Metabolomics Signature in Prediabetes and Diabetes: Insights From Tandem Mass Spectrometry Analysis.

OBJECTIVE: This study investigates the metabolic differences between normal, prediabetic and diabetic patients with good and poor glycaemic control (GGC and PGC). DESIGN: In this study, 1102 individuals were included, and 50 metabolites were analysed using tandem mass spectrometry. The diabetes diagnosis and treatment standards of the American Diabetes Association (ADA) were used to classify patients. METHODS: The nearest neighbour method was used to match controls and cases in each group on the basis of age, sex and BMI. Factor analysis was used to reduce the number of variables and find influential underlying factors. Finally, Pearson's correlation coefficient was used to check the correlation between both glucose and HbAc1 as independent factors with binary classes. RESULTS: Amino acids such as glycine, serine and proline, and acylcarnitines (AcylCs) such as C16 and C18 showed significant differences between the prediabetes and normal groups. Additionally, several metabolites, including C0, C5, C8 and C16, showed significant differences between the diabetes and normal groups. Moreover, the study found that several metabolites significantly differed between the GGC and PGC diabetes groups, such as C2, C6, C10, C16 and C18. The correlation analysis revealed that glucose and HbA1c levels significantly correlated with several metabolites, including glycine, serine and C16, in both the prediabetes and diabetes groups. Additionally, the correlation analysis showed that HbA1c significantly correlated with several metabolites, such as C2, C5 and C18, in the controlled and uncontrolled diabetes groups. CONCLUSIONS: These findings could help identify new biomarkers or underlying markers for the early detection and management of diabetes.

LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

Association of Glutathione Peroxidase 3 (GPx3) and miR-196a with Carbohydrate Metabolism Disorders in the Elderly.

The escalating prevalence of carbohydrate metabolism disorders (CMDs) prompts the need for early diagnosis and effective markers for their prediction. Hyperglycemia, the primary indicator of CMDs including prediabetes and type 2 diabetes mellitus (T2DM), leads to overproduction of reactive oxygen species (ROS) and oxidative stress (OxS). This condition, resulting from chronic hyperglycemia and insufficient antioxidant defense, causes damage to biomolecules, triggering diabetes complications. Additionally, aging itself can serve as a source of OxS due to the weakening of antioxidant defense mechanisms. Notably, previous research indicates that miR-196a, by downregulating glutathione peroxidase 3 (GPx3), contributes to insulin resistance (IR). Additionally, a GPx3 decrease is observed in overweight/obese and insulin-resistant individuals and in the elderly population. This study investigates plasma GPx3 levels and miR-196a expression as potential CMD risk indicators. We used ELISA to measure GPx3 and qRT-PCR for miR-196a expression, supplemented by multivariate linear regression and receiver operating characteristic (ROC) analysis. Our findings included a significant GPx3 reduction in the CMD patients (n = 126), especially in the T2DM patients (n = 51), and a decreasing trend in the prediabetes group (n = 37). miR-196a expression, although higher in the CMD and T2DM groups than in the controls, was not statistically significant, potentially due to the small sample size. In the individuals with CMD, GPx3 levels exhibited a negative correlation with the mass of adipose tissue, muscle, and total body water, while miR-196a positively correlated with fat mass. In the CMD group, the analysis revealed a weak negative correlation between glucose and GPx3 levels. ROC analysis indicated a 5.2-fold increased CMD risk with GPx3 below 419.501 ng/mL. Logistic regression suggested that each 100 ng/mL GPx3 increase corresponded to a roughly 20% lower CMD risk (OR = 0.998; 95% CI: 0.996-0.999; p = 0.031). These results support the potential of GPx3 as a biomarker for CMD, particularly in T2DM, and the lack of a significant decline in GPx3 levels in prediabetic individuals suggests that it may not serve reliably as an early indicator of CMDs, warranting further large-scale validation.

Pregestational Prediabetes Induces Maternal Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation and Results in Adverse Foetal Outcomes.

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.

Sex-specific differences in myocardial glucose metabolic rate in non-diabetic, pre-diabetic and type 2 diabetic subjects.

