affects appetite and glucose tolerance postoperatively is unknown. We investigated the effects of ghrelin infusion on appetite and glucose tolerance in individuals with obesity before and 3 mo after SG. Twelve participants scheduled for SG were included. Before and 3 mo after surgery, a mixed-meal test followed by an ad libitum meal test was performed with concomitant infusions of acyl-ghrelin (1 pmol/kg/min) or placebo. Infusions began 60 min before meal intake to reach a steady state before the mixed-meal and were continued throughout the study day. Two additional experimental days with 0.25 pmol/kg/min and 10 pmol/kg/min of acyl-ghrelin infusions were conducted 3 mo after surgery. Both before and after SG, postprandial glucose concentrations increased dose dependently during ghrelin infusions compared with placebo. Ghrelin infusions inhibited basal and postprandial insulin secretion rates, resulting in lowered measures of β-cell function, but no effect on insulin sensitivity was seen. Ad libitum meal intake was unaffected by the administration of ghrelin. In conclusion, ghrelin infusion increases postprandial plasma glucose concentrations and impairs β-cell function before and after SG but has no effect on ad libitum meal intake. We speculate that the lower concentration of ghrelin after SG may impact glucose metabolism following this procedure. NEW & NOTEWORTHY: Ghrelin's effect on glucose tolerance and food intake following sleeve gastrectomy (SG) was evaluated. Acyl-ghrelin was infused during a mixed-meal and ad libitum meals before and 3 mo after surgery. Postprandial glucose concentrations increased during ghrelin infusions, both before and after surgery, while insulin production was inhibited. However, ad libitum meal intake did not differ during ghrelin administration compared with placebo. The decreased ghrelin concentration following SG may contribute to the glycemic control after surgery. [ABSTRACT FROM AUTHOR]

Background: Childhood exercise enhances brain structure, while diabetes detrimentally affects it. This study examines early-life exercise's influence on adult diabetic rats' memory and neuroplasticity. Methods: Male Wistar pups were divided into Control, Diabetes, Exercise Training, and Diabetes exercise groups. Diabetes was induced on day 23 with Alloxan (200 mg/kg). A 3-week regimen included aerobic and resistance training thrice weekly. The aerobic intensity was 70%, and resistance varied from 50% to 100% of the maximal carrying capacity (MCC). Following the last training sessions, spatial memory and retrieval tests were performed in infancy, childhood, and emerging adulthood using the Morris Water Maze test (MWM). The hippocampus was excised to measure protein and gene expression of brain-derived neurotrophic factor (BDNF), calmodulin-dependent protein kinase (CAMKII), N-methyl-D-aspartate receptors (NMDAR), and cAMP-response element-binding protein (CREB) by western blotting and reverse transcription–polymerase-chain reaction (RT-PCR) methods. Blood samples were collected during each developmental stage to measure glucose levels, at the study's conclusion, to assess Interleukin-1β levels using the ELISA method. The Nissel staining assessed dead hippocampal cells in CA1. Results: Post-natal exercise improved spatial memory (p < 0.05) and glucose levels (p < 0.05) in diabetic rats during adolescence and emerging adulthood. Despite reduced mRNA expression (NMDAR 40%, BDNF 62%, CREB 43%, CAMKII 66%), diabetic rats, by study end, showed increased BDNF, NMDARR, CAMKII, CREB protein/gene expression (p < 0.05) in emerging adulthood for both training groups. Conclusion: Early-life exercise influenced hippocampal BDNF/NMDAR-CAMKII/CREB pathways in a diabetic rat model, highlighting post-natal exercise's role in neuroplasticity memory enhancement and improved glucose level. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

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.

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.

