Peripheral Insulin Sensitivity Research Articles

In vivo mapping of postprandial hepatic glucose metabolism using dynamic magnetic resonance spectroscopy combined with stable isotope flux analysis in Roux-en-Y gastric bypass adults and non-operated controls: A case-control study.

Roux-en-Y gastric bypass (RYGB) surgery alters postprandial glucose profiles, causing post-bariatric hypoglycaemia (PBH) in some individuals. Due to the liver's central role in glucose homeostasis, hepatic glucose handling might differ in RYGB-operated patients with PBH compared to non-operated healthy controls (HC). We enrolled RYGB-operated adults with PBH and HCs (n = 10 each). Participants ingested 60 g of [6,6'-2H2]-glucose (d-glucose) after an overnight fast. Deuterium metabolic imaging (DMI) with interleaved 13C magnetic resonance spectroscopy was performed before and until 150 min post-d-glucose intake, with frequent blood sampling to quantify glucose enrichment and gluco-regulatory hormones until 180 min. Glucose fluxes were assessed by mathematical modelling. Outcome trajectories were described using generalized additive models. In RYGB subjects, the hepatic d-glucose signal increased early, followed by a decrease, whereas HCs exhibited a gradual increase and consecutive stabilization. Postprandial hepatic glycogen accumulation and the suppression of endogenous glucose production were lower in RYGB patients than in HCs, despite higher insulin exposure, indicating lower hepatic insulin sensitivity. The systemic rate of ingested d-glucose was faster in RYGB, leading to a higher, earlier plasma glucose peak and increased insulin secretion. Postprandial glucose disposal increased in RYGB patients, without between-group differences in peripheral insulin sensitivity. Exploiting DMI with stable isotope flux analysis, we observed distinct postprandial hepatic glucose trajectories and parameters of glucose-insulin homeostasis in RYGB patients with PBH versus HCs. Despite altered postprandial glucose kinetics and higher insulin exposure, there was no evidence of impaired hepatic glucose uptake or output predisposing to PBH in RYGB patients.

The Assessment of Anthropometric Measures and Changes in Selected Biochemical Parameters in Obese Children in Relation to Blood Lead Level.

Our paper draws attention to the impact of lead (Pb) on the specificity of obesity development in children exposed to environmental pollution. An advantage of this paper is the homogeneous study group comprising children of identical age from a single geographic region. Moreover, while the influence of environmental toxins on adults has been extensively explored, this study delves into pediatric populations, which have yet to receive comprehensive scrutiny within the scientific literature. Initially, a group of 136 obese children (the research program lasted three consecutive years: 2016, 2017, and 2018) living in the north-western region of Poland, from whom biochemical tests and auxological data were obtained, were enrolled for analysis. Blood lead levels (BLLs) were determined in 115 children. The age of the children ranged from 7.1 to 10.4 years. The body mass index (BMI) of children averaged 21.5 ± 2.2. The results showed that a large proportion of the participants had BLLs above the threshold for Pb. BLLs ≤ 5 µg/dL (considered safe for children and pregnant women) were found in over 70% of the participants, with BLLs in the range of 5.01-10.00 µg/dL in over 26% of the children, and concentrations > 10 µg/dL (considered toxic threshold for adults) in nearly 2% of the children. The results of our research revealed a positive association between BLLs and average systolic and diastolic blood pressure in the studied children. Moreover, we found a negative correlation between BLLs and absolute fat tissue content and triglyceride concentration. Among the included biochemical factors, only insulin demonstrated a statistically significant relationship with fat mass. This result suggests that early carbohydrate metabolism disorders in overweight children involve decreased peripheral tissue insulin sensitivity. Lead exposure may significantly contribute to the development of hypertension, insulin resistance, and glucose metabolism disorders in overweight and obese children. It is essential to implement multidirectional actions to increase awareness of the harmful effects of xenobiotic exposure, including lead, in order to prevent early-life exposure.

Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21

Glucose metabolism disturbances may result in diabetes-associated cognitive decline (DACI). Methionine restriction (MR) diet has emerged as a potential dietary strategy for managing glucose homeostasis. However, the effects and underlying mechanisms of MR on DACI have not been fully elucidated. Here, we found that a 13-week MR (0.17 % methionine, w/w) intervention starting at 8 weeks of age improved peripheral insulin sensitivity in male db/db mice, a model for type 2 diabetes. Notably, MR significantly improved working as well as long-term memory in db/db mice, accompanied by increased PSD-95 level and reduced neuroinflammatory factors, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). We speculate that this effect may be mediated by MR activating hepatic fibroblast growth factor 21 (FGF21) and the brain FGFR1/AMPK/GLUT4 signaling pathway to enhance brain glucose metabolism. To further delineate the mechanism, we used intracerebroventricular injection of adeno-associated virus to specifically knock down FGFR1 in the brain to verify the role of FGFR1 in MR-mediated DACI. It was found that the positive effects of MR on DACI were offset, reflected in decreased cognitive function, impaired synaptic plasticity, upregulated neuroinflammation, and balanced enzymes regulating reactive oxygen species (Sod1, Sod2, Nox4). Of note, the FGFR1/AMPK/GLUT4 signaling pathway and brain glucose metabolism were inhibited. In summary, our study demonstrated that MR increased peripheral insulin sensitivity, activated brain FGFR1/AMPK/GLUT4 signaling through FGF21, maintained normal glucose metabolism and redox balance in the brain, and thereby alleviated DACI. These results provide new insights into the effects of MR diet on cognitive dysfunction caused by impaired brain energy metabolism.

Single-Atom Ce-N-C Nanozyme Ameliorates Type 2 Diabetes Mellitus by Improving Glucose Metabolism Disorders and Reducing Oxidative Stress.

Type 2 diabetes mellitus (T2DM) as a chronic metabolic disease has become a global public health problem. Insulin resistance (IR) is the main pathogenesis of T2DM. Oxidative stress refers to an imbalance between free radical production and the antioxidant system, causing insulin resistance and contributing to the development of T2DM via several molecular mechanisms. Besides, the reduction in hepatic glycogen synthesis also leads to a decrease in peripheral insulin sensitivity. Thus, reducing oxidative stress and promoting glycogen synthesis are both targets for improving insulin resistance and treating T2DM. The current study aims to investigate the pharmacological effects of single-atom Ce-N-C nanozyme (SACe-N-C) on the improvement of insulin resistance and to elucidate its underlying mechanisms using HFD/STZ-induced C57BL/6J mice and insulin-resistant HepG2 cells. The results indicate that SACe-N-C significantly improves hepatic glycogen synthesis and reduces oxidative stress, as well as pancreatic and liver injury. Specifically, compared to the T2DM model group, fasting blood glucose decreased by 29%, hepatic glycogen synthesis increased by 17.13%, and insulin secretion increased by 18.87%. The sod and GPx in the liver increased by 17.80% and 25.28%, respectively. In terms of mechanism, SACe-N-C modulated glycogen synthesis through the PI3K/AKT/GSK3β signaling pathway and activated the Keap1/Nrf2 pathway to alleviate oxidative stress. Collectively, this study suggests that SACe-N-C has the potential to treat T2DM.

Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

P3]PP, a stable, long-acting pancreatic polypeptide analogue, evokes weight lowering and pancreatic beta-cell-protective effects in obesity-associated diabetes.

To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesity-associated diabetes. Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to high-fat-fed mice with streptozotocin-induced insulin deficiency, known as HFF/STZ mice. Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PP-treated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucose-stimulated insulin secretion were improved in [P3]PP-treated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and beta-cell areas. Positive effects on islet architecture were linked to increased beta-cell proliferation and decreased apoptosis. Treatment intervention also decreased islet alpha-cell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PP-treated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes.

Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements. Following medical diagnosis of MASH, individuals were randomized to treatment (n= 16) or control (n= 8). Liver fat (magnetic resonance spectroscopy), 18-hour plasma biochemical measurements, and isotopically labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO2peak) were also measured mid-intervention. Those in the treatment group were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Controls continued physician-directed care. Treatment induced significant (p <0.05) reductions in body weight, fat mass, and liver injury, while VO2peak (p <0.05) and non-esterified fatty acid suppression (p= 0.06) were improved. Both groups exhibited reductions in total energy intake, hemoglobin A1c, hepatic insulin resistance, and liver fat (p <0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO2peak and resolution of liver disease. Exercise and energy restriction elicited significant and clinically meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH. The mechanisms that underpin histologic improvement in individuals with metabolic dysfunction-associated steatohepatitis (MASH) are not well understood. This study evaluated the relationship between liver and metabolic health, testing how changes in one may affect the other. We investigated the effects of energy restriction and exercise on the association between multi-tissue insulin sensitivity and histologic improvements in participants with biopsy-proven MASH. For the first time, these results show that an improvement in peripheral (but not hepatic) insulin sensitivity and systemic markers of muscle function (i.e. cardiorespiratory fitness) were strongly related to resolution of liver disease. Extrahepatic disposal of substrates and improved fitness levels supported histologic improvement, confirming the addition of exercise as crucial to lifestyle interventions in MASH. NCT03151798.

