Brown adipose tissue (BAT) and beige adipose tissues are important contributors to cold-induced whole body thermogenesis in rodents. The documentation in humans of cold- and ß-adrenergic receptor agonist-stimulated BAT glucose uptake using positron emission tomography (PET) and of a decrease of this response in individuals with cardiometabolic disorders led to the suggestion that BAT/beige adipose tissues could be relevant targets for prevention and treatment of these conditions. In this brief review, we will critically assess this question by first describing the basic rationale for this affirmation, second by examining the evidence in human studies, and third by discussing the possible means to activate the thermogenic response of these tissues in humans.

OBJECTIVE: Glycoprotein acetyls (GlycA\'s) are biomarkers of systemic inflammation and cardiovascular disease, yet little is known about their role in type 1 diabetes (T1D). In this study we examined the associations among GlycA\'s, central adiposity, insulin resistance, and early kidney injury in youth with T1D.
METHODS: Glomerular filtration rate and renal plasma flow by iohexol and p-aminohippurate clearance, urine albumin-to-creatinine ratio (UACR), central adiposity by dual-energy x-ray absorptiometry, and estimated insulin sensitivity were assessed in 50 youth with T1D (16±3.0 years of age, 50% female, glycated hemoglobin 8.7%±1.3%, T1D duration 5.7±2.6 years). Concentrations of GlycA were quantified by targeted nuclear magnetic resonance spectroscopy. Correlation and multivariable linear regression analyses were performed.
RESULTS: GlycA\'s were higher in girls vs boys (1.05±0.26 vs 0.84±0.15 mmol/L, p=0.001) and in participants living with overweight/obesity vs normal weight (1.12±0.23 vs 0.87±0.20 mmol/L, p=0.0004). GlycA\'s correlated positively with estimated intraglomerular pressure (r=0.52, p=0.001), UACR (r=0.53, p<0.0001), and trunk mass (r=0.45, p=0.001), and inversely with estimated insulin sensitivity (r=-0.36, p=0.01). All relationships remained significant after adjustment for age, sex, and glycated hemoglobin.
CONCLUSIONS: As biomarkers of inflammation, GlycA\'s were higher in girls and those with overweight or obese body habitus in T1D. GlycA\'s associated with parameters of early kidney dysfunction, central adiposity, and insulin resistance.

OBJECTIVE: Our aim in this study was to assess attitudes toward exercise and quality of life (QoL) in adults with type 1 diabetes (T1D) with and without insulin resistance (IR).
METHODS: We pooled baseline pretreatment data from a subset of individuals with T1D from 2 randomized controlled trials. Estimated glucose disposal rate (eGDR), a validated surrogate marker of IR, was calculated using an established formula to classify individuals according to IR status with a cutpoint of <6 mg/kg/min for the determination of IR. Self-reported barriers to exercise were obtained using a validated questionnaire, the Barriers to Physical Activity in T1D (BAPAD-1). In addition, QoL was determined using the 36-item Short Form (SF-36) questionnaire. Differences between dichotomized variables were assessed using the independent t test, Mann-Whitney U test, or Fisher exact test. Linear regression was employed to explore the association of eGDR with BAPAD-1 and QoL scores, with sequential adjustment for potential confounders.
RESULTS: Of the 85 individuals included in our study, 39 were classified as having IR. The mean BAPAD-1 total score was higher for individuals with IR (IR: 3.87±0.61; non-IR: 2.83±0.55; p<0.001). The highest exercise barrier scores for individuals with IR were risk of hypoglycemia (5.67±1.26) and risk of hyperglycemia (5.23±1.20), whereas the highest scoring exercise barrier scores for non-IR individuals were not diabetes-related, with low level of fitness (3.91±1.26) and physical health status, excluding diabetes (3.67±1.48), ranked highest. QoL scores were comparable between groups (p>0.05).
CONCLUSIONS: Risk of hypoglycemia was the greatest barrier to exercise in individuals with T1D with IR, whereas non-diabetes-related barriers to exercise were more salient in individuals with T1D without IR.

OBJECTIVE: Insulin resistance (IR) leads to type 2 diabetes mellitus. Multiple IR causes have been identified, including inflammation. This study determines the association between IR and the inflammatory marker C-reactive protein (CRP) in a healthy Canadian population and examines potential differences by sex and age.
METHODS: Participants were adults with no self-reported history of diabetes, a glycated hemoglobin (A1C) of <6.5%, and a fasting blood glucose of <7 mmol/L, and who had participated in the Canadian Health Measures Survey, cycles 1 to 4 (2007-2015). IR was calculated using the Homeostasis Model of Insulin Resistance (HOMA-IR) assessment. The crude geometric mean HOMA-IR was calculated using a one-way analysis of variance. The association between CRP levels and HOMA-IR was examined using multivariate linear regression.
RESULTS: A total of 4,024 eligible nondiabetic adults (1,994 [49.5%] men and 2,030 [50.4%] women) were identified. Eighty percent of the subjects were Caucasian. Among all subjects, 36% had a CRP of ≥2 mg/L. The crude geometric mean HOMA-IR was 1.33 in men and 1.24 in women. Participants with a CRP of <0.7 mg/L had a crude geometric mean HOMA-IR of 1.15 (1.13 to 1.16), compared with 1.41 (1.39 to 1.43) for those with a CRP of ≥2 mg/L. After adjusting for sex, age, race, high-density lipoprotein cholesterol, triglycerides, body mass index, smoking, and diastolic blood pressure, the HOMA-IR-CRP association remained significant. A positive trend for CRP values in men with increasing values of HOMA-IR was observed. However, this trend was not consistent with the increase in women\'s CRP levels.
CONCLUSIONS: Elevated CPR levels are independently associated with IR in men. Prospective cohort studies can confirm the causal relationship between high CRP levels and IR and identify the underlying mechanisms.

