Glucose Tolerance In Males Research Articles

Female Psammomys obesus Are Protected from Circadian Disruption-Induced Glucose Intolerance, Cardiac Fibrosis and Adipocyte Dysfunction.

Circadian disruption increases the development of cardiovascular disease and diabetes. We found that circadian disruption causes glucose intolerance, cardiac fibrosis and adipocyte tissue dysfunction in male sand rats, Psammomys obesus. Whether these effects occur in female P. obesus is unknown. Male and female P. obesus were fed a high energy diet and exposed to a neutral (12 light:12 dark, control) or short (5 light:19 dark, circadian disruption) photoperiod for 20 weeks. Circadian disruption impaired glucose tolerance in males but not females. It also increased cardiac perivascular fibrosis and cardiac expression of inflammatory marker Ccl2 in males, with no effect in females. Females had reduced proapoptotic Bax mRNA and cardiac Myh7:Myh6 hypertrophy ratio. Cardiac protection in females occurred despite reductions in the clock gene Per2. Circadian disruption increased adipocyte hypertrophy in both males and females. This was concomitant with a reduction in adipocyte differentiation markers Pparg and Cebpa in males and females, respectively. Circadian disruption increased visceral adipose expression of inflammatory mediators Ccl2, Tgfb1 and Cd68 and reduced browning marker Ucp1 in males. However, these changes were not observed in females. Collectively, our study show that sex differentially influences the effects of circadian disruption on glucose tolerance, cardiac function and adipose tissue dysfunction.

Gestational Early-Time Restricted Feeding Results in Sex-Specific Glucose Intolerance in Adult Male Mice.

The timing of food intake is a novel dietary component that impacts health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. The timing of eating may be an important factor to consider during critical periods, such as pregnancy. Nutrition during pregnancy, too, can have a lasting impact on offspring health. The timing of food intake has not been thoroughly investigated in models of pregnancy, despite evidence that interest in the practice exists. Therefore, using a mouse model, we tested body composition and glycemic health of gestational early TRF (eTRF) in male and female offspring from weaning to adulthood on a chow diet and after a high-fat, high-sucrose (HFHS) diet challenge. Body composition was similar between groups in both sexes from weaning to adulthood, with minor increases in food intake in eTRF females and slightly improved glucose tolerance in males while on a chow diet. However, after 10 weeks of HFHS, male eTRF offspring developed glucose intolerance. Further studies should assess the susceptibility of males, and apparent resilience of females, to gestational eTRF and assess mechanisms underlying these changes in adult males.

Effect of different levels of acute hypoxia on subsequent oral glucose tolerance in males with overweight: A balanced cross-over pilot feasibility study.

Previous research has shown that ≤60 min hypoxic exposure improves subsequent glycaemic control, but the optimal level of hypoxia is unknown and data are lacking from individuals with overweight. We undertook a cross-over pilot feasibility study investigating the effect of 60-min prior resting exposure to different inspired oxygen fractions (CON FI O2 =0.209; HIGH FI O2 =0.155; VHIGH FI O2 =0.125) on glycaemic control, insulin sensitivity, and oxidative stress during a subsequent oral glucose tolerance test (OGTT) in males with overweight (mean (SD) BMI=27.6 (1.3) kg/m2 ; n=12). Feasibility was defined by exceeding predefined withdrawal criteria for peripheral blood oxygen saturation (SpO2 ), partial pressure of end-tidal oxygen or carbon dioxide and acute mountain sickness (AMS), and dyspnoea symptomology. Hypoxia reduced SpO2 in a stepwise manner (CON=97(1)%; HIGH=91(1)%; VHIGH=81(3)%, p < 0.001), but did not affect peak plasma glucose concentration (CON=7.5(1.8) mmol∙L-1 ; HIGH=7.7(1.1) mmol∙L-1 ; VHIGH=7.7(1.1) mmol∙L-1 ; p=0.777; η2 =0.013), plasma glucose area under the curve, insulin sensitivity, or metabolic clearance rate of glucose (p > 0.05). We observed no between-conditions differences in oxidative stress (p > 0.05), but dyspnoea and AMS symptoms increased in VHIGH (p < 0.05), with one participant meeting the withdrawal criteria. Acute HIGH or VHIGH exposure prior to an OGTT does not influence glucose homeostasis in males with overweight, but VHIGH is associated with adverse symptomology and reduced feasibility.