Myofiber-specific lipidomics unveil differential contributions to insulin sensitivity in individuals of African and European ancestry

AimsIndividuals of African ancestry (AA) present with lower insulin sensitivity compared to their European counterparts (EA). Studies show ethnic differences in skeletal muscle fiber type (lower type I fibers in AA), muscle fat oxidation capacity (lower in AA), whilst no differences in total skeletal muscle lipids. However, skeletal muscle lipid subtypes have not been examined in this context. We hypothesize that lower insulin sensitivity in AA is due to a greater proportion of type II (non-oxidative) muscle fibers, and that this would result in an ancestry-specific association between muscle lipid subtypes and peripheral insulin sensitivity. To test this hypothesis, we examined the association between insulin sensitivity and muscle lipids in AA and EA adults, and in an animal model of insulin resistance with muscle-specific fiber types. MethodsIn this cross-sectional study, muscle biopsies were obtained from individuals with a BMI ranging from normal to overweight with AA (N = 24) and EA (N = 19). Ancestry was assigned via genetic admixture analysis; peripheral insulin sensitivity via hyperinsulinaemic–euglycemic clamp; and myofiber content via myosin heavy chain immunohistochemistry. Further, muscle types with high (soleus) and low (vastus lateralis) type I fiber content were obtained from high-fat diet-induced insulin resistant F1 mice and littermate controls. Insulin sensitivity in mice was assessed via intraperitoneal glucose tolerance test. Mass spectrometry (MS)-based lipidomics was used to measure skeletal muscle lipid. ResultsCompared to EA, AA had lower peripheral insulin sensitivity and lower oxidative type 1 myofiber content, with no differences in total skeletal muscle lipid content. Muscles with lower type I fiber content (AA and vastus from mice) showed lower levels of lipids associated with fat oxidation capacity, i.e., cardiolipins, triacylglycerols with low saturation degree and phospholipids, compared to muscles with a higher type 1 fiber content (EA and soleus from mice). Further, we found that muscle diacylglycerol content was inversely associated with insulin sensitivity in EA, who have more type I fiber, whereas no association was found in AA. Similarly, we found that insulin sensitivity in mice was associated with diacylglycerol content in the soleus (high in type I fiber), not in vastus (low in type I fiber).Conclusions; Our data suggest that the lipid contribution to altered insulin sensitivity differs by ethnicity due to myofiber composition, and that this needs to be considered to increase our understanding of underlying mechanisms of altered insulin sensitivity in different ethnic populations.

Kisspeptin signalling and its correlation with placental ultrastructure and clinical outcomes in pregnant South African women with obesity and gestational diabetes

IntroductionGestational diabetes mellitus (GDM) is a major pregnancy metabolic disorder and is strongly linked with obesity. Kisspeptin is a hormone that increases several thousand-fold in the maternal circulation during human pregnancy, with placenta as its main source. Studies have suggested that kisspeptin regulates trophoblast invasion and promotes pancreatic insulin secretion and peripheral insulin sensitivity. MethodsIn a well-characterized cohort of pregnant South African women and molecular and histological techniques, this study explored the impact and interaction of maternal obesity and GDM on kisspeptin (KISS1) signalling in relation to placental morphology and maternal and neonatal parameters. ResultsWe found that GDM had no effect on placental KISS1 and KISS1R (KISS1 receptor) mRNA and/or protein expression. However, obesity reduced placental KISS1R mRNA expression even though overall KISS1 protein abundance or localization was not different from the non-obese group. Maternal and cord circulating KISS1 concentrations did not vary with obesity or GDM, but maternal circulating KISS1 was positively correlated with placenta weight in non-GDM obese women, and negatively correlated with placental intervillous space volume in non-GDM non-obese women. Cord serum KISS1 was positively correlated with infant weight in GDM obese women, but negatively correlated with maternal BMI in the non-obese GDM group. Placental syncytiotrophoblast extracellular vesicles exhibited detectable KISS1 and its abundance was ∼50 % lower in those from obese GDM compared to non-GDM women. DiscussionThis study shows maternal obesity and GDM can modulate placental kisspeptin signalling and placental morphological development with potential pathophysiological implications for clinically-relevant pregnancy and perinatal outcomes.