Objective: During an oral glucose tolerance test (OGTT), typically fasting plasma glucose is lower than 2-h postprandial plasma glucose. However, postprandial plasma glucose (PPG) levels lower than fasting plasma glucose (FPG) levels may also occur. This study aims to describe the prevalence, clinical characteristics and contributing risk factors for PPG ≤ FPG in a large diverse Chinese population. Methods: We conducted a cross-sectional analysis of baseline data from a nationwide cohort study conducted in China. In addition to sociodemographic and anthropometric data collection, individuals had OGTT and blood chemistry tests. We determined the prevalence of PPG ≤ FPG ('Low Post Load' group) and PPG > FPG ('High Post Load' group) and used logistic regression to evaluate the association of risk factors with the occurrence of Low Post Load. Results: The prevalence of Low Post Load was 26.04% (n = 3773) and High Post Load was 73.96% (n = 10,714). Low Post Load was found to be related to younger age, male, lower BMI, lower blood pressure, higher HDL cholesterol levels and lower triglycerides levels. Compared with participants in the High Post Load group, participants in Low Post Load group had lower PPG (4.59 ± 0.83 mmol/L vs 7.15 ± 1.41 mmol/L) and HbA1c (5.30 ± 0.43% vs 5.39 ± 0.45%). People in Low Post Load group were more likely to have hypoglycaemic episodes (2.12% vs 0.01%) and impaired fasting glucose (12.30% vs 4.81%) compared with people with High Post Load, all p < 0.001. Conclusions: We found a high prevalence of people with Low Post Load glucose (26.04%) in a Chinese population cohort. The relationship between Low Post Load and the progression to or protection from diabetes and related complications and future incidence of cardiovascular disease needs further exploration in longitudinal analyses. [ABSTRACT FROM AUTHOR]

17α-Estradiol (17αE2), a less-feminising enantiomer of 17β-estradiol, has been shown to prolong lifespan and improve metabolic health in a sex-specific manner in male, but not in female mice. Recent studies have demonstrated the pivotal role of estrogen receptor α (ERα) in mediating the effects of 17αE2 on metabolic health. However, the specific tissues and/or neuronal signalling pathways that 17αE2 acts through remain to be elucidated. ERα expression in glutamatergic and GABAergic neurons (principal excitatory and inhibitory neurons respectively) in the hypothalamus is essential for estradiol signalling. Therefore, we hypothesised that knocking out ERα from one of these neuronal populations would attenuate the established beneficial metabolic effects of 17αE2 in male mice exposed to a high fat diet. To test this hypothesis we used two established brain specific ERα KO models, targeting either glutamatergic or GABAergic neurons (Vglut2/Vgat-ERαKO). We show that both of these ERα KO models exhibit a strong reduction in ERα expression in the arcuate nucleus of the hypothalamus, a control centre for metabolic regulation. Deletion of ERα from GABAergic neurons significantly diminished the effect of 17αE2 on body weight relative to controls, although these animals still show metabolic benefits with 17αE2 treatment. The response to 17αE2 was unaffected by ERα deletion in glutamatergic neurons. Our results support a benefit of 17αE2 treatment in protection against metabolic dysfunction, but these effects do not depend on exclusive ERα expression in glutamatergic and GABAergic neurons and persist when ERα expression is strongly reduced in the arcuate nucleus of the hypothalamus. [ABSTRACT FROM AUTHOR]

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.

