Development Of Glucose Intolerance Research Articles

Alteration of Sweet and Bitter Taste Sensitivity with Development of Glucose Intolerance in Non-insulin-Dependent Diabetes Mellitus Model OLETF Rats.

Patients with diabetes exhibit altered taste sensitivity, but its details have not been clarified yet. Here, we examined alteration of sweet taste sensitivity with development of glucose intolerance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of non-insulin-dependent diabetes mellitus. Compared to the cases of Long Evans Tokushima Otsuka (LETO) rats as a control, glucose tolerance of OLETF rats decreased with aging, resulting in development of diabetes at 36-weeks-old. In brief-access tests with a mixture of sucrose and quinine hydrochloride, OLETF rats at 25 or more-weeks-old seemed to exhibit lower sweet taste sensitivity than age-matched LETO ones, but the lick ratios of LETO, but not OLETF, rats for the mixture and quinine hydrochloride solutions decreased and increased, respectively, aging-dependently. Expression of sweet taste receptors, T1R2 and T1R3, in circumvallate papillae (CP) was almost the same in LETO and OLETF rats at 10- and 40-weeks-old, while expression levels of a bitter taste receptor, T2R16, were greater in 40-weeks-old rats than in 10-weeks-old ones in both strains. There was no apparent morphological alteration in taste buds in CP between 10- and 40-weeks-old LETO and OLETF rats. Metagenomic analysis of gut microbiota revealed strain- and aging-dependent alteration of mucus layer-regulatory microbiota. Collectively, we concluded that the apparent higher sweet taste sensitivity in 25 or more-weeks-old OLETF rats than in age-matched LETO rats was due to the aging-dependent increase of bitter taste sensitivity in LETO rats with alteration of the gut microbiota.

Exploring the impacts of ketogenic diet on reversible hepatic steatosis: initial analysis in male mice.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. Ketogenic diet (KD), a diet with very low intake in carbohydrates, gained popularity as a weight-loss approach. However, in mice models, it has been reported that an excess exposition of dietary fat induces hepatic insulin resistance and steatosis. However, data published is inconsistent. Herein, we investigated in a mouse model, the metabolic effects of KD and its contribution to the pathogenesis of NALFD. Mice were exposed to KD or CHOW diet for 12 weeks while a third group was exposed to KD for also 12 weeks and then switched to CHOW diet for 4 weeks to determine if we can rescue the phenotype. We evaluated the effects of diet treatments on fat distribution, glucose, and insulin homeostasis as well as hepatic steatosis. Mice fed with KD developed glucose intolerance but not insulin resistance accompanied by an increase of inflammation. KD-fed mice showed an increase of fat accumulation in white adipose tissue and liver. This effect could be explained by an increase in fat uptake by the liver with no changes of catabolism leading to MAFLD. Interestingly, we were able to rescue the phenotype by switching KD-fed mice for 4 weeks on a CHOW diet. Our studies demonstrate that even if mice develop hepatic steatosis and glucose intolerance after 12 weeks of KD, they do not develop insulin resistance and more importantly, the phenotype can be reversed by switching the mice from a KD to a CHOW.

Circadian Disruption across Lifespan Impairs Glucose Homeostasis and Insulin Sensitivity in Adult Mice.

Circadian rhythm disruption is associated with impaired glucose homeostasis and type 2 diabetes. For example, night shift work is associated with an increased risk of gestational diabetes. However, the effects of chronic circadian disruption since early life on adult metabolic health trajectory remain unknown. Here, using the "Short Day" (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was used to disrupt mouse circadian rhythms across the lifespan, we investigated glucose homeostasis in adult mice. Adult SD mice were fully entrained into the 8 h/8 h LD cycle, and control mice were entrained into the 12 h/12 h LD cycle. Under a normal chow diet, female and male SD mice displayed a normal body weight trajectory. However, female but not male SD mice under a normal chow diet displayed glucose intolerance and insulin resistance, which are associated with impaired insulin signaling/AKT in the skeletal muscle and liver. Under high-fat diet (HFD) challenges, male but not female SD mice demonstrated increased body weight gain compared to controls. Both male and female SD mice developed glucose intolerance under HFD. Taken together, these results demonstrate that environmental disruption of circadian rhythms contributes to obesity in a sexually dimorphic manner but increases the risk of glucose intolerance and insulin resistance in both males and females.