Positive Effects of Physical Activity on Insulin Signaling.

Physical activity is integral to metabolic health, particularly in addressing insulin resistance and related disorders such as type 2 diabetes mellitus (T2DM). Studies consistently demonstrate a strong association between physical activity levels and insulin sensitivity. Regular exercise interventions were shown to significantly improve glycemic control, highlighting exercise as a recommended therapeutic strategy for reducing insulin resistance. Physical inactivity is closely linked to islet cell insufficiency, exacerbating insulin resistance through various pathways including ER stress, mitochondrial dysfunction, oxidative stress, and inflammation. Conversely, physical training and exercise preserve and restore islet function, enhancing peripheral insulin sensitivity. Exercise interventions stimulate β-cell proliferation through increased circulating levels of growth factors, further emphasizing its role in maintaining pancreatic health and glucose metabolism. Furthermore, sedentary lifestyles contribute to elevated oxidative stress levels and ceramide production, impairing insulin signaling and glucose metabolism. Regular exercise induces anti-inflammatory responses, enhances antioxidant defenses, and promotes mitochondrial function, thereby improving insulin sensitivity and metabolic efficiency. Encouraging individuals to adopt active lifestyles and engage in regular exercise is crucial for preventing and managing insulin resistance and related metabolic disorders, ultimately promoting overall health and well-being.

Chronic UCN2 Administration Alters Muscle Mass, Exercise Metabolism, and Exercise Capacity in Lean Mice

Urocortin 2 (UCN2) is a member of the corticotropin-releasing hormone (CRH) family and an agonist of the G protein-coupled receptor CRH receptor type 2 (CRHR2), which is highly expressed in skeletal muscle but absent from liver in both rodents and humans. UCN2 overexpression or chronic administration increases muscle mass in both lean and diet-induced obese (DIO) mice and is also believed to increase peripheral insulin sensitivity, reminiscent of the effect of acute exercise. However, how these effects of UCN2 may impact muscle function and exercise capacity remain incompletely understood. We hypothesized that treatment with a long term UCN2 treatment would increase lean and muscle mass and improve aerobic exercise capacity in lean, healthy mice. Lean 10-week-old male C57Bl/6J mice completed treadmill acclimatization and an incremental running test to exhaustion to determine maximal running distance and peak oxygen consumption (VO2). Mice were assigned to sedentary or maximal running groups and were treated with UCN2 for 18 days. After the final dose, body composition was assessed by qNMR. Vehicle- and UCN2-treated mice assigned to the maximal running group completed a second maximal test, and immediately upon completion of exercise, blood glucose was measured, and tissues were collected. Blood glucose and tissues were collected from sedentary vehicle- and UCN2-treated mice in the fed state. UCN2 treatment increased food intake, qNMR lean mass, and individual muscle weights. UCN2-treated mice had reduced maximal running distance, peak VO2, and blood glucose in response to exercise compared to vehicle mice. In addition, UCN2-treated mice had reduced hepatic glycogen in both the sedentary and post maximal exercise states. Gastrocnemius muscle from sedentary UCN2-treated mice had increased glycogen content and reduced phosphorylation of glycogen synthase. Following maximal exercise, UCN2-treated mice had higher gastrocnemius glycogen compared to vehicle mice. This indicated similar total glycogen utilization between treatment groups in response to maximal exercise, despite UCN2-treated mice performing less work. Follow-up studies in sedentary mice demonstrated UCN2 dosing increased phosphorylation of proteins involved in insulin-dependent and -independent glucose uptake in gastrocnemius muscle. These findings indicate that UCN2 affects whole-body and muscle substrate utilization and glucose regulation and signaling which results in increased muscle mass and altered exercise capacity. However, the unpredictability of the effects of UCN2 agonism on these parameters requires much further study. This research was funded by Eli Lilly and Company. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Beta cell-derived exosomes from KDM6A KO mice enhances glucose uptake via upregulation of GLUT4 in skeletal muscles and adipocytes