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. Plain English summary: Cardiovascular disease is the leading cause of death worldwide. Multiple factors influence the incidence and severity of cardiovascular disease including adverse life experiences, biological sex, and age. Alterations of heart structure predict negative cardiovascular health by impacting blood circulation; however, the potential interactions of stress history and biological sex on the aged heart are unknown. In this study, we examined how chronic stress exposure impacts heart structure in male and female rats after aging. Adolescent male and female rats were chronically stressed and then acutely challenged to examine behavioral, endocrine, and metabolic parameters both immediately following chronic stress and after aging. Heart morphology was quantified to examine how behavioral and physiological responses related to cardiac remodeling. Our results indicate that, as a group, female rats previously exposed to chronic stress were uniquely susceptible to inward remodeling of the heart. Subjects were further divided into sub-groups based on the level of inward remodeling of the ventricle. While male rats did not exhibit group effects on heart structure, individual variability in male heart morphology related to endocrine and metabolic parameters in a stress history-dependent manner. Here, there were interactions with multiple systems including coping behavior, stress hormones, and body composition. Moreover, males without a prior history of chronic stress had correlations between stress hormones and the degree of heart remodeling. However, males that were exposed to chronic stress had correlations between heart structure and abdominal fat. Overall, our results indicate that biological sex and stress history interact to predict cardiovascular susceptibility. Highlights: • Aged female rats had greater left ventricular hypertrophy (VH) than males after early-life chronic variable stress. • Tertile divisions based on susceptibility or resilience to concentric VH indicated interactions between VH, sex, and stress on multiple behavioral and physiological measures. • In males, VH correlated with endocrine and metabolic parameters in a stress history-dependent manner. • Prior adverse experience and biological sex interact across the lifespan to impact cardiovascular risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Global obesity rates are rising due to rapid urbanisation and sedentary lifestyles, affecting health and economics. Modifications to one's way of life, medical interventions, and surgical procedures are among the methods that can be utilised to manage obesity. New dopaminergic drugs show promise, but regulatory hurdles remain. Dopamine modulation may reduce metabolic dysfunctions, but more research is needed. Aim and objectives: This study aims to examine the impact of Cabergoline on glucose tolerance and weight in obese adults. Method: The impact of cabergoline on blood glucose levels was examined in a double-blind research including 120 obese patients who were given either the active ingredient or a placebo. There was no statistically significant difference seen between the groups (P = 0.792). Medications were delivered every week for 3 months in addition to the ongoing therapy. The study involved the implementation of fundamental laboratory tests and measures to continuously monitor the outcomes. Result: This study presents the initial characteristics of the Cabergoline and Control groups, and compares them at 3 and 6 months. There were no notable disparities observed in terms of weight, waist circumference, blood pressure, or BMI. Once more, it examines the laboratory attributes before and following a 3-month therapy period, revealing that there are no notable disparities between the Cabergoline and Control groups in the majority of measures. Conclusion: Cabergoline did not differ significantly from the control group in terms of weight, waist circumference, blood pressure, body mass index (BMI), or the majority of laboratory values after three months. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Functional microbial communities producing β-glucosidases differentially regulate the expression of glucose/non-glucose-tolerant β-glucosidases in response to carbon catabolite repression (CCR), which is a common phenomenon. To better understand their biological roles in a composting environment, four representative β-glucosidase genes were cloned from the metatranscriptome of the compost for expression and characterization. BGLA contains conserved sites Trp168 and Leu173, associated with glucose tolerance. In the presence of 100 mM glucose, BGLA's hydrolysis activity increases by 80%. BGLB also contains Trp168 and Leu173; however, its hydrolysis activity is significantly inhibited by glucose. On the contrary, Trp168 of BGLC was replaced by Phe, yet its hydrolysis activity increased by 20% in the presence of 25 mM glucose. However, BGLD did not exhibit any enzymatic activity. Molecular docking and dynamic simulations revealed the structural basis of glucose tolerance. Metatranscriptomic analysis of the four genes showed that functional microbial communities upregulated or downregulated gene expression in response to different CCR environments to maintain overall carbon metabolic balance. These findings demonstrate that the enzymatic activity characteristics of individual glucose/non-glucose-tolerant β-glucosidases are consistent with their transcriptional regulation under CCR in the complex composting environment. [Display omitted] • Four new GH1 family β-glucosidases cloned from compost. • BGLA activity increased by 80% with added glucose. • Computational biology elucidates β-glucosidase glucose tolerance mechanism. • Glucose tolerance of β-glucosidases correlates with their expression level. [ABSTRACT FROM AUTHOR]

Background Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic β cells are implicated in diabetes. Nephrin signaling is mediated in part through its 3 cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and β cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate β cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined. Methods To further explore the role of nephrin YDxV phosphorylation in β cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests. Results Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between wild-type (WT) and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls. Conclusion Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve β cell function. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A healthy diet is at the forefront of measures to prevent type 2 diabetes. Certain vegetable and fish oils, such as pine nut oil (PNO), have been demonstrated to ameliorate the adverse metabolic effects of a high-fat diet. The present study investigates the involvement of the free fatty acid receptors 1 (FFAR1) and 4 (FFAR4) in the chronic activity of hydrolysed PNO (hPNO) on high-fat diet-induced obesity and insulin resistance. Male C57BL/6J wild-type, FFAR1 knockout (-/-) and FFAR4-/- mice were placed on 60 % high-fat diet for 3 months. Mice were then dosed hPNO for 24 d, during which time body composition, energy intake and expenditure, glucose tolerance and fasting plasma insulin, leptin and adiponectin were measured. hPNO improved glucose tolerance and decreased plasma insulin in the wild-type and FFAR1-/- mice, but not the FFAR4-/- mice. hPNO also decreased high-fat diet-induced body weight gain and fat mass, whilst increasing energy expenditure and plasma adiponectin. None of these effects on energy balance were statistically significant in FFAR4-/- mice, but it was not shown that they were significantly less than in wild-type mice. In conclusion, chronic hPNO supplementation reduces the metabolically detrimental effects of high-fat diet on obesity and insulin resistance in a manner that is dependent on the presence of FFAR4. [ABSTRACT FROM AUTHOR]