Role of myeloid cell leptin signaling in the regulation of glucose metabolism

Although innate immunity is linked to metabolic health, the effect of leptin signaling in cells from the innate immune system on glucose homeostasis has not been thoroughly investigated. We generated two mouse models using Cre-lox methodology to determine the effect of myeloid cell-specific leptin receptor (Lepr) reconstitution and Lepr knockdown on in vivo glucose metabolism. Male mice with myeloid cell-specific Lepr reconstitution (Lyz2Cre+LeprloxTB/loxTB) had better glycemic control as they aged compared to male mice with whole-body transcriptional blockade of Lepr (Lyz2Cre−LeprloxTB/loxTB). In contrast, Lyz2Cre+LeprloxTB/loxTB females only had a trend for diminished hyperglycemia after a prolonged fast. During glucose tolerance tests, Lyz2Cre+LeprloxTB/loxTB males had a mildly improved plasma glucose profile compared to Cre− controls while Lyz2Cre+LeprloxTB/loxTB females had a similar glucose excursion to their Cre− controls. Myeloid cell-specific Lepr knockdown (Lyz2Cre+Leprflox/flox) did not significantly alter body weight, blood glucose, insulin sensitivity, or glucose tolerance in males or females. Expression of the cytokine interleukin 10 (anti-inflammatory) tended to be higher in adipose tissue of male Lyz2Cre+LeprloxTB/loxTB mice (p = 0.0774) while interleukin 6 (pro-inflammatory) was lower in male Lyz2Cre+Leprflox/flox mice (p < 0.05) vs. their respective controls. In conclusion, reconstitution of Lepr in cells of myeloid lineage has beneficial effects on glucose metabolism in male mice.

Female African Green Monkeys Exhibit Higher Insulin Sensitivity and Lower Blood Pressure than Age‐matched Males

Type 2 Diabetes (T2DM) has become the most prevalent form of diabetes worldwide. In some studies, females have increased insulin sensitivity with greater glucose tolerance than males. Pre-menopausal females may also be protected from early onset T2DM, hypertension and early onset end stage renal disease. A subpopulation of African Green Monkeys (AGM; Chlorocebus aethiops sabaeus) exhibit spontaneous glucose intolerance and co-morbidities such as insulin insensitivity, and spontaneous hypertension. The AGM’ similarities to human pathologies make them an optimal experimental model for diabetes. Thus, we hypothesize that female AGM may differ in insulin sensitivity compared to age-matched males. Healthy, middle-aged AGM were utilized (n= 22 female, n=13 male). Systolic blood pressure (SBP) was measured by forearm plethysmography. Glucose tolerance was assessed via conscious and anesthetized oral glucose tolerance tests (OGTT). All AGM were fasted 12-18 hours with water provided ad libitum. Blood glucose was measured via standard glucometry at 0, 15, 30, 60, 90, and 120 min after an oral glucose load. Conscious AGM’ OGTT were delivered as 0.75g glucose/kg body weight. Anesthetized AGM (ketamine, 15mg/kg, i.m.), received 5g/dl glucose and 15 ml/kg in water. Venous blood samples were taken at 0, 30, 90 and 120 min after glucose administration in anesthetized AGM. All data between conscious and anesthetized OGTT were similar. All AGM were normotensive, however, male SBPs averaged 117.6 ± 4.2 mmHg compared with female SBPs of 104.1 ± 4.1 mmHg (p< 0.05). Female AGM area under the curve (AUC) for glucose was 12,102±466.9 min*mg/dl compared to 13,799.4±564.1 min*mg/dl for males over the 120 min after the glucose load. The peak blood glucose AUC response for females was 6,211.4 ± 219.5 min*mg/dl and 7,482 ±600.1 min*mg/dl in males (p<0.05). Insulin and C-peptide were also compared at the same time points. There were no differences in insulin or C-peptide responses between males and females. Overall renal glomerular function was assessed by measuring fasted, plasma creatinine concentrations. Average plasma creatinine was not different between males and females. These data demonstrate that middle-aged, males have decreased glucose tolerance compared to age-matched females despite similar OGTT induced changes in plasma insulin and C-peptide. Thus, middle-aged males have decreased insulin sensitivity in their response to glucose following an oral glucose load compared to females. All AGM in this study were normotensive however, females had significantly lower SBP than males, indicating that reduced glucose tolerance in males may contribute to elevated SBP. Together, the glucose and SBP data may suggest early onset of T2DM in males compared to age-matched females. This potential early onset T2DM has yet to induce overt alterations in renal glomerular filtration. Long-term studies are needed to assess whether further blood pressure elevation can lead to a decline in renal function and renal injury. Future studies will include differentiation of renal function in males and females including proteinuria, glomerular filtration, and kidney histology of AGM.

Metabolic responses to intermittent hypoxia are regulated by sex and estradiol in mice.