Exosomes are small extracellular vesicles secreted by various cell types which have gained prominence as potent mediators of intercellular communication. Beta cells play a critical role in glucose homeostasis through the production and secretion of insulin. Lysine demethylase 6A (KDM6A) belongs to the KDM6 family of histone H3 lysine 27 (H3K27) demethylases which is important for the development of various organs. Our previous study showed that beta cell-specific knockout of KDM6A increased glucose tolerance and enhanced peripheral insulin sensitivity in mice. The aim of this study is to investigate whether beta cell-derived exosomes, particularly those derived from KDM6A knockout (INS1-KDM6A-KO) beta cells, regulates glucose uptake in skeletal muscles and adipocytes. We found that serum exosome concentrations were increased significantly in the INS1-KDM6A-KO group. Skeletal muscles were isolated from WT and INS1-KDM6A-K mice. GLUT4 protein expression was upregulated in skeletal muscles in INS1-KDM6A-KO mice. Moreover, pancreatic islets isolated from the INS1-KDM6A-KO mice exhibited a notable increase in exosome release. Interestingly, exosomes from beta islets largely enhanced glucose uptake in cultured skeletal muscle cells and 3T3-L1 adipocytes. Meanwhile, beta cell-derived exosomes from KDM6A-KO mice upregulated GLUT4 in NOR-10 cells, especially in the presence of insulin. The findings suggest that beta cell-derived exosomes may play an important role in KDM6A deficiency-induced enhancement in insulin sensitivity likely via upregulation of GLUT4 in skeletal muscle cells and adipocytes. This work was supported by NIH R01 Grants - HL154147 and AG062375. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

Consideration of sex as a biological variable in diabetes research across twenty years

BackgroundSex differences exist in the risk of developing type 1 and type 2 diabetes, and in the risk of developing diabetes-associated complications. Sex differences in glucose homeostasis, islet and β cell biology, and peripheral insulin sensitivity have also been reported. Yet, we lack detailed information on the mechanisms underlying these differences, preventing the development of sex-informed therapeutic strategies for persons living with diabetes. To chart a path toward greater inclusion of biological sex as a variable in diabetes research, we first need a detailed assessment of common practices in the field.MethodsWe developed a scoring system to evaluate the inclusion of biological sex in manuscripts published in Diabetes, a journal published by the American Diabetes Association. We chose Diabetes as this journal focuses solely on diabetes and diabetes-related research, and includes manuscripts that use both clinical and biomedical approaches. We scored papers published across 3 years within a 20-year period (1999, 2009, 2019), a timeframe that spans the introduction of funding agency and journal policies designed to improve the consideration of biological sex as a variable.ResultsOur analysis showed fewer than 15% of papers used sex-based analysis in even one figure across all study years, a trend that was reproduced across journal-defined categories of diabetes research (e.g., islet studies, signal transduction). Single-sex studies accounted for approximately 40% of all manuscripts, of which > 87% used male subjects only. While we observed a modest increase in the overall inclusion of sex as a biological variable during our study period, our data highlight significant opportunities for improvement in diabetes research practices. We also present data supporting a positive role for journal policies in promoting better consideration of biological sex in diabetes research.ConclusionsOur analysis provides significant insight into common practices in diabetes research related to the consideration of biological sex as a variable. Based on our analysis we recommend ways that diabetes researchers can improve inclusion of biological sex as a variable. In the long term, improved practices will reveal sex-specific mechanisms underlying diabetes risk and complications, generating knowledge to enable the development of sex-informed prevention and treatment strategies.

Molecular mechanism responsible for sex differences in electrical activity of mouse pancreatic β cells.

