Maternal Serum Polyols and Its Link to Gestational Diabetes Mellitus: A Population-Based Nested Case-Control Study.

CONTEXT: Sugar alcohols (also called polyols) are regarded as a "healthy" sugar substitute. One of the possible reasons for their safe use in pregnant women is their natural origin and the presence of polyols in maternal and fetal samples during normal human gestation. But little is known about the association between circulating sugar alcohols levels and maternal metabolic disorders during pregnancy. OBJECTIVE: We aimed to detect the concentration of the polyols in participants with and without gestational diabetes mellitus (GDM), and to investigate the association between maternal serum levels of polyols and GDM, as well as newborn outcomes. METHODS: A nested population-based case-control study was conducted in 109 women with and without GDM. Maternal concentrations of serum erythritol, sorbitol, and xylitol in the fasting state were quantified using a time of flight mass spectrometry system. RESULT: In women with GDM, serum concentrations of erythritol and sorbitol were higher, but serum concentrations of xylitol were lower than those in women without GDM. Per 1-SD increment of Box-Cox-transformed concentrations of erythritol and sorbitol were associated with the increased odds of GDM by 43% and 155% (95% CI 1.07-1.92 and 95% CI 1.77-3.69), while decreased odds were found for xylitol by 25% (95% CI 0.57-1.00). Additionally, per 1-SD increase of Box-Cox-transformed concentrations of serum sorbitol was associated with a 52% increased odds of large for gestational age newborns controlling for possible confounders (95% CI 1.00-2.30). CONCLUSION: Maternal circulating sugar alcohols levels during pregnancy were significantly associated with GDM. These findings provide the potential roles of polyols on maternal metabolic health during pregnancy.

Elevated Fructose and Uric Acid Through Aldose Reductase Contribute to Experimental and Human Alcoholic Liver Disease.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) is a common chronic liver disease worldwide with high morbidity and mortality, and no Food and Drug Administration-approved therapies. Fructose (dietary or endogenous), its metabolite uric acid, and aldose reductase (AR, the only endogenous enzyme that produces fructose) are strongly associated with the development of nonalcoholic fatty liver disease. However, the role of AR or its metabolites in ALD remains understudied and was examined using human specimens, cultured cells, and mouse model systems. APPROACH AND RESULTS: We demonstrated in liver specimens from patients with alcoholic hepatitis, the AR up-regulation and elevated AR metabolites (sorbitol, fructose, and uric acid), which correlated significantly with (1) increased lipid peroxidation byproducts and endoplasmic reticulum (ER) stress, (2) decreased protective ER chaperones, and (3) greater cell death and liver injury. Furthermore, we established a causal role for AR in ALD by showing that the genetic deficiency of AR (knockout mice) prevented alcohol-induced increase in harmful AR metabolites, toxic aldehydes, steatosis, ER stress, apoptosis, and liver injury. Finally, we demonstrated the therapeutic potential of pharmacological AR inhibition against alcohol-induced hepatic injury in experimental ALD. CONCLUSIONS: Our data demonstrate that hepatic AR up-regulation, and consequent elevation in fructose, sorbitol and/or uric acid, are important factors contributing to alcohol-induced steatosis, ER stress, apoptosis, and liver injury in both experimental and human ALD. Our study provides a strong rationale to evaluate AR as a potential therapeutic target and to test AR inhibitors to ameliorate alcohol-induced liver injury.

Sugar Alcohols of Polyol Pathway Serve as Alarmins to Mediate Local-Systemic Innate Immune Communication in Drosophila.

Interorgan immunological communication is critical to connect the local-systemic innate immune response and orchestrate a homeostatic host defense. However, the factors and their roles in this process remain unclear. We find Drosophila IMD response in guts can sequentially trigger a systemic IMD reaction in the fat body. Sugar alcohols of the polyol pathway are essential for the spatiotemporal regulation of gut-fat body immunological communication (GFIC). IMD activation in guts causes elevated levels of sorbitol and galactitol in hemolymph. Aldose reductase (AR) in hemocytes, the rate-limiting enzyme of the polyol pathway, is necessary and sufficient for the increase of plasma sugar alcohols. Sorbitol relays GFIC by subsequent activation of Metalloprotease 2, which cleaves PGRP-LC to activate IMD response in fat bodies. Thus, this work unveils how GFIC relies on the intermediate activation of the polyol pathway in hemolymph and demonstrates that AR provides a critical metabolic checkpoint in the global inflammatory response.