BACKGROUND: Evidence has shown that women with type 2 diabetes (T2DM) have a higher excess risk for cardiovascular disease (CVD) than men with T2DM. Subjects with either T2DM or prediabetes exhibit myocardial insulin resistance, but it is still unsettled whether sex-related differences in myocardial insulin resistance occur in diabetic and prediabetic subjects. METHODS: We aimed to evaluate sex-related differences in myocardial glucose metabolic rate (MRGlu), assessed using dynamic PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp, in subjects with normal glucose tolerance (NGT; n = 20), prediabetes (n = 11), and T2DM (n = 26). RESULTS: Women with prediabetes or T2DM exhibited greater relative differences in myocardial MRGlu than men with prediabetes or T2DM when compared with their NGT counterparts. As compared with women with NGT, those with prediabetes exhibited an age-adjusted 35% lower myocardial MRGlu value (P = 0.04) and women with T2DM a 74% lower value (P = 0.006), respectively. Conversely, as compared with men with NGT, men with T2DM exhibited a 40% lower myocardial MRGlu value (P = 0.004), while no significant difference was observed between men with NGT and prediabetes. The statistical test for interaction between sex and glucose tolerance on myocardial MRGlu (P < 0.0001) was significant suggesting a sex-specific association. CONCLUSIONS: Our data suggest that deterioration of glucose homeostasis in women is associated with a greater impairment in myocardial glucose metabolism as compared with men. The sex-specific myocardial insulin resistance could be an important factor responsible for the greater effect of T2DM on the excess risk of cardiovascular disease in women than in men.

Metabolic Alteration Bridging the Prediabetic State and Colorectal Cancer.

Prediabetes and colorectal cancer (CRC) represent compelling health burdens responsible for high mortality and morbidity rates, sharing several modifiable risk factors. It has been hypothesized that metabolic abnormalities linking prediabetes and CRC are hyperglycemia, hyperinsulinemia, and adipokines imbalance. The chronic stimulation related to these metabolic signatures can favor CRC onset and development, as well as negatively influence CRC prognosis. To date, the growing burden of prediabetes and CRC has generated a global interest in defining their epidemiological and molecular relationships. Therefore, a deeper knowledge of the metabolic impairment determinants is compelling to identify the pathological mechanisms promoting the onset of prediabetes and CRC. In this scenario, this review aims to provide a comprehensive overview on the metabolic alterations of prediabetes and CRC as well as an overview of recent preventive and therapeutic approaches for both diseases, focusing on the role of the metabolic state as a pivotal contributor to consider for the development of future preventive and therapeutic strategies.

Tannic acid- and N-acetylcysteine-chitosan-modified magnetic nanoparticles reduce hepatic oxidative stress in prediabetic rats.

Magnetic nanoparticles (MNPs) modified with tannic acid (TA) have shown remarkable success as an antioxidant and antimicrobial therapeutic agent. Herein, we report a synthetic procedure for the preparation of silica-coated MNPs modified with N-acetylcysteine-modified chitosan and TA. This was achieved by free-radical grafting of NAC onto chitosan (CS), a layer-by-layer technique for modifying negatively charged MNP@SiO2 nanoparticles with positively charged CS-NAC, and crosslinking CS with TA. The antioxidant and metabolic effects of MNP@SiO2-CS-NAC and MNP@SiO2-CS-NAC-TA nanoparticles were tested in a model of prediabetic rats with hepatic steatosis, the hereditary hypertriglyceridemic rats (HHTg). The particles exhibited significant antioxidant properties in the liver, increasing the activity of the antioxidant enzymes superoxide dismutase (SOD), glutathione reductase (GR) and glutathione peroxidase (GPx), decreasing the concentration of the lipoperoxidation product malondialdehyde (MDA), and improving the antioxidant status determined as the ratio of reduced to oxidized glutathione; in particular, TA increased some antioxidant parameters. MNPs carrying antioxidants such as NAC and TA could thus represent a promising therapeutic agent for the treatment of various diseases accompanied by increased oxidative stress.

Review of the direct and indirect effects of hyperglycemia on the HPA axis in T2DM and the co-occurrence of depression.

Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which is further associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Several studies have shown that HPA axis hyperactivity is heightened in the chronic hyperglycemic state with severe hyperglycemic events more likely to result in a depressive disorder. The HPA axis is also regulated by the immune system. Upon stress, under homeostatic conditions, the immune system is activated via the sympatho-adrenal-medullary axis resulting in an immune response which secretes proinflammatory cytokines. These cytokines aid in the activation of the HPA axis during stress. However, in T2DM, where there is persistent hyperglycemia, the immune system is dysregulated resulting in the elevated concentrations of these cytokines. The HPA axis, already activated by the hyperglycemia, is further activated by the cytokines which all contribute to a diagnosis of depression in patients with T2DM. However, the onset of T2DM is often preceded by pre-diabetes, a reversible state of moderate hyperglycemia and insulin resistance. Complications often seen in T2DM have been reported to begin in the pre-diabetic state. While the current management strategies have been shown to ameliorate the moderate hyperglycemic state and decrease the risk of developing T2DM, research is necessary for clinical studies to profile these direct effects of moderate hyperglycemia in pre-diabetes on the HPA axis and the indirect effects moderate hyperglycemia may have on the HPA axis by investigating the components of the immune system that play a role in regulating this pathway.

Effect of Blueberry Supplementation on a Diet-Induced Rat Model of Prediabetes-Focus on Hepatic Lipid Deposition, Endoplasmic Stress Response and Autophagy.

Blueberries, red fruits enriched in polyphenols and fibers, are envisaged as a promising nutraceutical intervention in a plethora of metabolic diseases. Prediabetes, an intermediate state between normal glucose tolerance and type 2 diabetes, fuels the development of complications, including hepatic steatosis. In previous work, we have demonstrated that blueberry juice (BJ) supplementation benefits glycemic control and lipid profile, which was accompanied by an amelioration of hepatic mitochondrial bioenergetics. The purpose of this study is to clarify the impact of long-term BJ nutraceutical intervention on cellular mechanisms that govern hepatic lipid homeostasis, namely autophagy and endoplasmic reticulum (ER) stress, in a rat model of prediabetes. Two groups of male Wistar rats, 8-weeks old, were fed a prediabetes-inducing high-fat diet (HFD) and one group was fed a control diet (CD). From the timepoint where the prediabetic phenotype was achieved (week 16) until the end of the study (week 24), one of the HFD-fed groups was daily orally supplemented with 25 g/kg body weight (BW) of BJ (HFD + BJ). BW, caloric intake, glucose tolerance and insulin sensitivity were monitored throughout the study. The serum and hepatic lipid contents were quantified. Liver and interscapular brown and epidydimal white adipose tissue depots (iBAT and eWAT) were collected for histological analysis and to assess thermogenesis, ER stress and autophagy markers. The gut microbiota composition and the short-chain fatty acids (SCFAs) content were determined in colon fecal samples. BJ supplementation positively impacted glycemic control but was unable to prevent obesity and adiposity. BJ-treated animals presented a reduction in fecal SCFAs, increased markers of arrested iBAT thermogenesis and energy expenditure, together with an aggravation of HFD-induced lipotoxicity and hepatic steatosis, which were accompanied by the inhibition of autophagy and ER stress responses in the liver. In conclusion, despite the improvement of glucose tolerance, BJ supplementation promoted a major impact on lipid management mechanisms at liver and AT levels in prediabetic animals, which might affect disease course.

Berberine attenuates cognitive dysfunction and hippocampal apoptosis in rats with prediabetes.