In humans, type 2 diabetes mellitus shows a higher prevalence in men compared with women, a phenotype that has been attributed to a lower peripheral insulin sensitivity in men. Whether sex-specific differences in pancreatic β cell function also contribute is largely unknown. Here, we characterized the electrophysiological properties of β cells in intact male and female mouse islets. Elevation of glucose concentration above 5 mM triggered an electrical activity with a similar glucose dependence in β cells of both sexes. However, female β cells had a more depolarized membrane potential and increased firing frequency compared with males. The higher membrane depolarization in female β cells was caused by approximately 50% smaller Kv2.1 K+ currents compared with males but otherwise unchanged KATP, large-conductance and small-conductance Ca2+-activated K+ channels, and background TASK1/TALK1 K+ current densities. In female β cells, the higher depolarization caused a membrane potential-dependent inactivation of the voltage-gated Ca2+ channels (CaV), resulting in reduced Ca2+ entry. Nevertheless, this reduced Ca2+ influx was offset by a higher action potential firing frequency. Because exocytosis of insulin granules does not show a sex-specific difference, we conclude that the higher electrical activity promotes insulin release in females, improving glucose tolerance.

Mixed nut consumption improves brain insulin sensitivity: a randomized, single-blinded, controlled, crossover trial in older adults with overweight or obesity

BackgroundImproving brain insulin sensitivity, which can be assessed by measuring regional cerebral blood flow (CBF) responses to intranasal insulin, may prevent age-related metabolic and cognitive diseases. ObjectivesThis study aimed to investigate longer-term effects of mixed nuts on brain insulin sensitivity in older individuals with overweight/obesity. MethodsIn a randomized, single-blinded, controlled, crossover trial, 28 healthy adults (mean ± standard deviation: 65 ± 3 years; body mass index: 27.9 ± 2.3 kg/m2) received either daily 60-g mixed nuts (15 g of walnuts, pistachio, cashew, and hazelnuts) or no nuts (control) for 16 weeks, separated by an 8-week washout period. Throughout the study, participants were instructed to adhere to the Dutch food-based dietary guidelines. During follow-up, brain insulin action was assessed by quantifying acute effects of intranasal insulin on regional CBF using arterial spin labeling magnetic resonance imaging. Furthermore, effects on peripheral insulin sensitivity (oral glucose tolerance test), intrahepatic lipids, and cardiometabolic risk markers were assessed. ResultsBody weight and composition did not change. Compared with control, mixed nut consumption improved regional brain insulin action in 5 clusters located in the left (difference in CBF responses to intranasal insulin: −4.5 ± 4.7 mL/100 g/min; P < 0.001; −4.6 ± 4.8 mL/100 g/min; P < 0.001; and −4.3 ± 3.6 mL/100 g/min; P = 0.007) and right occipital lobes (−4.3 ± 5.6 mL/100 g/min; and −3.9 ± 4.9 mL/100 g/min; P = 0.028). A fifth cluster was part of the left frontal lobe (−5.0 ± 4.6 mL/100 g/min; P < 0.001). Peripheral insulin sensitivity was not affected. Intrahepatic lipid content (−0.7%-point; 95% CI: −1.3%-point to −0.1%-point; P = 0.027), serum low-density lipoprotein cholesterol concentration (−0.24 mmol/L; 95% CI: −0.44 to −0.04 mmol/L; P = 0.019), and systolic blood pressure (−5 mm Hg; 95% CI: −8 to −1 mm Hg; P = 0.006) were lower after the mixed nut intervention. ConclusionsLonger-term mixed nut consumption affected insulin action in brain regions involved in the modulation of metabolic and cognitive processes in older adults with overweight/obesity. Intrahepatic lipid content and different cardiometabolic risk markers also improved, but peripheral insulin sensitivity was not affected.This trial was registered at clinicaltrials.gov as NCT04210869.

Fetuin B in white adipose tissue induces inflammation and is associated with peripheral insulin resistance in mice and humans.

Fetuin B is a steatosis-responsive hepatokine that causes glucose intolerance in mice, but the underlying mechanisms remain incompletely described. This study aimed to elucidate the mechanisms of action of fetuin B by investigating its putative effects on white adipose tissue metabolism. First, fetuin B gene and protein expression was measured in multiple organs in mice and in cultured adipocytes. Next, the authors performed a hyperinsulinemic-euglycemic clamp in mice and in humans to examine the link between white adipose tissue fetuin B content and indices of insulin sensitivity. Finally, the effect of fetuin B on inflammation was investigated in cultured adipocytes by quantitative polymerase chain reaction and full RNA sequencing. This study demonstrated in adipocytes and mice that fetuin B was produced and secreted by the liver and taken up by adipocytes and adipose tissue. There was a strong negative correlation between white adipose tissue fetuin B content and peripheral insulin sensitivity in mice and in humans. RNA sequencing and polymerase chain reaction analysis revealed that fetuin B induced an inflammatory response in adipocytes. Fetuin B content in white adipose tissue strongly associated with peripheral insulin resistance in mice and humans. Furthermore, fetuin B induced a proinflammatory response in adipocytes, which might drive peripheral insulin resistance.