Sox9 regulates alternative splicing and pancreatic beta cell function

Despite significant research, mechanisms underlying the failure of islet beta cells that result in type 2 diabetes (T2D) are still under investigation. Here, we report that Sox9, a transcriptional regulator of pancreas development, also functions in mature beta cells. Our results show that Sox9-depleted rodent beta cells have defective insulin secretion, and aging animals develop glucose intolerance, mimicking the progressive degeneration observed in T2D. Using genome editing in human stem cells, we show that beta cells lacking SOX9 have stunted first-phase insulin secretion. In human and rodent cells, loss of Sox9 disrupts alternative splicing and triggers accumulation of non-functional isoforms of genes with key roles in beta cell function. Sox9 depletion reduces expression of protein-coding splice variants of the serine-rich splicing factor arginine SRSF5, a major splicing enhancer that regulates alternative splicing. Our data highlight the role of SOX9 as a regulator of alternative splicing in mature beta cell function.

TO STUDY EFFECT OF MEDICAL NUTRITION THERAPY IN PATIENTS OF GESTATIONAL DIABETES MELLITUS

Aim:To studyeffect of medical nutrition therapy on patients with gestational diabetes mellitus. Design:This is an prospective observational study and techniques used are clinical and noninvasive. Methods:The prospective observational study was conducted on 890 antenatal subjects attending antenatal clinic at tertiary care hospital during their second trimester of pregnancy. The study was conducted from 1st march 2021 to 31st august 2022.DIPSI criteria recommended by FOGSI and FIGO(2020) for GDM was used . Single step test was used irrespective of last meal and cutoff value of> 140 was used [after 2 hours] to diagnose GDM. All the subjects were followed till delivery and were divided in two groups on the basis of sugar charting 24 hours before starting any treatment. Statistical Analysis: Data was analysed using IBM- Statistical Package for Social Sciences (SPSS) version 23.0. Frequency distribution, percentages and Chi square test and spearson correlation test was used for statistical analysis. P value <0.05 was considered significant. Results:Out of 890 cases ,84 cases were screened positive .Hence incidence of GDM in present study was 9.4%.24 hours sugar charting was done and those who were having normal sugar profile around 65 patients were kept on observation only and around 17 were managed by medical nutrition therapy and other require pharmacotherapy. Conclusion:In Indian context, screening for GDM is essential in all pregnant women as the Indian women have 11 fold increased risk of developing glucose intolerance during pregnancy compared to Caucasian women. Simple test which is economical, feasible,does not require long stay or frequent visit to hospital is and causes least disturbance to pregnant womensdaily activities is required. DIPSI as a diagnostic tool for GDM issimple,one step, low cost and veryconvenient.An early diagnosis is always better as it gives enough .time to correct and prevent complications.Medical nutrition therapy is very much effective way to treat gestational diabetes mellitus as it doesnt harm baby as well as no side effects are there in this therapy. Abbreviations:Gestational diabetes mellitus-GDM,diabetes in pregnancy and study group-DIPSI.

Chronic triclosan exposure induce impaired glucose tolerance by altering the gut microbiota

Triclosan (TCS) is an antimicrobial compound incorporated into more than 2000 consumer products. This compound is frequently detected in the human body and causes ubiquitous contamination in the environment, thereby raising concerns about its impact on human health and environmental pollution. Here, we demonstrated that 20 weeks’ exposure of TCS drove the development of glucose intolerance by inducing compositional and functional alterations in intestinal microbiota in rats. Fecal-transplantation experiments corroborated the involvement of gut microbiota in TCS-induced glucose-tolerance impairment. 16S rRNA gene-sequencing analysis of cecal contents showed that TCS disrupted the gut microbiota composition in rats and increased the ratio of Firmicutes to Bacteroidetes. Cecal metabolomic analyses detected that TCS altered host metabolic pathways that are linked to host glucose and amino acid metabolism, particularly branched-chain amino acid (BCAA) biosynthesis. BCAA measurement confirmed the increase in serum BCAAs in rats exposed to TCS. Western blot and immunostaining results further confirmed that elevated BCAAs stimulated mTOR, a nutrient-sensing complex, and following IRS-1 serine phosphorylation, resulted in insulin resistance and glucose intolerance. These results suggested that TCS may induce glucose metabolism imbalance by regulating BCAA concentration by remodeling the gut microbiota.