OBJECTIVE: The purpose of this study was to evaluate the effects of maternal high folic acid (FA) supplementation during pregnancy on glucose intolerance in dams and insulin resistance in offspring.
METHODS: Wistar female rats (n=18) were mated and randomly divided into 3 groups: a control group and 2 experimental groups. Three different feeding protocols were administered during pregnancy: control group, 2 mg/kg FA (recommended level FA supplementation); experimental 1 group, 5 mg/kg FA (tolerable upper intake level of FA supplementation [ULFolS]); and experimental 2 group, 40 mg/kg FA (high FA supplementation [HfolS]). All dams were fed the same FA content diet (2 mg/kg FA) during the lactation period. An oral glucose tolerance test was performed on day 16 of pregnancy. After the lactation period, body weight and food intake of 36 pups were monitored. Dams were euthanized at the end of the lactation period and half of the pups were euthanized at the end of week 7 and the others at the end of week 12. Serum FA, homocysteine, vitamin B12, insulin, glucose, interleukin-6, tumor necrosis factor-alpha, glycated hemoglobin (A1C), and adiponectin levels of mothers and pups were evaluated. The homeostatic model of insulin resistance (HOMA-IR) was used to determine insulin resistance in dams and offspring.
RESULTS: According to glucose tolerance test results of dams, blood glucose values at minutes 0, 60, 90, and 120 for the HFolS group were significantly higher compared with the control group (p<0.05). The A1C level in HFolS dams was significantly higher than in the control group (p<0.05). The mean birthweight of the pups in the HFolS group was significantly higher than that of control pups (p<0.05). HOMA-IR values for control and HFolS offspring were similar at weeks 7 and 12 and higher than in ULFolS offspring (p>0.05).
CONCLUSIONS: It was determined that high doses of FA exposure during pregnancy might be effective in the development of glucose intolerance in dams and insulin resistance in offspring in this study.

OBJECTIVE: Administration of Δ9-tetrahydrocannabinol (Δ9-THC) to pregnant rats results in glucose intolerance, insulin resistance and reduced islet mass in female, but not male, offspring. The effects of Δ9-THC on other islet hormones is not known. One downstream target of the cannabinoid receptor, stathmin-2 (Stmn2), has recently been shown to suppress glucagon secretion, thereby suggesting Δ9-THC may also affect alpha-cell function. The aim of the present study was to determine the effects of in-utero Δ9-THC exposure on the profile of glucagon, insulin and Stmn2 in the rat offspring islet and serum.
METHODS: Pregnant Wistar rat dams were injected with Δ9-THC (3 mg/kg per day, intraperitoneally) or vehicle from gestational day 6 to birth. Offspring were euthanized at postnatal day 21 (PND21) or at 5 months (adult) to collect blood and pancreata.
RESULTS: At PND21, control and Δ9-THC-exposed offspring showed that Stmn2 had a strong colocalization with glucagon (Pearson\'s correlation coefficient ≥0.6), and a weak colocalization with insulin (Pearson\'s correlation coefficient <0.4) in both males and females, with no changes by either treatment or sex. In adult female offspring in the Δ9-THC group, intensity analysis indicated an increased insulin-to-glucagon (I/G; p<0.05) ratio and a decreased glucagon-to-Stmn2 (G/S; p<0.01) ratio, and no changes in these ratios in adult males. Furthermore, Δ9-THC did not alter fasting blood glucose and serum insulin levels in either male or female adult offspring. However, female Δ9-THC-exposed offspring exhibited an increased I/G ratio (p<0.05) and decreased G/S ratio in serum by adulthood (p<0.05).
CONCLUSIONS: Collectively, the reduced G/S ratio in both islet and serum in association with an increased serum I/G ratio has direct correlations with early glucose intolerance and insulin resistance observed exclusively in females\' offspring in this prenatal cannabinoid model.