The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation.

Epalrestat is an inhibitor of aldose reductase in the polyol pathway and is used for the management of diabetic neuropathy clinically. Our pilot experiments and accumulated evidences showed that epalrestat inhibited polyol pathway and reduced sorbitol production, and suggested the potential renal protection effects of epalrestat on diabetic nephropathy (DN). To evaluate the protective effect of epalrestat, the db/db mice were used and exposed to epalrestat for 8 weeks, both the physiopathological condition and function of kidney were examined. For the first time, we showed that epalrestat markedly reduced albuminuria and alleviated the podocyte foot process fusion and interstitial fibrosis of db/db mice. Metabolomics was employed, and metabolites in the plasma, renal cortex, and urine were profiled using a gas chromatography-mass spectrometry (GC/MS)-based metabolomic platform. We observed an elevation of sorbitol and fructose, and a decrease of myo-inositol in the renal cortex of db/db mice. Epalrestat reversed the renal accumulation of the polyol pathway metabolites of sorbitol and fructose, and increased myo-inositol level. Moreover, the upregulation of aldose reductase, fibronectin, collagen III, and TGF-ß1 in renal cortex of db/db mice was downregulated by epalrestat. The data suggested that epalrestat has protective effects on DN, and the inhibition of aldose reductase and the modulation of polyol pathway in nephritic cells be a potentially therapeutic strategy for DN.

Modulation of Advanced Glycation End Products, Sorbitol, and Aldose Reductase by Hydroalcohol Extract of Lagenaria siceraria Mol Standl in Diabetic Complications: An In Vitro Approach.

Herbal medicines have become a core interest, and they are used widely. Lagenaria siceraria is known for its antihyperglycemic, antidyslipidemic, antioxidant potential, and the present study was designed to explore the possible role of L. siceraria in attenuation of diabetic complications via in vitro modulation of advanced glycation end products (AGEs), sorbitol, and aldose reductase (ALR)-three major biomarkers of diabetic complications. To the best of our knowledge, no study has yet been carried out to explore L. siceraria to inhibit these biomarkers. Hydroalcohol extract of L. siceraria (LHA) was evaluated for its ability to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide, nitric oxide, and superoxide radicals, total antioxidant capacity, and reducing-power assay. Antiglycation activity was carried out by bovine serum albumin (BSA) fluorescence method. Sorbitol accumulation was evaluated in red blood cells (RBCs) and ALR1 was obtained from kidney of rat to carry out the study. Quercetin was also quantified by high-performance liquid chromatography (HPLC) analysis with 14.3 mg per 100 g of LHA. LHA exhibited 854 mg/g gallic acid equivalent of phenol content and 104 mg/g quercetin equivalent of flavonoids and was found to be significantly active against the antioxidant assays evaluated. LHA has shown 80.12% inhibition of AGE formation. LHA was found to be effective against sorbitol accumulation and ALR1 inhibition with IC50 198.25 µg/ml and 6.24 µg/ml, respectively. These results reveal that LHA may exert beneficial effects against diabetic complications by its antioxidant and antiglycation potential.

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus.

Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by promoting urinary glucose excretion (UGE). A clinical pharmacology study conducted in Japanese patients with T2DM confirmed dose-dependency of UGE with once-daily administration of luseogliflozin; however, the reason for sustained UGE after plasma luseogliflozin decreased was unclear. To elucidate the effect of inhibition rate constants, Kon and Koff, and to explain the sustained UGE, a pharmacokinetic-pharmacodynamic (PK-PD) model was built based on the mechanisms of glucose filtration in the glomerulus and reabsorption in the renal proximal tubule of kidney as well as the kinetics of competitive inhibition of SGLT1/2 and inhibition rate constants of SGLT2, by using UGE and plasma glucose levels and luseogliflozin concentrations. This acquired population PK-PD model adequately described the sustained UGE and the estimated population means of the inhibition constant for SGLT2 (Ki2) and inhibition-rate constants for SGLT2 (Kon and Koff) were 0.31- and 3.6-fold lower or higher than the in vitro values. Because the dissociation half-time of luseogliflozin from SGLT2 calculated from Koff, 6.81 h, was consistent with the value in vitro, we considered that the sustained UGE could be explained by the long dissociation half-time. Moreover, by calculating the SGLT2 inhibition ratio using the model, we discuss other properties of the UGE time course after luseogliflozin administration.