Maternal Obesity Causes Sex Specific Long-Term Hematopoietic and Metabolic Defects

Maternal obesity is increasingly common and can negatively impact offspring health. Children born to obese mothers are at higher risk of developing diseases involved with metabolic health (e.g., type 2 diabetes). Many of these diseases are associated with abnormalities within the hematopoietic system such as atypical immune profiles or hematopoiesis. Interestingly, disease incidence and/or severity is often dependent on the offspring's gender. This suggests that there may be sex-specific reprogramming of hematopoietic stem and progenitor cells (HSPCs) during immune cell development. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health. To test this, C57BL/6 (CD45.2+) dams were fed standard chow (2018SX, Envigo, IN) or western-style diet (TD.88137, Envigo, IN) for four weeks prior to mating, through pregnancy, and the lactating period. At postnatal day 21, HSPCs (Lineage negative, Sca1 positive, cKit positive cells) were flow-sorted from bone marrow (BM) of offspring from dams fed chow (Con) or western-style diet (MatOb) and used for competitive transplant (Boy/J BM competitor cells; CD45.1+) into same-sex lethally irradiated C57BL/6 x Boy/J F1 (CD45.1+CD45.2+) recipient mice (8-10 weeks of age) or for RNA-sequencing analysis. Secondary transplants were performed to look at long-term engraftment potential of HSPCs. Body weight, body adiposity, fasting insulin, glucose tolerance test (GTT), and pancreatic β and α-cell area were assessed on male and female recipients of both primary and secondary transplants. Compared to mice that received male Con HSPCs, recipient mice that received male MatOb HSPCs had significantly lower donor chimerism in the blood and BM post-secondary transplantation. This was associated with a significant reduction in donor hematopoietic stem cell (HSC) numbers in the BM 16 weeks post-secondary transplant, indicating male MatOb HSPCs had decreased long-term engraftment capability due to an exhaustion of the HSC pool. This reduction in HSPC engraftment seen between male MatOb versus Con HSPCs was not seen when using HSPCs from female offspring. Next, metabolic parameters of our recipient mice was examined. Sixteen weeks after primary transplant, there were no differences detected in body weight and adiposity in the Con and MatOb HSPC recipient mice. Compared to sex-matched controls, we found that recipients transplanted with male MatOb HSPCs developed glucose intolerance, increased fasting serum insulin concentrations, and decreased β-cell area, supporting the presence of impaired glucose metabolism due to a combination of insulin resistance and lower β-cell mass. There was no difference in recipients of HSPCs from female Con and female MatOb pups. RNA-seq of BM HSPCs at time of transplant (p21) from Con or MatOb revealed 100 differentially expressed genes (DEG) in male MatOb HSPCs and 1788 DEG in female MatOb HSPCs. There were more and higher magnitude of differential gene expression in female mice than male, despite the long-term phenotypic differences being evident in males but not females, and the majority of genes changed in males were also altered in females. This suggests that the gene programs responsible for the observed phenotypes may be altered by maternal obesity in both male and female offspring, but that female offspring have a transcriptomic profile that confers protection on the HSPC population. One of the most striking findings from the transcriptomic analysis was a marked enrichment in gene programs associated with immune response, interferon signaling, and cytokine production in female MatOb offspring compared to sex matched controls that is not seen in male MatOb offspring. Pathway analysis identified upregulation of programs involving both IFNγ and IL-10 in the female MatOb HSPCs when compared to sex-mated Con HSPCs which correlated with an increase in IL-10 concentrations in the serum of p21 female MatOb mice. These pathways were downregulated or unaltered in males with no change in systemic IL-10 concentration.Our results demonstrate that maternal obesity results in sex-specific changes in offspring HSPC function and a novel role HSPCs may play in regulating glucose metabolism in the offspring of obese dams.

The Role of Adipokines and Myokines in the Pathogenesis of Different Obesity Phenotypes-New Perspectives.