The cognitive dysfunction caused by prediabetes causes great difficulties in human life, and the terrible thing is that the means to prevent the occurrence of this disease are very limited at present, Berberine has shown the potential to treat diabetes and cognitive dysfunction, but it still needs to be further explored to clarify the mechanism of its therapeutic effect. Therefore, the aim of this study was to investigate the effects and mechanisms of Berberine on prediabetes-induced cognitive dysfunction. Prediabetes rat model was induced by a high-fat diet and a normal diet was used as a control. They were fed for 20 weeks. At week 13, the model rats were given 100 mg/kg Berberine by gavage for 7 weeks. The cognitive function of rats was observed. At the same time, OGTT, fasting blood glucose, blood lipids, insulin and other metabolic parameters, oxidative stress, and apoptosis levels were measured. The results showed that the model rats showed obvious glucose intolerance, elevated blood lipids, and insulin resistance, and the levels of oxidative stress and apoptosis were significantly increased. However, after the administration of Berberine, the blood glucose and lipid metabolism of prediabetic rats were significantly improved, and the oxidative stress level and apoptosis level of hippocampal tissue were significantly reduced. In conclusion, Berberine can alleviate the further development of diabetes in prediabetic rats, reduce oxidative stress and apoptosis in hippocampal tissue, and improve cognitive impairment in prediabetic rats.

Subcutaneous adipose tissue dopamine D2 receptor is increased in prediabetes and T2D.

PURPOSE: To evaluate the dopaminergic signaling in human adipose tissue in the context of obesity and type 2 diabetes (T2D) and potential direct implications in adipose tissue metabolism. METHODS: mRNA and protein expression of dopamine receptors D1 and D2 (DRD1 and DRD2) were determined in subcutaneous adipose tissue from subjects without or with T2D and with different body weight, and correlated with markers of obesity, hyperglycemia, and insulin resistance. Glucose uptake and lipolysis were measured in adipocytes ex vivo following short-term exposure to dopamine, DRD1 receptor agonist (SKF81297), or DRD2 receptor agonist (bromocriptine). RESULTS: DRD1 and DRD2 gene expression in subcutaneous adipose tissue correlated positively with clinical markers of insulin resistance (e.g. HOMA-IR, insulin, and triglycerides) and central obesity in subjects without T2D. Protein expression of DRD2 in subcutaneous adipose tissue, but not DRD1, is higher in subjects with impaired fasting glucose and T2D and correlated positively with hyperglycemia, HbA1c, and glucose AUC, independent of obesity status. DRD1 and DRD2 proteins were mainly expressed in adipocytes, compared to stromal vascular cells. Dopamine and dopaminergic agonists did not affect adipocyte glucose uptake ex vivo, but DRD1 and DRD2 agonist treatment inhibited isoproterenol-stimulated lipolysis. CONCLUSION: The results suggest that protein expression of DRD2 in subcutaneous adipose tissue is up-regulated with hyperglycemia and T2D. Whether DRD2 protein levels contribute to T2D development or occur as a secondary compensatory mechanism needs further investigation. Additionally, dopamine receptor agonists inhibit adipocyte beta-adrenergic stimulation of lipolysis, which might contribute to the beneficial effects in lipid metabolism as observed in patients taking bromocriptine.

Acid-sensing ion channel 3 mediates pain hypersensitivity associated with high-fat diet consumption in mice.

ABSTRACT: Lipid-rich diet is the major cause of obesity, affecting 13% of the worldwide adult population. Obesity is a major risk factor for metabolic syndrome that includes hyperlipidemia and diabetes mellitus. The early phases of metabolic syndrome are often associated with hyperexcitability of peripheral small diameter sensory fibers and painful diabetic neuropathy. Here, we investigated the effect of high-fat diet-induced obesity on the activity of dorsal root ganglion (DRG) sensory neurons and pain perception. We deciphered the underlying cellular mechanisms involving the acid-sensing ion channel 3 (ASIC3). We show that mice made obese through consuming high-fat diet developed the metabolic syndrome and prediabetes that was associated with heat pain hypersensitivity, whereas mechanical sensitivity was not affected. Concurrently, the slow conducting C fibers in the skin of obese mice showed increased activity on heating, whereas their mechanosensitivity was not altered. Although ASIC3 knockout mice fed with high-fat diet became obese, and showed signs of metabolic syndrome and prediabetes, genetic deletion, and in vivo pharmacological inhibition of ASIC3, protected mice from obesity-induced thermal hypersensitivity. We then deciphered the mechanisms involved in the heat hypersensitivity of mice and found that serum from high-fat diet-fed mice was enriched in lysophosphatidylcholine (LPC16:0, LPC18:0, and LPC18:1). These enriched lipid species directly increased the activity of DRG neurons through activating the lipid sensitive ASIC3 channel. Our results identify ASIC3 channel in DRG neurons and circulating lipid species as a mechanism contributing to the hyperexcitability of nociceptive neurons that can cause pain associated with lipid-rich diet consumption and obesity.