OBJECTIVE: At the time of diagnosis, the blood glucose of women with gestational diabetes mellitus (GDM) who require subsequent insulin treatment does not differ from that of women with adequate diet control. Hence, in this study, we aimed to determine the role of maternal gut microbiota as a marker of insulin necessity in GDM and to identify the effect of insulin therapy on gut microbiota composition in mothers with GDM and their newborns.
METHODS: Seventy-one pregnant women were enrolled into the study, including 38 GDM and 33 non-GDM participants. During the follow-up period, 8 of the 38 GDM subjects required insulin therapy (GDM-I group), whereas 30 of the 38 GDM cases with sufficient glycemic control by diet alone (GDM-D group). Maternal blood and feces were obtained at the time of GDM diagnosis (pretreatment; 24 to 28 weeks of gestation) and before delivery (posttreatment; ≥37 weeks of gestation). Meconium and first feces of the newborns were also collected.
RESULTS: Pretreatment, the glycemic profile did not differ between the GDM-D and GDM-I groups. However, the proportions of Clostridiales, Lactobacillus and Bacteroidetes were higher in the GDM-I group than in the non-GDM and GDM-D groups. After treatment, gut microbiota composition showed no difference between non-GDM and GDM-I groups. Interestingly, a higher Firmicutes/Bacteroidetes (F/B) ratio was displayed in GDM-D mothers at posttreatment, and this was also observed in both meconium and first feces of GDM-D newborns.
CONCLUSIONS: Insulin therapy changed maternal gut microbiota composition, which could be transferable to the mothers\' newborns.

Our lab recently reported that the blockade of endothelin-1 (ET-1) receptors attenuates insulin resistance in obese mice; therefore, we hypothesized that patients taking ET-1 receptor antagonists (ERAs) will have improved glycemic control. University of Mississippi Medical Center (2013-2020) electronic health record (EPIC) data were extracted from patients ≥18 years old with a clinical diagnosis of pulmonary hypertension (Food and Drug Administration indication for ERA use) and at least two clinical visits within 2 years. Patients prescribed ERAs (n = 11) were similar in age (61 ± 14 years vs. 60 ± 14 years), body mass index (BMI) (34 ± 8 kg/m 2 vs. 35 ± 11 kg/m2), diabetes prevalence (73% vs. 80%, p = 0.59), and follow-up time (209 ± 74 days vs. 283 ± 180 days) compared with patients not taking ERAs (n = 137). There was a small but similar decrease in BMI at follow-up in the ERA (-1.9 ± 3 kg/m2) and control patients (-1.6 ± 5 kg/m2). At follow-up, hemoglobin A1c (HbA1c) significantly decreased -12% ± 11% of baseline in patients taking ERAs, while this did not occur in the control patients (2% ± 20% increase in HbA1c). In the whole population, baseline HbA1c and ERA prescription predicted the fall in HbA1c, while there was no significant association with demographics, diabetes prevalence, and diabetic treatment. These data suggest a potential role of ET-1 in promoting insulin resistance and warrant further investigation into using these drugs for glycemic control.

d-chiro-Inositol (DCI), an isomer of inositol, possesses antioxidative and endothelial protective properties. Possibly due to a deficiency of insulin mediators, polycystic ovary syndrome (PCOS) is often associated with insulin resistance (IR) and hyperinsulinemia, likely responsible for an elevated production of reactive oxygen species. We investigated oxidative-related alterations of inositol in the blood of women with PCOS before and after treatment with DCI. A total of 38 normal-weight PCOS women were investigated before and after DCI administration (500 mg/day for 12 weeks; n = 38) by evaluating serum testosterone, serum androstenedione, fasting serum insulin, fasting serum glucose, and parameters of IR. From the blood, we determined biomarkers of oxidative stress: superoxide anion radicals, hydrogen peroxide, nitric oxide, and the index of lipid peroxidation. The activity of catalase and superoxide dismutase and the reduced glutathione (GSH) content in the hemolysate were also assessed. Data showed that PCOS patients\' plasma underwent oxidative stress, as indicated by the higher level of prooxidants and reduced cytosolic GSH content. DCI treatment significantly improved the metabolic parameters. Also, serum values of testosterone were reduced. In conclusion, PCOS patients suffer from a systemic oxidative stress that induces endothelial dysfunction. Treatment with DCI is effective in reducing hormonal, metabolic, and oxidative abnormalities in PCOS patients by improving IR.

The activation of Nod-like receptor proteins (NLRP3) containing the pyrin domain inflammasome is a hallmark of the pathogenesis of metabolic disorders. Inhibition of the NLRP3 inflammasome by phytoconstituents has been attempted as a strategy to mitigate these disorders. Therefore, the present study aimed to evaluate the efficacy of an NLRP3 inflammasome inhibitor, parthenolide (PN; 5 mg/kg i.p.) against inflammation and insulin resistance in high-fat diet (HFD) - obese mice. Treatment with PN and pioglitazone (PIO; 30 mg/kg p.o.) attenuated lipopolysaccharide (LPS; 1 ng/ml) - induced elevation of tumor necrosis factor-α and interleukin-1β in mouse peritoneal macrophages in a dose-dependent manner. Sixty days of PN and PIO treatment marginally reduced obesity-induced insulin resistance in HFD-obese mice. PN treatment also decreased blood glucose from 14th to 60th day, supporting the hypothesis of simultaneous attenuation of inflammation and insulin resistance in obese mice. Thus, PN treatment was also evident with significant improvement in glucose tolerance and peripheral insulin resistance validated through the respective tolerance tests. Therefore, the present study suggests that PN, an NLRP3 inflammasome inhibitor, could be a possible therapeutic agent for attenuating obesity-induced insulin resistance.