Obesity is a characteristic disease of the twenty-first century that is affecting an increasing percentage of society. Obesity expresses itself in different phenotypes: normal-weight obesity (NWO), metabolically obese normal-weight (MONW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). A range of pathophysiological mechanisms underlie the occurrence of obesity, including inflammation, oxidative stress, adipokine secretion, and other processes related to the pathophysiology of adipose tissue (AT). Body mass index (BMI) is the key indicator in the diagnosis of obesity; however, in the case of the NWO and MONW phenotypes, the metabolic disturbances are present despite BMI being within the normal range. On the other hand, MHO subjects with elevated BMI values do not present metabolic abnormalities. The MUO phenotype involves both a high BMI value and an abnormal metabolic profile. In this regard, attention has been focused on the variety of molecules produced by AT and their role in the development of obesity. Nesfatin-1, neuregulin 4, myonectin, irisin, and brain-derived neurotrophic factor (BDNF) all seem to have protective effects against obesity. The primary mechanism underlying the action of nesfatin-1 involves an increase in insulin sensitivity and reduced food intake. Neuregulin 4 sup-presses lipogenesis, decreases lipid accumulation, and reduces chronic low-grade inflammation. Myonectin lowers the amount of fatty acids in the bloodstream by increasing their absorption in the liver and AT. Irisin stimulates the browning of white adipose tissue (WAT) and consequently in-creases energy expenditure, additionally regulating glucose metabolism. Another molecule, BDNF, has anorexigenic effects. Decorin protects against the development of hyperglycemia, but may also contribute to proinflammatory processes. Similar effects are shown in the case of visfatin and chemerin, which may predispose to obesity. Visfatin increases adipogenesis, causes cholesterol accumulation in macrophages, and contributes to the development of glucose intolerance. Chemerin induces angiogenesis, which promotes the expansion of AT. This review aims to discuss the role of adipokines and myokines in the pathogenesis of the different obesity phenotypes.

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.

Abstract 029: Hypertensive Disorder Of Pregnancy Results In Loss Of Pancreatic Beta Cell Area In Female Rat Offspring Without Development Of Glucose Intolerance

Hypertensive disorders of pregnancy can result in increased risk for type 2 diabetes (T2D) in offspring. Reduced pancreatic beta cell area can also influence development of glucose intolerance or T2D. Using a rat model of reduced uterine perfusion pressure (RUPP) which leads to hypertension during pregnancy and intrauterine growth restriction, we previously demonstrated reduced beta cell area in female RUPP offspring vs Sham at embryonic day 19 persisting to postnatal day (PD)13. To determine if this alteration in beta cell area is associated with phenotypic changes in glucose handling as offspring mature, we assessed IPGTT (intraperitoneal glucose tolerance test), OGTT (oral glucose tolerance test) and ITT (insulin tolerance test) in PD14, PD28, 8 week and 6 month female offspring (n=5-11/group). Our results demonstrate no change in fasting blood glucose and no alteration in glucose handling with IP glucose administration at any age. However, peak glucose following oral glucose administration was significantly less in RUPP offspring at PD14 (196.3+/-8.6 mg/dl, RUPP; 218.3+/-9.5 mg/dl, Sham; p=0.05), PD28 (220.0+/-4.1 mg/dl, RUPP; 280.0+/-12.8 mg/dl, Sham; p<0.05) and 6 months (139.6+/-3.8 mg/dl, RUPP; 150.9+/-4.5 mg/dl, Sham; p<0.05) compared to Sham, suggesting the incretin effect on pancreas and non-pancreas tissues is more effective in controlling blood glucose in RUPP offspring vs Sham. In addition, the decrease in glucose level in response to insulin injection in ITT was significantly greater in RUPP offspring vs Sham at PD28 (58.9+/-5.0 mg/dl, RUPP; 78.3+/-8.9 mg/dl, Sham; p<0.05) suggesting increased insulin sensitivity in non-pancreatic tissues in RUPP compared to Sham offspring. Our studies demonstrate female offspring of hypertensive pregnancies are not glucose intolerant by 6 months of age. Despite reduced pancreatic beta cell area in female RUPP offspring early in development, glucose handling was maintained and even improved after oral glucose challenge in older RUPP offspring. Overall, these data suggest that increased peripheral insulin sensitivity may reduce the demand for beta cell function, and our studies reinforce the idea that adverse pregnancy can have a lasting effect on development and function of the pancreas.

Interaction of Iron Homeostasis and Fatty Acid Metabolism in the Development of Glucose Intolerance in Women with Previous Gestational Diabetes Mellitus.