Increased Plasma Branched Short-Chain Fatty Acids and Improved Glucose Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Short-chain fatty acids (SCFAs) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched SCFAs (BSCFAs; isobutyrate, isovalerate, and methylbutyrate) is largely unknown. In a cohort of 219 non-Hispanic White participants and 126 African American participants, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, and lipid traits, and other SCFAs. We observed a bimodal distribution of BSCFAs, with 25 individuals having high levels (H-BSCFA group) and 320 individuals having lower levels (L-BSCFA group). The prevalence of dysglycemia was lower in the H-BSCFA group compared with the L-BSCFA group (16% vs. 49%; P = 0.0014). This association remained significant after adjustment for age, sex, race, BMI, and levels of other SCFAs. Consistent with the lower rate of dysglycemia, fasting and postprandial glucose levels were lower and the disposition index was higher in the H-BSCFA group. Additional findings in H-BSCFA versus L-BSCFA included lower fasting and postprandial C-peptide levels and lower insulin clearance without differences in insulin levels, insulin sensitivity, insulin secretion, or other variables examined, including diet and physical activity. As one of the first human studies associating higher BSCFA levels with lower odds of dysglycemia and improved glucose homeostasis, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes.

Single-Cell Transcriptome Profiling of Pancreatic Islets From Early Diabetic Mice Identifies Anxa10 for Ca2+ Allostasis Toward ß-Cell Failure.

Type 2 diabetes is a progressive disorder denoted by hyperglycemia and impaired insulin secretion. Although a decrease in ß-cell function and mass is a well-known trigger for diabetes, the comprehensive mechanism is still unidentified. Here, we performed single-cell RNA sequencing of pancreatic islets from prediabetic and diabetic db/db mice, an animal model of type 2 diabetes. We discovered a diabetes-specific transcriptome landscape of endocrine and nonendocrine cell types with subpopulations of ß- and α-cells. We recognized a new prediabetic gene, Anxa10, that was induced by and regulated Ca2+ influx from metabolic stresses. Anxa10-overexpressed ß-cells displayed suppression of glucose-stimulated intracellular Ca2+ elevation and potassium-induced insulin secretion. Pseudotime analysis of ß-cells predicted that this Ca2+-surge responder cluster would proceed to mitochondria dysfunction and endoplasmic reticulum stress. Other trajectories comprised dedifferentiation and transdifferentiation, emphasizing acinar-like cells in diabetic islets. Altogether, our data provide a new insight into Ca2+ allostasis and ß-cell failure processes. ARTICLE HIGHLIGHTS: The transcriptome of single-islet cells from healthy, prediabetic, and diabetic mice was studied. Distinct ß-cell heterogeneity and islet cell-cell network in prediabetes and diabetes were found. A new prediabetic ß-cell marker, Anxa10, regulates intracellular Ca2+ and insulin secretion. Diabetes triggers ß-cell to acinar cell transdifferentiation.

CT-based measurement of visceral adipose tissue volume as a reliable tool for assessing metabolic risk factors in prediabetes across subtypes.

Visceral adipose tissue (VAT) is a well-established risk factor for the development of diabetes in individuals with prediabetes. We aimed to evaluate various adiposity and metabolic indices, including visceral adipose tissue (VAT) volume measured by CT, in individuals with prediabetes, based on their different subtypes. This retrospective study included 78 prediabetes individuals aged ≥ 20 years whose VAT volumes were evaluated by CT. Individuals were classified into prediabetes subtypes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG and IGT (C-IFG/IGT). We conducted a comparison of the patients' adiposity indices and their associations with one other, as well as with insulin resistance, based on the different prediabetes subtypes. Individuals with C-IFG/IGT had higher levels of visceral obesity than those with IFG or IGT. VAT volume was more strongly associated with insulin resistance than other adiposity indices, regardless of prediabetes subtypes. Additionally, VAT volume and liver attenuation index showed a significant correlation with the other indices studied across the prediabetes subtypes. CT-based measurement of VAT volume may be a valuable tool for evaluating metabolic risk factors among individuals with prediabetes.