A decreased level of high-density lipoprotein is a possible risk factor for type 2 diabetes mellitus: A review.

Type 2 diabetes mellitus (T2DM) is characterized primarily by dyslipidemia and hyperglycemia due to insulin resistance. High-density lipoprotein (HDL) play a significant role in preventing the incidence of dyslipidemia and its complications. HDL has different protective functions, such as reducing oxidation, vascular inflammation, and thrombosis; additionally, its anti-diabetic role is one of the most significant recent discoveries about HDL and some of its constituent lipoproteins. This research reviews ongoing studies and preliminary investigations into the assessment of relation between decreased level of HDL and T2DM. The levels of HDL and its functions contribute to glucose hemostasis and the development of T2DM through four possible mechanisms, including insulin secretion by beta cells, peripheral insulin sensitivity, non-insulin-dependent glucose uptake, and adipose tissue metabolic activity. Additionally, the anti-oxidant properties of HDL protect beta cells from apoptosis caused by oxidative stress and inflammation induced by low-density lipoprotein, which facilitate insulin secretion. Therefore, HDL and its compositions, especially Apo A-I, play an important role in regulating glucose metabolism, and decreased levels of HDL can be considered a risk factor for DM. Different factors, such as hypoalphalipoproteinemia that manifests as a consequence of genetic factors, such as Apo A-I deficiency, as well as secondary causes arising from lifestyle choices and underlying medical conditions that decrease the level of HDL, could be associated with DM. Moreover, intricate connections between HDL and diabetic complications extend beyond glucose metabolism to encompass complications like cardiovascular disease and kidney disease. Therefore, the exact interactions between HDL level and DM should be evaluated in future studies.

Imaging the brain to assess brain insulin action

AbstractBackgroundEver since the brain was identified as an insulin‐sensitive organ, it was quickly appreciated that insulin action in the brain affects cognitive and metabolic processes [1]. Epidemiological evidence suggests a strong link between reduced peripheral insulin sensitivity and age‐related neurodegenerative processes, including Alzheimer’s disease (AD) [2].MethodCharacterization of brain insulin resistance in humans is challenging and relies on different neuroimaging methods in combination with insulin stimulation techniques. In my talk, I will focus on the administration of intranasal insulin, which has been established over the last decades to disentangle peripheral from brain insulin effects [1]. In combination with functional neuroimaging, I will show recent data on the quantification of brain insulin sensitivity non‐invasively in humans of different age and weight groups [3].ResultWe could show that intranasal insulin can affect region‐specific activity and functional connectivity of the human brain. These diverse central insulin responses largely depend on its action in the hypothalamus, amygdala, hippocampus, striatum and parts of the insula and prefrontal cortex and influences a variety of metabolic and cognitive processes [3]. Specifically, I will show that disrupted brain insulin action can result in increased accumulation of visceral fat and altered reward learning in persons at high risk to develop T2D [4], but also in healthy individuals after overconsumption of high caloric foods (unpublished). Moreover, I will show that the effect of intranasal insulin in the hippocampus decreases with age in women but not men and that brain insulin responsivity is affected by the menstrual cycle (unpublished). Moreover, just recently, we could link enhanced brain insulin action in the mesocorticolimbic circuitry with improved cognitive and metabolic functions [5].ConclusionAs brain insulin acts on striatal dopamine function and hippocampal plasticity, enhancing brain insulin action could lead to new treatment options in diabetes and aging‐associated diseases.

Endothelial cell-specific reduction in mTOR ameliorates age-related arterial and metabolic dysfunction.

Systemic inhibition of the mammalian target of rapamycin (mTOR) delays aging and many age-related conditions including arterial and metabolic dysfunction. However, the mechanisms and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate that activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell-specific deletion of mTOR reduced protein expression by 60-70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium-dependent dilation (EDD) in old mice, indicating an improvement in age-related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial-rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development.