A gestational diabetes mellitus (GDM) diagnosis during pregnancy means an increased risk of developing type 2 diabetes later in life. By following up with women after GDM we aimed to examine the relationship between iron parameters, individual fatty acids (FAs) and desaturases in the development of impaired glucose metabolism (IGM). Based on an oral glucose tolerance test (OGTT), six years after GDM, 157 women were grouped as having normal glucose tolerance (NGT) or IGM. Fasting serum FAs, activity of desaturases and iron parameters (ferritin, transferrin, iron, soluble transferrin receptor, total iron binding capacity, hepcidin) were measured, and clinical and anthropometric measurements taken. Soluble transferrin receptor was higher in the IGM group compared to the NGT group (3.87 vs. 3.29 mg/L, p-value = 0.023) and associated positively with saturated FAs and negatively with monounsaturated FAs in the IGM group (adjusted for BMI, age and high sensitivity C-reactive protein; p-value < 0.05). Iron, as well as transferrin saturation, showed a positive association with MUFAs and desaturase activity. These associations were not seen in the NGT group. These results suggest that iron homeostasis and FA metabolism interact in the development of glucose intolerance in women with previous GDM.

Pancreastatin deteriorates hepatic lipid metabolism via elevating fetuin B in ovariectomized rats

Hepatic steatosis is an important mstetabolic complication in women encountering postmenopausal phase of life. Pancreastatin (PST), has previously been investigated in diabetic and insulin resistant rodents. The present study highlighted the role of PST in ovariectomized rats. Female SD rats were ovariectomized and subsequently fed high fructose diet for 12 weeks. PST inhibitor peptide was intraperitoneally administered for 14 days and further examined for insulin resistance, glucose intolerance development, body mass composition, lipid profile detection and hepatic fibrosis. Gut microbial alterations has also been investigated. Results showed development of glucose intolerance in high fructose fed ovariectomized rats with reduced level of reproductive hormones including estradiol and progesterone. Enhanced lipid production was detected in these rats as they showed increased triglycerides, lipid accumulation in liver tissue (determined by HE staining, Oil Red O staining, Nile Red staining). Sirius Red and Masson's trichome analysis depicted positive results for fibrosis development. We also found gut microbiota alterations in fecal samples of these rats. Furthermore, PST inhibition decreased the expression of hepatic Fetuin B and resumed gut microbial diversity. PST deregulates hepatic lipid metabolism which leads to altered expression of Fetuin B in liver and gut dysbiosis in postmenopausal rats.

Microbiota-dependent and -independent effects of obesity on transplant rejection and hyperglycemia

Obesity is associated with dysbiosis and a state of chronic inflammation that contributes to the pathogenesis of metabolic diseases, including diabetes. We have previously shown that obese mice develop glucose intolerance, increased alloreactivity, and accelerated transplant rejection. In the present study, we investigated the influence of the microbiota on diet-induced obesity (DIO)–associated transplant rejection and hyperglycemia. Antibiotic treatment prolonged graft survival and reduced fasting glycemia in high-fat diet (HFD)–fed specific-pathogen-free (SPF) mice, supporting a role for the microbiota in promoting accelerated graft rejection and hyperglycemia induced by DIO. Further supporting a microbiota-dependent effect, fecal microbiota transfer from DIO SPF mice into germ-free mice also accelerated graft rejection when compared with lean mice-fecal microbiota transfer. Notably, HFD could be also detrimental to the graft independently from microbiota, obesity, and hyperglycemia. Thus, whereas HFD-associated hyperglycemia was exclusively microbiota-dependent, HFD affected transplant outcomes via both microbiota-dependent and -independent mechanisms. Importantly, hyperglycemia in DIO SPF mice could be reduced by the addition of the gut commensal Alistipes onderdonkii, which alleviated both HFD-induced inflammation and glucose intolerance. Thus, microbial dysbiosis can be manipulated via antibiotics or select probiotics to counter some of the pathogenic effects of obesity in transplantation.