Megalin (Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. Studies in our lab have shown that knockout (KO) of Lrp2 in opossum PT cells leads to a dramatic reduction in sodium–glucose co-transporter 2 (SGLT2) transcript and protein levels, as well as differential expression of genes involved in mitochondrial and metabolic function. SGLT2 transcript levels are reduced more modestly in Lrp2 KO mice. Here, we investigated the effects of Lrp2 KO on kidney function and health in mice fed regular chow (RC) or a Western-style diet (WD) high in fat and refined sugar. Despite a modest reduction in SGLT2 expression, Lrp2 KO mice on either diet showed increased glucose tolerance compared to control mice. Moreover, Lrp2 KO mice were protected against WD-induced fat gain. Surprisingly, renal function in male Lrp2 KO mice on WD was compromised, and the mice exhibited significant kidney injury compared with control mice on WD. Female Lrp2 KO mice were less susceptible to WD-induced kidney injury than male Lrp2 KO. Together, our findings reveal both positive and negative contributions of megalin expression to metabolic health, and highlight a megalin-mediated sex-dependent response to injury following WD. Graphical Abstract [ABSTRACT FROM AUTHOR]

Cold‐active enzymes support life at low temperatures due to their ability to maintain high activity in the cold and can be useful in several biotechnological applications. Although information on the mechanisms of enzyme cold adaptation is still too limited to devise general rules, it appears that very diverse structural and functional changes are exploited in different protein families and within the same family. In this context, we studied the cold adaptation mechanism and the functional properties of a member of the glycoside hydrolase family 1 (GH1) from the Antarctic bacterium Marinomonas sp. ef1. This enzyme exhibits all typical functional hallmarks of cold adaptation, including high catalytic activity at 5 °C, broad substrate specificity, low thermal stability, and higher lability of the active site compared to the overall structure. Analysis of the here‐reported crystal structure (1.8 Å resolution) and molecular dynamics simulations suggest that cold activity and thermolability may be due to a flexible region around the active site (residues 298–331), whereas the dynamic behavior of loops flanking the active site (residues 47–61 and 407–413) may favor enzyme‐substrate interactions at the optimal temperature of catalysis (Topt) by tethering together protein regions lining the active site. Stapling of the N‐terminus onto the surface of the β‐barrel is suggested to partly counterbalance protein flexibility, thus providing a stabilizing effect. The tolerance of the enzyme to glucose and galactose is accounted for by the presence of a "gatekeeping" hydrophobic residue (Leu178), located at the entrance of the active site. [ABSTRACT FROM AUTHOR]

While therapies based on endogenous gut peptides such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been compelling therapeutic agents for obesity and type 2 diabetes (T2D), only a few have achieved long-term weight loss and all have shown significant side-effects, including nausea/malaise and gastrointestinal ailments. As the pathophysiology of obesity is driven by dysregulation of multiple, inter-related, pathways, we tested a novel peptide targeting multiple receptors of complementary neurocircuits regulating the controls of energy balance. Response to daily injections of GEP44, a GLP-1R and neuropeptide Y1R and Y2R receptor (Y1R/Y2R) triple agonist was tested vs. the GLP-1R agonist liraglutide (LIRA) in diet-induced obese (DIO) male and female rats. Glucose tolerance tests after intraperitoneal injection of glucose (IPGTT) were performed at baseline and after 14-d of treatment in GEP44 treated rats. Other metabolic parameters were assessed in blood at the end of a 28-d intervention. Upon conclusion at 28-d, body weight reduction compared to vehicle was −15.6%/-11.9% in response to GEP44, vs. −9.7%/-5.1% after LIRA, males, and females, respectively. Significant reductions of cumulative food intake occurred over 28-d in female rats treated with GEP44 (−30%; p < 0.0001), vs. LIRA (−10%), and in male rats GEP44 (−39%; p < 0.0001), vs. LIRA (−20%; p = 0.003). In IPGTTs, a similar stimulation glucose induced insulin secretion was noted in rats treated with GEP44 and LIRA. The strong reductions of body weight in response to long-term applications of the triple agonist GEP44 confirms the therapeutic potential of targeting multiple receptors for achieving more robust and potentially more sustained improvement of energy balance. • Novel therapeutic obesity drug concept addressing multiple inter-related pathways. • GEP44 is a GLP-1 receptor and neuropeptide Y1 and Y2 receptor triple agonist. • Daily GEP44 outperformed LIRA on reduction of food intake and body weight. • GEP44 was safe in chronic testing up to 28-d in diet-induced obese rats. [ABSTRACT FROM AUTHOR]