The roles of sex and sex-hormones on the metabolic consequences of intermittent hypoxia (IH, a reliable model of sleep apnea) are unknown. We used intact male or female mice and ovariectomized (OVX) females treated with vehicle (Veh) or estradiol (E2) and exposed to normoxia (Nx) or IH (6% O2, 10 cycles/h, 12 h/day, 2 wk). Mice were then fasted for 6 h, and we measured fasting glucose and insulin levels and performed insulin or glucose tolerance tests (ITT or GTT). We also assessed liver concentrations of glycogen, triglycerides (TGs), and expression levels of genes involved in aerobic or anaerobic metabolism. In males, IH lowered fasting levels of glucose and insulin, slightly improved glucose tolerance, but altered glucose tolerance in females. In OVX-Veh females, IH reduced fasting glucose and insulin levels and strongly impaired glucose tolerance. E2 supplementation reversed these effects and improved homeostasis model assessment of β-cell function (HOMA-β), a marker of pancreatic glucose-induced insulin released. IH decreased liver TG concentration in males and slightly increased glycogen in OVX-Veh females. Liver expression of glycolytic (Ldha) and mitochondrial (citrate synthase, Pdha1) genes was reduced by IH in males and in OVX-Veh females, but not in intact or OVX-E2 females. We conclude that 1) IH reduced fasting levels of glycemia in males and in ovariectomized females. 2) IH improves glucose tolerance only in males. 3) In females IH decreased glucose tolerance, this effect was amplified by ovariectomy, and reversed by E2 supplementation. 4) During IH exposures, E2 supplementation appears to improve pancreatic β cells functions.NEW & NOTEWORTHY We assessed fasting glycemic control, and tolerance to insulin and glucose in male and female mice exposed to intermittent hypoxia. IH improves glucose tolerance in males but had opposite effects in females. This response was amplified following ovariectomy in females and prevented by estradiol supplementation. Metabolic consequences of IH differ between males and females and are regulated by estradiol in female mice.

Deconstructing circadian disruption: Assessing the contribution of reduced peripheral oscillator amplitude on obesity and glucose intolerance in mice.

Disturbing the circadian regulation of physiology by disruption of the rhythmic environment is associated with adverse health outcomes but the underlying mechanisms are unknown. Here, the response of central and peripheral circadian clocks to an advance or delay of the light-dark cycle was determined in mice. This identified transient damping of peripheral clocks as a consequence of an advanced light-dark cycle. Similar depression of peripheral rhythm amplitude was observed in mice exposed to repeated phase shifts. To assess the metabolic consequences of such peripheral amplitude depression in isolation, temporally chimeric mice lacking a functional central clock (Vgat-Cre+ Bmal1fl/fl ) were housed in the absence of environmental rhythmicity. In vivo PER2::LUC bioluminescence imaging of anesthetized and freely moving mice revealed that this resulted in a state of peripheral amplitude depression, similar in severity to that observed transiently following an advance of the light-dark cycle. Surprisingly, our mice did not show alterations in body mass or glucose tolerance in males or females on regular or high-fat diets. Overall, our results identify transient damping of peripheral rhythm amplitude as a consequence of exposure to an advanced light-dark cycle but chronic damping of peripheral clocks in isolation is insufficient to induce adverse metabolic outcomes in mice.

Sex-specific metabolic responses to 6 hours of fasting during the active phase in young mice.

Night time/active phase food restriction for 6 h impaired glucose intolerance in young male and female mice. Females displayed increased capacity for lipogenesis and triglyceride storage in response to a short daily fast. Females had lower fasting insulin levels and an increased potential for utilizing fat for energy through β-oxidation compared to males. The need for the inclusion of both sexes, and the treatment of sex as an independent variable, is emphasized within the context of this fasting regime. There is growing interest in understanding the mechanistic significance and benefits of fasting physiology in combating obesity. Increasing the fasting phase of a normal day can promote restoration and repair mechanisms that occur during the post-absorptive period. Most studies exploring the effect of restricting food access on mitigating obesity have done so with a large bias towards the use of male mice. Here, we disentangle the roles of sex, food intake and food withdrawal in the response to a short-term daily fasting intervention, in which food was removed for 6h in the dark/active phase of young, 8-week-old mice. We showed that the removal of food during the dark phase impaired glucose tolerance in males and females, possibly due to the circadian disruption induced by this feeding protocol. Although both sexes demonstrated similar patterns of food intake, body composition and various metabolic markers, there were clear sex differences in the magnitude and extent of these responses. While females displayed enhanced capacity for lipogenesis and triglyceride storage, they also had low fasting insulin levels and an increased potential for utilizing available energy sources such as fat for energy through β-oxidation. Our results highlight the intrinsic biological and metabolic disparities between male and female mice, emphasizing the growing need for the inclusion of both sexes in scientific research. Furthermore, our results illustrate sex-specific metabolic pathways that regulate lipogenesis, obesity and overall metabolic health.