1578-P: Hyaluronidase-1 Inhibits Hepatic Gluconeogenesis

Hyaluronidase-1 (Hyal1) is a lysosomal hyaluronidase that intracellularly hydrolyzes hyaluronan (HA). Studies have demonstrated the critical role of Hyal1 in the development of diabetes-induced endothelium dysfunction. However, whether it plays a role in the development of glucose intolerance and obesity remains unclear. We treated Hyal1 whole-body knockout (Hyal1 KO) mice and liver specific overexpression (OE) of Hyal1 mice with a low-fat diet (LFD) or high-fat diet (HFD), Hyal1 KO mice gained similar body weight but developed glucose intolerance compared to littermate wildtype (WT) mice on HFD, the latter is primarily contributed by an increase in gluconeogenesis in the Hyal1 KO liver. In contrast, Hepatic OE of Hyal1 suppressed gluconeogenesis. However, the change in gluconeogenesis is unlikely mediated by digestion of extracellular HA by Hyal1 in the liver as albumin-driven expression of a more potent hyaluronidase Ph20 had no effect on glucose tolerance nor gluconeogenesis from pyruvate. Liver metabolites in the gluconeogenesis pathway were significantly increased by HFD, whereas this was significantly attenuated in hepatic Hyal1-OE mice. Glucose transportersGLUT1 and GLUT2 were not affected by Hyal1 OE. Hyal1 deletion does not affect overall gene expression, as revealed by mRNA-sequencing of liver. However, ATP generation measured by OCR before and after inhibiting ATPase is decreased in hepatocytes OE of Hyal1, which likely contributes to the reduced energy-consuming gluconeogenesis process in Hyal1 overexpressing hepatocytes. In summary, Hyal1 regulates gluconeogenesis independent of changes in extracellular HA content, gene expression, or glucose transporter abundance in hepatocytes. Reduced gluconeogenesis is likely due to the reprogramming of intracellular metabolism and a reduction in ATP production through a remain-to-understand lysosome to mitochondria crosstalk. Disclosure X.Chen: None. Y.Zhu: None. Funding U.S. Department of Agriculture-Agricultural Research Service (3092-51000-062)

75-OR: Cold-Responsive Proteolytic Rewiring of Mitochondria Safeguards White Fat Thermogenic Remodeling

Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity acting both as protein quality surveillance and regulatory enzymes. It remains unclear, however, whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switch such as white-to-beige conversion of adipocytes. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for conversion from white-to-beige adipocytes during white adipose tissue (WAT) browning. MitoTimer reporter and chemical thiol probe analysis reveal that thermogenic stimulation selectively promotes mitochondrial proteostasis in WAT via mitochondrial protease LONP1 both in vivo and in vitro. Disruption of LONP1-dependent proteolysis substantially impairs cold or b3-AR agonist induced adipocyte identity programming, evidenced by the remarkably attenuated formation of UCP1+ multilocular adipocytes in IWAT from Lonp1 f/f/Adipoq-Cre (LONP1 AKO) mice. LONP1 AKO mice exposed to cold had lower body temperature, elevated serum TG and FFA levels. Chow-fed LONP1 AKO mice also developed glucose intolerance. “AdipoChaser” system “pulse-chase” lineage tracing experiments confirm that LONP1 ablation markedly blocks the direct cell fate programming of pre-existing mature adipocytes. Importantly, augmented LONP1 expression corrects aging-related impairments in white-to-beige adipocytes conversion. 10-month-old adipocyte-specific Lonp1 overexpression mice had significantly lower body weight and fat mass as a result of elevated energy expenditure. Thus, the identification of LONP1 as a critical safeguard of WAT beiging holds promise for translational applications in enhancing white-to-beige adipocytes conversion capacity relevant to a variety of metabolic disease states and during aging. Disclosure T.Fu: None. W.Sun: None. Z.Zhou: None. Z.Xu: None. M.Yan: None. L.Yang: None. Y.Yin: None. Z.Gan: None.

Maternal low-calorie sweetener consumption rewires hypothalamic melanocortin circuits via a gut microbial co-metabolite pathway.

The prevalence of obesity and type 2 diabetes is growing at an alarming rate, including among pregnant women. Low-calorie sweeteners (LCSs) have increasingly been used as an alternative to sugar to deliver a sweet taste without the excessive caloric load. However, there is little evidence regarding their biological effects, particularly during development. Here, we used a mouse model of maternal LCS consumption to explore the impact of perinatal LCS exposure on the development of neural systems involved in metabolic regulation. We report that adult male, but not female, offspring from both aspartame- and rebaudioside A-exposed dams displayed increased adiposity and developed glucose intolerance. Moreover, maternal LCS consumption reorganized hypothalamic melanocortin circuits and disrupted parasympathetic innervation of pancreatic islets in male offspring. We then identified phenylacetylglycine (PAG) as a unique metabolite that was upregulated in the milk of LCS-fed dams and the serum of their pups. Furthermore, maternal PAG treatment recapitulated some of the key metabolic and neurodevelopmental abnormalities associated with maternal LCS consumption. Together, our data indicate that maternal LCS consumption has enduring consequences on the offspring's metabolism and neural development and that these effects are likely to be mediated through the gut microbial co-metabolite PAG.