Relationship of cardiac remodeling and perfusion alteration with hepatic lipid metabolism in a prediabetic high fat high sucrose diet female rat model.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is known to be linked with metabolic associated fatty liver disease and type 2 diabetes, but few studies assessed this relationship in prediabetes, especially among women, who are at greater risk of CVD. We aimed to evaluate cardiac alterations and its relationship with hepatic lipid metabolism in prediabetic female rats submitted to high-fat-high-sucrose diet (HFS). METHODS AND RESULTS: Wistar female rats were divided into 2 groups fed for 5 months with standard or HFS diet. We analyzed cardiac morphology, function, perfusion and fibrosis by Magnetic Resonance Imaging. Hepatic lipid contents along with inflammation and lipid metabolism gene expression were assessed. Five months of HFS diet induced glucose intolerance (p < 0.05), cardiac remodeling characterized by increased left-ventricular volume, wall thickness and mass (p < 0.05). No significant differences were found in left-ventricular ejection fraction and cardiac fibrosis but increased myocardial perfusion (p < 0.01) and reduced cardiac index (p < 0.05) were shown. HFS diet induced hepatic lipid accumulation with increased total lipid mass (p < 0.001) and triglyceride contents (p < 0.05), but also increased mitochondrial (CPT1a, MCAD; (p < 0.001; p < 0.05) and peroxisomal (ACO, LCAD; (p < 0.05; p < 0.001) ß-oxidation gene expression. Myocardial wall thickness and perfusion were correlated with hepatic ß-oxidation genes expression. Furthermore, myocardial perfusion was also correlated with hepatic lipid content and glucose intolerance. CONCLUSION: This study brings new insights on the relationship between cardiac sub-clinical alterations and hepatic metabolism in female prediabetic rats. Further studies are warranted to explore its involvement in the higher CVD risk observed among prediabetic women.

Metformin restores prohormone processing enzymes and normalizes aberrations in secretion of proinsulin and insulin in palmitate-exposed human islets.

AIM: To elucidate how proinsulin synthesis and insulin was affected by metformin under conditions of nutrient overstimulation. MATERIALS AND METHODS: Isolated human pancreatic islets from seven donors were cultured at 5.5 mmol/L glucose and 0.5 mmol/L palmitate for 12, 24 or 72 h. Metformin (25 µmol/L) was introduced after initial 12 h with palmitate. Proinsulin and insulin were measured. Expression of prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE), was determined by western blot. Adolescents with obesity, treated with metformin and with normal glucose tolerance (n = 5), prediabetes (n = 14), or type 2 diabetes (T2DM; n = 7) were included. Fasting proinsulin, insulin, glucose, 2-h glucose and glycated haemoglobin were measured. Proinsulin/insulin ratio (PI/I) was calculated. RESULTS: In human islets, palmitate treatment for 12 and 24 h increased proinsulin and insulin proportionally. After 72 h, proinsulin but not insulin continued to increase which was coupled with reduced expression of PC1/3 and CPE. Metformin normalized expression of PC1/3 and CPE, and proinsulin and insulin secretion. In adolescents with obesity, before treatment, fasting proinsulin and insulin concentrations were higher in subjects with T2DM than with normal glucose tolerance. PI/I was reduced after metformin treatment in subjects with T2DM as well as in subjects with prediabetes, coupled with reduced 2-h glucose and glycated haemoglobin. CONCLUSIONS: Metformin normalized proinsulin and insulin secretion after prolonged nutrient-overstimulation, coupled with normalization of the converting enzymes, in isolated islets. In adolescents with obesity, metformin treatment was associated with improved PI/I, which was coupled with improved glycaemic control.

Longitudinal analysis for the risk of depression according to the consumption of sugar-sweetened carbonated beverage in non-diabetic and diabetic population.