Fatty liver is characterized by the expansion of lipid droplets (LDs) and is associated with the development of many metabolic diseases. We assessed the morphology of hepatic LDs and performed quantitative proteomics in lean, glucose-tolerant mice compared with high-fat diet (HFD) fed mice that displayed hepatic steatosis and glucose intolerance as well as high-starch diet (HStD) fed mice who exhibited similar levels of hepatic steatosis but remained glucose tolerant. Both HFD- and HStD-fed mice had more and larger LDs than Chow-fed animals. We observed striking differences in liver LD proteomes of HFD- and HStD-fed mice compared with Chow-fed mice, with fewer differences between HFD and HStD. Taking advantage of our diet strategy, we identified a fatty liver LD proteome consisting of proteins common in HFD- and HStD-fed mice, as well as a proteome associated with glucose tolerance that included proteins shared in Chow and HStD but not HFD-fed mice. Notably, glucose intolerance was associated with changes in the ratio of adipose triglyceride lipase to perilipin 5 in the LD proteome, suggesting dysregulation of neutral lipid homeostasis in glucose-intolerant fatty liver. We conclude that our novel dietary approach uncouples ectopic lipid burden from insulin resistance-associated changes in the hepatic lipid droplet proteome. NEW & NOTEWORTHY: This study identified a fatty liver lipid droplet proteome and one associated with glucose tolerance. Notably, glucose intolerance was linked with changes in the ratio of adipose triglyceride lipase to perilipin 5 that is indicative of dysregulation of neutral lipid homeostasis. [ABSTRACT FROM AUTHOR]

This study evaluated the effects of Aronia melanocarpa fruit juice (AMFJ) on the liver in a model of high-fat, high-fructose (HFHF) diet-induced metabolic syndrome (MS). Fifty rats were allocated to five groups – Control, MS, MS+AMFJ2.5, MS+AMFJ5, and MS+AMFJ10. The control group was fed a standard diet, while the other groups were provided a HFHF diet. During MS induction, daily oral treatment was performed. Control and MS groups received 10.0 mL kg−1 distilled water, while the other three groups received AMFJ at doses of 2.5, 5.0, and 10.0 mL kg−1, respectively. After 10 weeks, liver samples were collected and inspected histologically as well as immunohistochemically to determine the expression of Bax, Bcl-2, and MAC387. Bax/Bcl-2 ratio was calculated. In MS rats, steatotic, inflammatory and degenerative alterations of the liver were detected, Bax and MAC387 were markedly elevated, while Bcl-2 was non-significantly reduced. The Bax/Bcl-2 ratio significantly increased. The histopathological alterations were prevented by the AMFJ treatment. Compared to MS group, Bax and MAC387 values were significantly lower and Bcl-2 value was higher resulting in significantly lower (P < 0.001) Bax/Bcl-2 ratio in all AMFJ-treated groups. AMFJ, administered during MS induction in rats, prevented the occurrence of inflammatory, steatotic, degenerative, and pro-apoptotic changes in the liver. [ABSTRACT FROM AUTHOR]

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%.

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. [ABSTRACT FROM AUTHOR]