The utility of plasma glycated CD59 in predicting postpartum glucose intolerance: a prospective study of women diagnosed with GDM during a period of universal GDM screening.

Gestational diabetes (GDM) is associated with the development of postpartum (PP) glucose intolerance. Plasma glycated CD59 (pGCD59) is an emerging biomarker for the detection of hyperglycaemia. The aim of this study was to assess the ability of PP pGCD59 to predict the development of PP GI as defined by the 2h 75 g OGTT using the ADA criteria, in a cohort of women diagnosed with prior GDM in the index pregnancy using the 2h 75 g OGTT at 24-28 weeks of gestation according to the World Health Organisation (WHO) 2013 criteria METHODS: Of the 2017 pregnant women recruited prospectively 140 women with gestational diabetes had samples for pGCD59 taken PP at the time of the OGTT. The ability of pGCD59 to predict the results of the PP OGTT was assessed using nonparametric receiver operating characteristic (ROC) curves. Women with PP glucose intolerance had significantly higher PP pGCD59 levels compared to women with normal glucose tolerance PP (3.8 vs 2.7 SPU). PP pGCD59 identified women who developed glucose intolerance PP with an AUC of 0.80 (95% CI:0.70-0.91). A PP pGCD59 cut-off value of 1.9 SPU generated a sensitivity of 100% (95%CI:83.9-100), specificity of 16.9% (95%CI:9.8-26.3), positive predictive value of 22.1% (95%CI:21.0-22.6), and negative predictive value of 100% (95%CI:87.4-100). PP fasting plasma glucose generated an AUC of 0.96 (95%CI:0.89-0.99) for the identification of PP glucose intolerance. Our study found that PP pGCD9 may be a promising biomarker to identify women not requiring PP glucose intolerance screening using the traditional OGTT. While the diagnostic accuracy of pGCD59 is good, fasting plasma glucose remains a better test for the identification of PP glucose intolerance.

Diet-Induced Obese Male Mice Treated with a Rationally Designed P450 8B1 Inhibitor for 28 Days Successfully Increased CDCA to CA Ratios but Lacked Improved Glucose Tolerance and Body Weight

Altering the bile acid composition by inhibiting cytochrome P450 8B1 enzyme (CYP8B1) activity results in a decrease in the production of cholic acid (CA, 12α-hydroxylated bile acids) while increasing chenodeoxycholic acid (CDCA). Previous studies have shown that knocking out the Cyp8b1 gene in mice protects against diet-induced obesity and improves glucose tolerance and fat deposition in the liver. The objective of this study was to test the hypothesis that the inhibition of P450 8B1 enzyme activity with a rationally designed small molecule drug would alleviate diet-induced obesity and improve metabolic health. Male C57BL/6J mice (8-10 weeks old) were fed a high-fat and high sucrose (HF) diet over 10 weeks. When mice in the HF group were obese and developed glucose intolerance, half of the mice were treated with P450 8B1 inhibitor (HF/D), and the other half were treated with vehicle (HF/V, 20% β-hydroxypropyl cycolodextrin in the PBS). Mice fed a low fat and low sucrose diet treated with vehicle were used as a reference control (LF/V). Mice in the HF/D group were treated with 100 mg/kg/day, while mice in the vehicle groups (HF/V and LF/V) were administered with the same volume of vehicle. All mice were treated at the same time each morning by oral gavage for 28 days. Bodyweight and food intake were measured weekly. Glucose (GTT)- and insulin tolerance (ITT) tests were conducted before treatment and after treatment. Stool samples were extracted to measure the amount of CDCA and CA by high-resolution mass spectrometry. We found that the HF/D group did not have altered body weight, food intake, and fat composition compared to the HF/V group for the duration of the treatment (28 days). In addition, the HF/D group did not show any improvement in GTT and ITT during the 28 days of treatment. Despite these results related to body weight, GTT, and ITT, the stool samples from the HF/D group generally had a larger ratio of CDCA to CA compared to the HF/V group (CDCA/CA ratios for HF/D vs. HF/V were: 5.5, 9.4, 2.7, 4.1, 3.3 vs. 0.5, 1.5, 2.2, 8.4), suggesting that the inhibition of P450 8B1 did occur in the HFD group. The lipid droplet in the liver also decreased in some mice treated in the HF/D group. Our results suggest that a newly designed inhibitor that has a higher affinity towards the P450 8B1 enzyme relative to our originally designed inhibitor may reduce fatty liver diseases by modifying bile acid composition more effectively. Alternatively, future studies are warranted where the HF mice will be treated for a duration longer than 28 days to check whether the CDCA/CA ratio matches the physiological alterations including body weight and glucose homeostasis. This study was supported by the National Institute of Health [NIH, NIGMS, grant GM125603] to E. Chung This is the full abstract presented at the American Physiology Summit 2023 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.