Studies have presented that high intake of sugar-sweetened carbonated beverage (SSCB) was more associated with the prevalence of depression. However, longitudinal evidence is still insufficient to identify whether the effect of SSCB on incident depression is independent of metabolic factors. Therefore, to evaluate the effect of SSCB consumption on the risk of depression, we analyzed the risk of depression according to the consumption of SSCB in 87,115 working aged Koreans who responded to Center for Epidemiologic Studies Depression (CES-D) scale. They were categorized into 5 groups by SSCB consumption based on one serving dose (200 ml) with never/almost never, < 1 serving/week, 1 ≤ serving/week < 3, 3 ≤ serving/week < 5, and 5 ≤ serving/week. During follow-up, CES-D ≥ 16 was determined as incident depressive symptom. Cox proportional hazards model was used to calculate the multivariable-adjusted hazard ratio (HR) and 95% confidence intervals (CI) for depressive symptom. In analysis for all study participants, the risk of depressive symptom significantly increased proportionally to SSCB consumption (never/almost never: reference, < 1 serving/week: 1.12 [1.07-1.17], 1 ≤ ~ < 3 serving/week: 1.26 [1.19-1.33], 3 ≤ ~ < 5 serving/week: 1.32 [1.23-1.42], and ≥ 5 serving/week: 1.45 [1.33-1.59]). This association was identically observed in men, women, normal glycemic subgroup and prediabetes subgroup.

Label-free optical metabolic imaging of adipose tissues for prediabetes diagnosis.

Rationale: Prediabetes can be reversed through lifestyle intervention, but its main pathologic hallmark, insulin resistance (IR), cannot be detected as conveniently as blood glucose testing. In consequence, the diagnosis of prediabetes is often delayed until patients have hyperglycemia. Therefore, developing a less invasive diagnostic method for rapid IR evaluation will contribute to the prognosis of prediabetes. Adipose tissue is an endocrine organ that plays a crucial role in the development and progression of prediabetes. Label-free visualizing the prediabetic microenvironment of adipose tissues provides a less invasive alternative for the characterization of IR and inflammatory pathology. Methods: Here, we successfully identified the differentiable features of prediabetic adipose tissues by employing the metabolic imaging of three endogenous fluorophores NAD(P)H, FAD, and lipofuscin-like pigments. Results: We discovered that 1040-nm excited lipofuscin-like autofluorescence could mark the location of macrophages. This unique feature helps separate the metabolic fluorescence signals of macrophages from those of adipocytes. In prediabetes fat tissues with IR, we found only adipocytes exhibited a low redox ratio of metabolic fluorescence and high free NAD(P)H fraction a1. This differential signature disappears for mice who quit the high-fat diet or high-fat-high-sucrose diet and recover from IR. When mice have diabetic hyperglycemia and inflamed fat tissues, both adipocytes and macrophages possess this kind of metabolic change. As confirmed with RNA-seq analysis and histopathology evidence, the change in adipocyte's metabolic fluorescence could be an indicator or risk factor of prediabetic IR. Conclusion: Our study provides an innovative approach to diagnosing prediabetes, which sheds light on the strategy for diabetes prevention.

Single-cell RNA-seq uncovers novel metabolic functions of Schwann cells beyond myelination.

Schwann cells (SCs) support peripheral nerves under homeostatic conditions, independent of myelination, and contribute to damage in prediabetic peripheral neuropathy (PN). Here, we used single-cell RNA sequencing to characterize the transcriptional profiles and intercellular communication of SCs in the nerve microenvironment using the high-fat diet-fed mouse, which mimics human prediabetes and neuropathy. We identified four major SC clusters, myelinating, nonmyelinating, immature, and repair in healthy and neuropathic nerves, in addition to a distinct cluster of nerve macrophages. Myelinating SCs acquired a unique transcriptional profile, beyond myelination, in response to metabolic stress. Mapping SC intercellular communication identified a shift in communication, centered on immune response and trophic support pathways, which primarily impacted nonmyelinating SCs. Validation analyses revealed that neuropathic SCs become pro-inflammatory and insulin resistant under prediabetic conditions. Overall, our study offers a unique resource for interrogating SC function, communication, and signaling in nerve pathophysiology to help inform SC-specific therapies.