Aim: Acyl‐coenzyme A dehydrogenase family member 10 (ACAD10) is a mitochondrial protein purported to be involved in the fatty acid oxidation pathway. Metformin is the most prescribed therapy for type 2 diabetes; however, its precise mechanisms of action(s) are still being uncovered. Upregulation of ACAD10 is a requirement for metformin's ability to inhibit growth in cancer cells and extend lifespan in Caenorhabditis elegans. However, it is unknown whether ACAD10 plays a role in metformin's metabolic actions. Materials and Methods: We assessed the role for ACAD10 on whole‐body metabolism and metformin action by generating ACAD10KO mice on a C57BL/6J background via CRISPR‐Cas9 technology. In‐depth metabolic phenotyping was conducted in both sexes on a normal chow and high fat‐high sucrose diet. Results: Compared with wildtype mice, we detected no difference in body composition, energy expenditure or glucose tolerance in male or female ACAD10KO mice, on a chow diet or high‐fat, high‐sucrose diet (p ≥.05). Hepatic mitochondrial function and insulin signalling was not different between genotypes under basal or insulin‐stimulated conditions (p ≥.05). Glucose excursions following acute administration of metformin before a glucose tolerance test were not different between genotypes nor was body composition or energy expenditure altered after 4 weeks of daily metformin treatment (p ≥.05). Despite the lack of a metabolic phenotype, liver lipidomic analysis suggests ACAD10 depletion influences the abundance of specific ceramide species containing very long chain fatty acids, while metformin treatment altered clusters of cholesterol ester, plasmalogen, phosphatidylcholine and ceramide species. Conclusions: Loss of ACAD10 does not alter whole‐body metabolism or impact the acute or chronic metabolic actions of metformin in this model. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare the effects of fasting for 48 h on the evoked insulin and glucose responses in males and females, and to explore factors such as stress and estrogen levels that might influence these responses. Methods: Healthy, nonobese male (n = 14) and female (n = 14) subjects underwent 48-h fasting trial. Changes in glucose tolerance and insulin levels in response to the oral glucose tolerance test, subjectively perceived stress and catecholamine concentrations were measured in all participants. Estrogen levels were also measured in the female participants during the 48-h fast. Results: Glucose area under the curve (AUC) values increased similarly in both sexes after 48-h fasting (P < 0.05), but females displayed a greater rise in insulin AUC values than males (P < 0.05). Fasting increased plasma epinephrine concentrations in both sexes (P < 0.05), whereas plasma norepinephrine concentrations and subjective stress increased only in females (P < 0.05). Plasma 17-β-estradiol concentrations in females decreased after fasting (P < 0.05). Conclusion: Fasting for 48 h induced a similar glucose intolerance in females and males, despite decreased 17-β-estradiol levels and greater psychological and physiological stress in females. These differences represent a plausible explanation for the gender-based differences observed in insulin responses. Trial registration: Retrospectively registered on ClinicalTrials.gov (NCT05545943) in September 19, 2022. [ABSTRACT FROM AUTHOR]