A simple and rapid LC-MS/MS method for quantitation of luseogliflozin in rat plasma and its application to a PK study.

AIM: Luseogliflozin is a novel sodium-dependent glucose cotransporter-2 inhibitor for the treatment of Type 2 diabetes mellitus. To assist pharmacokinetic and toxicodynamic studies, a rapid LC-MS/MS method were developed and validated for the quantitation of luseogliflozin in rat plasma. RESULTS: Sample preparation was carried out using simplified protein precipitation and liquid-liquid extraction procedures, and the run time was only 4 min. Extraction recovery was 92.9 to 95.3%, and the method was validated over the range 0.5 to 500 ng/ml for luseogliflozin with acceptable specificity, accuracy and precision. CONCLUSION: The validated method is considered suitable to quantify luseogliflozin in pharmacokinetic and pharmacodynamic/toxicodynamic studies in rats.

Effects of S-Allylcysteine on Biomarkers of the Polyol Pathway in Rats with Type 2 Diabetes.

OBJECTIVES: We evaluated the effects of S-allylcysteine (SAC) on biomarkers of the polyol pathway in streptozotocin-nicotinamide (STZ-NA)-induced diabetes in rats. METHODS: Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (55 mg kg-1 bw-1) and NA (110 mg kg-1 bw-1). SAC (150 mg kg-1 bw-1) was orally administered to the rats with diabetes for 45 days to assess its effects on blood glucose, insulin, insulin resistance, glycated hemoglobin, aldose reductase (AR), sorbitol dehydrogenase (SDH), sorbitol, fructose, thiobarbituric acid-reactive substances (TBARS), hydroperoxide, hemoglobin and glutathione (GSH). RESULTS: On SAC administration in the rats with diabetes, the levels of blood glucose, insulin resistance, glycated hemoglobin, AR, SDH, sorbitol, fructose, TBARS and hydroperoxide increased significantly (p<0.05), whereas those of insulin, hemoglobin and GSH decreased. SAC showed therapeutic effects similar to those of gliclazide in decreasing blood glucose, AR, SDH, sorbitol, fructose, glycosylated hemoglobin, TBARS and hydroperoxides levels and significant increases in insulin, hemoglobin and GSH activity in rats with diabetes. Moreover, histopathologic studies also revealed the protective effect of SAC on pancreatic beta cells. CONCLUSIONS: The results indicate that SAC prevents complications of diabetes by reducing the influx of glucose in the polyol pathway, thereby elevating the GSH level and reducing the activities of AR and SDH. Therefore, SAC may have imperative implications for the deterrence and early treatment of type 2 diabetes.

A mixed (long- and medium-chain) triglyceride lipid emulsion extracts local anesthetic from human serum in vitro more effectively than a long-chain emulsion.

BACKGROUND: Lipid emulsion infusion reverses cardiac toxicity of local anesthetics. The predominant effect is likely creation of a "lipid sink." This in vitro study determined the extent to which Intralipid® (Fresenius Kabi, Uppsala, Sweden) and Lipofundin® (B. Braun Melsungen AG, Melsungen, Germany) sequester anesthetics from serum, and whether it varies with pH. METHODS: Bupivacaine, ropivacaine, and mepivacaine were added to human drug-free serum (pH 7.4) at 10 µg/ml. The lipid emulsions were added, and the mixture shaken and incubated at 37°C. Lipid was removed by ultracentrifugation and drug remaining in the serum measured. Additional experiments were performed using 100 µg/ml bupivacaine and at pH 6.9. RESULTS: Lipofundin® extracted all three anesthetics to a greater extent than Intralipid® (34.7% vs..22.3% for bupivacaine, 25.8% vs..16.5% for ropivacaine, and 7.3% vs..4.7% for mepivacaine). By increasing either concentration of bupivacaine or lipid, there was an increase in drug extraction from serum. Adjusting the pH to 6.9 had no statistically significant effect on the percentage of bupivacaine sequestered. CONCLUSIONS: Bupivacaine, ropivacaine, and mepivacaine were sequestered to an extent consistent with their octanol:water partition constants (logP). In contrast with previous studies of extraction of lipids from buffer solutions, an emulsion containing 50% each of medium- and long-chain triglycerides extracted local anesthetics to a greater extent from human serum than one containing exclusively long-chain triglycerides, calling into question recent advanced cardiac life support guidelines for resuscitation from anesthetic toxicity that specify use of a long-chain triglyceride. The current data also do not support recent recommendations to delay administration until pH is normalized.