Sex differences in the metabolic effects of diet-induced obesity vary by age of onset.

Sex differences in the effect of diet-induced obesity (DIO) have been reported in juvenile mice. However, thorough side by side comparisons of the effects of DIO in males and females at different ages of onset have yet to be examined. We hypothesized that aged females would lose their protection, relative to males, from the effects of DIO. We examined the effect of DIO on body weight and glucose tolerance in juvenile, young adult, and middle-aged male and female mice. Our data show DIO in juvenile mice causes a greater increase in body weight and greater impairment in glucose tolerance in males than females. However, if the diet is initiated in young adult mice, these sex differences are absent. Further, if the diet is initiated in middle-aged mice, the sex difference is reversed, and females gain more weight and have greater impairment in glucose tolerance than males. Our data show that sex differences in the effect of DIO vary by age of onset; thus highlighting the importance of both age and sex as biological variables in DIO research.

Moderate vitamin A supplementation in obese mice regulates tissue factor and cytokine production in a sex-specific manner

Vitamin A (vitA) regulates obesity, insulin resistance, inflammation, dyslipidemia and hemostasis through its metabolites retinaldehyde (Rald) and retinoic acid (RA) produced in endogenous enzymatic reactions. Combination of at least 3 of these conditions leads to development of metabolic syndrome (Msyn) and, consequently, type 2 diabetes and/or cardiovascular disease. Although many foods are fortified with vitA, it remains unknown what conditions of Msyn are influenced by moderate dietary vitA supplementation. A family of aldehyde dehydrogenase 1 (Aldh1) enzymes is a key contributor to obesity via sex- and fat depot-specific production of RA in adipose tissue. Therefore, we studied effects of moderate vitamin A supplementation of an obesogenic high-fat (HF) diet (4IUvitA/g and 20IUvitA/g HF diet) on multiple conditions and mediators of Msyn in wild-type (WT, C57Bl/6) and Aldh1a1−/− mice. We found that mild vitamin A supplementation did not influence obesity, fat distribution, and glucose tolerance in males and females of the same genotype. In contrast, multiplex analysis of bioactive proteins in blood showed moderately increased concentrations (10–15%) of inflammatory IL-18 and MIP-1γ in vitA supplemented vs. control WT males. Marked decrease (28–31%) in concentrations of lymphotactin and tissue factor, a key protein contributing to thrombogenesis during injury, was achieved by vitA supplementation in WT females compared to control WT females. Aldh1a1 deficiency reduced obesity, insulin resistance, suppressed many pro-inflammatory cytokines, and abolished the effects of vitA supplementation seen in WT mice. Our study revealed specific inflammatory and pro-thrombotic proteins in plasma regulated by dietary vitamin A and the critical role of endogenous vitA metabolism in these processes. The sex-specific decrease of plasma tissue factor concentrations by moderate dietary vitA supplementation could potentially reduce pro-thrombotic states in obese females.

High fat diet induced insulin resistance and glucose intolerance are gender-specific in IGF-1R heterozygous mice

Interactions between genes and environment play a critical role in the pathogenesis of type 2 diabetes. Low birth weight, due to genetic and environmental variables affecting fetal growth, is associated with increased susceptibility to the development of type 2 diabetes and metabolic disorders in adulthood. Clinical studies have shown that polymorphisms in the Insulin-like growth factor 1 (IGF-1) gene or heterozygous mutations in IGF-1 and IGF-1 receptor (IGF-1R) genes, resulting in reduced IGF-1 action, are associated with low birth weight and post-natal growth. Mice lacking one of the IGF-1R alleles ( Igf1r +/− ) exhibit a 10% reduction in post-natal growth, and develop glucose intolerance (males) and insulin resistance (males and females) as they age. To investigate whether adverse environmental factors could accelerate the onset of the metabolic syndrome, we conducted a short duration intervention of high fat diet (HFD) feeding in male and female Igf1r +/− and wild-type (WT) control mice. The HFD resulted in insulin resistance, hyperglycemia, and impaired glucose tolerance in males of both genotypes whereas in females exacerbated diabetes was observed only in the Igf1r +/− genotype, thus suggesting a sexual dimorphism in the influence of obesity on the genetic predisposition to diabetes caused by reduced IGF-1 action.