Aims: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Methods: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [18F]FDG positron emission tomography/computed tomography (PET/CT) and [11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Results: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, µmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, µmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, µmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14±9, 10-9 min-1, p < 0.01) and glucose effectiveness (2.6 x 10-2 ± 0.3 x 10-2 vs. 2.4 x 10-2 ± 0.3 x 10-2, dL/kg/min, p = 0.02). Conclusions: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: As the prevalence of insulin resistance and glucose intolerance is increasing throughout the world, diabetes-induced eye diseases are a global health burden. We aim to identify distinct optical bands which are closely related to insulin and glucose metabolism, using non-invasive, high-resolution spectral domain optical coherence tomography (SD-OCT) in a large, population-based dataset. Methods: The LIFE-Adult-Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. Cross-sectional, standardised phenotyping included the assessment of various metabolic risk markers and ocular imaging, such as SD-OCT-derived thicknesses of ten optical bands of the retina. Global and Early Treatment Diabetic Retinopathy Study (ETDRS) subfield-specific optical retinal layer thicknesses were investigated in 7384 healthy eyes of 7384 participants from the LIFE-Adult-Study stratified by normal glucose tolerance, prediabetes (impaired fasting glucose and/or impaired glucose tolerance and/or HbA1c 5.7–6.4% [39–47 mmol/mol]) and diabetes. The association of optical retinal band characteristics with different indices of glucose tolerance (e.g. fasting glucose, area under the glucose curve), insulin resistance (e.g. HOMA2-IR, triglyceride glucose index), or insulin sensitivity (e.g. estimated glucose disposal rate [eGDR], Stumvoll metabolic clearance rate) was determined using multivariable linear regression analyses for the individual markers adjusted for age, sex and refraction. Various sensitivity analyses were performed to validate the observed findings. Results: In the study cohort, nine out of ten optical bands of the retina showed significant sex- and glucose tolerance-dependent differences in band thicknesses. Multivariable linear regression analyses revealed a significant, independent, and inverse association between markers of glucose intolerance and insulin resistance (e.g. HOMA2-IR) with the thickness of the optical bands representing the anatomical retinal outer nuclear layer (ONL, standardised β=−0.096; p<0.001 for HOMA2-IR) and myoid zone (MZ; β=−0.096; p<0.001 for HOMA2-IR) of the photoreceptors. Conversely, markers of insulin sensitivity (e.g. eGDR) positively and independently associated with ONL (β=0.090; p<0.001 for eGDR) and MZ (β=0.133; p<0.001 for eGDR) band thicknesses. These global associations were confirmed in ETDRS subfield-specific analyses. Sensitivity analyses further validated our findings when physical activity, neuroanatomical cell/tissue types and ETDRS subfield categories were investigated after stratifying the cohort by glucose homeostasis. Conclusions/interpretation: An impaired glucose homeostasis associates with a thinning of the optical bands of retinal ONL and photoreceptor MZ. Changes in ONL and MZ thicknesses might predict early metabolic retinal alterations in diabetes. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Detailed knowledge regarding the associations between intake of different types of seafood and meat and the risk of type 2 diabetes (T2D), and insight into possible mechanisms are warranted. In this study we aimed to evaluate the associations between intake of different types of seafood and meat and the subsequent risk of T2D using the Norwegian Mother, Father, and Child Cohort Study (MoBa), and furthermore, by using a mouse model to gain further insight into possible molecular mechanisms contributing to the associated metabolic changes. Women in MoBa who were free of pharmacologically treated diabetes at baseline (n = 60,777) were prospectively evaluated for incident T2D, identified on the basis of medication usages > 90 days after delivery, ascertained by the Norwegian Prescription Database. Dietary intake was obtained with a validated 255-item food frequency questionnaire which assessed habitual diet during the first 4–5 months of pregnancy. Metabolic phenotypes and plasma metabolome were investigated in female mice fed isocaloric diets with different types of seafood and meat mimicking the dietary intake in the human cohort. During maximum 10-year and mean (SD) 7.2 (1.6) years follow-up time, 681 (1.1%) women developed pharmacologically treated T2D. All statistical models identified a higher risk of T2D with increased shellfish intake, whereas no associations were observed for total seafood, fatty fish, total meat and red meat in the adjusted models. In mice, the shellfish-based western diet induced reduced glucose tolerance and insulin secretion compared to the diet based on lean fish, and we identified a number of metabolites elevated in plasma from shellfish-fed mice that correlated with glucose intolerance. Mice fed a western diet based on meat also exhibited reduced glucose tolerance in comparison to lean fish fed mice, whereas mice fed fatty fish, total seafood or red meat did not differ from lean fish fed mice. We observed a diet-specific metabolic signature in plasma demonstrating five distinct metabolite profiles in mice fed shellfish, fatty fish, total seafood/lean fish, a mixed diet and meat. In conclusion, these findings demonstrate that different types of seafood have different outcome on T2D risk. In women, intake of shellfish was associated with higher risk of T2D. In female mice, a shellfish enriched diet reduced glucose tolerance and altered the abundance of several distinct plasma metabolites correlating with glucose tolerance. [ABSTRACT FROM AUTHOR]

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

Maintaining blood glucose at an appropriate physiological level requires precise coordination of multiple organs and tissues. The vagus nerve bidirectionally connects the central nervous system with peripheral organs crucial to glucose mobilization, nutrient storage, and food absorption, thereby presenting a key pathway for the central control of blood glucose levels. However, the precise mechanisms by which vagal populations that target discrete tissues participate in glucoregulation are much less clear. Here we review recent advances unraveling the cellular identity, neuroanatomical organization, and functional contributions of both vagal efferents and vagal afferents in the control of systemic glucose metabolism. We focus on their involvement in relaying glucoregulatory cues from the brain to peripheral tissues, particularly the pancreatic islet, and by sensing and transmitting incoming signals from ingested food to the brain. These recent findings - largely driven by advances in viral approaches, RNA sequencing, and cell-type selective manipulations and tracings - have begun to clarify the precise vagal neuron populations involved in the central coordination of glucose levels, and raise interesting new possibilities for the treatment of glucose metabolism disorders such as diabetes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Metabolic tests are vital to determine in vivo insulin sensitivity and glucose metabolism in preclinical models, usually rodents. Such tests include glucose tolerance tests, insulin tolerance tests, and glucose clamps. Although these tests are not standardized, there are general guidelines for their completion and analysis that are constantly being refined. In this review, we describe metabolic tests in rodents as well as factors to consider when designing and performing these tests. [ABSTRACT FROM AUTHOR]

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.