Hepatic leucine carboxyl methyltransferase 1 (LCMT1) contributes to high fat diet-induced glucose intolerance through regulation of glycogen metabolism

Impaired glucose regulation is one of the most important risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which have become a major public health issue worldwide. Dysregulation of carbohydrate metabolism in liver has been shown to play a critical role in the development of glucose intolerance but the molecular mechanism has not yet been fully understood. In this study, we investigated the role of hepatic LCMT1 in the regulation of glucose homeostasis using a liver-specific LCMT1 knockout mouse model. The hepatocyte-specific deletion of LCMT1 significantly upregulated the hepatic glycogen synthesis and glycogen accumulation in liver. We found that the liver-specific knockout of LCMT1 improved high fat diet-induced glucose intolerance and insulin resistance. Consistently, the high fat diet-induced downregulation of glucokinase (GCK) and other important glycogen synthesis genes were reversed in LCMT1 knockout liver. In addition, the expression of GCK was significantly upregulated in MIHA cells treated with siRNA targeting LCMT1 and improved glycogen synthesis. In this study, we provided evidences to support the role of hepatic LCMT1 in the development of glucose intolerance induced by high fat diet and demonstrated that inhibiting LCMT1 could be a novel therapeutic strategy for the treatment of glucose metabolism disorders.

Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma

Glycemic alterations are frequent in patients with pheochromocytoma and paraganglioma (PPGL), but the real incidence of secondary diabetes mellitus (DM) is uncertain, because prospective multicenter studies on this topic are lacking in the literature. The main pathophysiological mechanisms of glucose homeostasis alterations in PPGL, related to catecholamine hypersecretion, are impaired insulin and glucagon-like peptide type 1 (GLP-1) secretion and increased insulin resistance. Moreover, it has been reported that different pathways leading to glucose intolerance may be related to the secretory phenotype of the chromaffin tumor. Predictive factors for the development of glucose intolerance in PPGL patients are a higher age at diagnosis, the need for a higher number of anti-hypertensive drugs, and the presence of secreting neoplasms. Tumor resection is strongly related to the resolution of DM in PPGL patients, with a significant improvement of glycemic control in most cases. We can hypothesize a different personalized therapeutic approach based on the secretory phenotype. The adrenergic phenotype is more closely related to reduced insulin secretion, so insulin therapy may be required. On the other hand, the noradrenergic phenotype mainly acts by increasing insulin resistance and, therefore, insulin-sensitizing antidiabetic agents can find a greater application. Regarding GLP-1 receptor agonists, the data suggest a possible promising therapeutic effect, based on the assumption that GLP-1 secretion is impaired in patients with PPGL. The principal predictors of remission of glycemic alterations after surgery for PPGL are a lower preoperative body mass index (BMI), a larger tumor, higher preoperative catecholamine levels, and a shorter duration of the disease (under three years). Otherwise, after resection of PPGL, hypoglycemia can occur as the result of an excessive rebound of preoperative hyperinsulinemia. It is a rare, but potentially severe complication reported in a lot of case reports and a few small retrospective studies. Higher 24-h urinary metanephrine levels, longer operative times and larger tumors are predictive factors for hypoglycemia in this setting. In conclusion, alterations of carbohydrate metabolism are clinically relevant manifestations of PPGL before and after surgery, but there is the need to conduct multicenter prospective studies to obtain an adequate sample size, and to allow the creation of shared strategies for the clinical management of these potentially severe manifestations of PPGL.