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.

Butyrate restores the fat/lean mass ratio balance and energy metabolism and reinforces the tight junction-mediated intestinal epithelial barrier in prediabetic mice independently of its anti-inflammatory and epigenetic actions.

Tissue/cellular actions of butyrate on energy metabolism and intestinal barrier in normal metabolic conditions or prediabetes are still unclear. In this work, we investigated the beneficial effect of dietary supplementation with sodium butyrate on energy metabolism, body mass composition, and intestinal epithelial barrier mediated by tight junction (TJ) in chow diet-fed normal and high-fat diet (HF)-fed prediabetic mice, considering the well-known butyrate action as an epigenetic and inflammatory regulator. Butyrate significantly reduced the fat/lean mass ratio, slightly ameliorated dyslipidemia, restored oral glucose tolerance, and increased basal energy expenditure in prediabetic HF-fed mice but had no effect on control animals. Such effects were observed in the absence of significant alterations in the hypothalamic expression of orexigenic and anorexigenic genes and motor activity. Also, butyrate suppressed the whitening effect of HF on brown adipose tissue but did not affect cell bioenergetics in immortalized UCP1-positive adipocytes in vitro. Butyrate reinforced the intestinal epithelial barrier in HF-fed mice and in Caco-2 monolayers, which involved higher trafficking of TJ proteins to the cell-cell contact region of the intestinal epithelia, without affecting TJ gene expression or the acetylation level of histones H3 and H4 in vivo. All metabolic and intestinal effects of butyrate in prediabetic mice occurred in the absence of detectable changes in systemic or local inflammation, or alterations in endotoxemia markers. Butyrate has no effect on chow diet-fed mice but, in the context of HF-induced prediabetes, it prevents metabolic and intestinal dysfunctions independently of its anti-inflammatory and epigenetic actions.

Vitamin D supplementation alleviates insulin resistance in prediabetic rats by modifying IRS-1 and PPARγ/NF-κB expressions.

Background: Prediabetes is a condition of intermediate hyperglycemia that may progress to type 2 diabetes. Vitamin D deficiency has been frequently linked to insulin resistance and diabetes. The study aimed to investigate the role of D supplementation and its possible mechanism of action on insulin resistance in prediabetic rats. Method: The study was conducted on 24 male Wistar rats that were randomly divided into 6 rats as healthy controls and 18 prediabetic rats. Prediabetic rats were induced with a high-fat and high-glucose diet (HFD-G) combined with a low dose of streptozotocin. Rats with the prediabetic condition were then randomized into three groups of 12-week treatment: one group that received no treatment, one that received vitamin D3 at 100 IU/kg BW, and one group that received vitamin D3 at 1000 IU/kg BW. The high-fat and high-glucose diets were continuously given throughout the twelve weeks of treatment. At the end of the supplementation period, glucose control parameters, inflammatory markers, and the expressions of IRS1, PPARγ, NF-κB, and IRS1 were measured. Results: Vitamin D3 dose-dependently improves glucose control parameters, as shown by the reduction of fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated albumin, insulin levels, and markers of insulin resistance (HOMA-IR). Upon histological analysis, vitamin D supplementation resulted in a reduction of the islet of Langerhans degeneration. Vitamin D also enhanced the ratio of IL-6/IL-10, reduced IRS1 phosphorylation at Ser307, increased expression of PPAR gamma, and reduced phosphorylation of NF-KB p65 at Ser536. Conclusion: Vitamin D supplementation reduces insulin resistance in prediabetic rats. The reduction might be due to the effects of vitamin D on IRS, PPARγ, and NF-κB expression.

Mulberry-Derived 1-Deoxynojirimycin Prevents Type 2 Diabetes Mellitus Progression via Modulation of Retinol-Binding Protein 4 and Haptoglobin.

Pre-diabetic or early-stage type 2 diabetes patients may develop an adverse diabetic progression, leading to several complications and increasing hospitalization rates. Mulberry leaves, which contain 1-deoxynojirimycin (DNJ), have been used as a complementary medicine for diabetes prevention and treatment. Our recent study demonstrated that mulberry leaf powder with 12 mg of DNJ improves postprandial hyperglycemia, fasting plasma glucose, and glycated hemoglobin. However, the detailed mechanisms are still unknown. This study investigates the effect of long-term (12-week) supplementation of mulberry leaves in obese people with prediabetes and patients with early-stage type 2 diabetes. Participants' blood was collected before and after supplementation. The protein profile of the plasma was examined by proteomics. In addition, the mitochondrial function was evaluated by energetic and homeostatic markers using immunoelectron microscopy. The proteomics results showed that, from a total of 1291 proteins, 32 proteins were related to diabetes pathogenesis. Retinol-binding protein 4 and haptoglobin protein were downregulated, which are associated with insulin resistance and inflammation, respectively. For mitochondrial function, the haloacid dehalogenase-like hydrolase domain-containing protein 3 (HDHD-3) and dynamin-related protein 1 (Drp-1) displayed a significant increment in the after treatment group. In summary, administration of mulberry leaf powder extract in prediabetes and the early stage of diabetes can alleviate insulin resistance and inflammation and promote mitochondrial function in terms of energy production and fission.

Re-interpretation of the mechanism of type 2 diabetes mellitus based on a framework of psychosomatic medicine: a real-world study.

OBJECTIVE: Using bipolar disorder (BD) as a control, we explored the possible developmental process of impaired glucose metabolism rhythm. METHODS: In total, 441 subjects (77, 162, 134, 54, and 14 in the pre-diabetes [pre-DM], DM, BD, BD + pre-DM, and BD + DM groups, respectively) and 160 controls were included. All subjects were assessed using the Neuroticism Extraversion Openness Five-Factor Inventory (NEO-FFI). The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes were measured. RESULTS: Cluster analysis showed that the BD, BD + DM, and DM groups were classified as the 'disease group, the BD + pre-DM group as the 'mixed period group', and the pre-DM group as the 'pre-disease group'. The conscientiousness factor scores of the NEO-FFI in the 'disease group' were higher than the norm but lower than the norm in the 'pre-disease group'. The scores of neurotic factors in the 'pre-disease' and 'mixed period' groups were both significantly higher than that in the 'disease group' (corrected p < 0.001). The incidences of the abnormal HPA axis decreased gradually from the 'pre-disease group' to the 'mixed period group' then to the 'disease group', while those of the HPT axis slightly increased at first and then significantly decreased. The overall prediction rate of the multiple logistic regression model was 92.7%. CONCLUSION: This study suggests that progression of pre-diabetes to DM is a continuous process from local abnormalities to rhythm disorder of glucose metabolism. This understanding can be applied to the whole course management and early intervention of DM and to the future development of optimised treatment based on rhythm regulation. TRIAL REGISTRATION: Clinical trial registration number: ChiCTR1800019064. Name of trial registration: Identify and the optimization of treatment for non-infectious chronic diseases under the "stress-dysrhythmia" theory hypothesis (Registration date: 24/10/2018). The full trial protocol can be accessed at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ).

Insulin-Related Liver Pathways and the Therapeutic Effects of Aerobic Training, Green Coffee, and Chlorogenic Acid Supplementation in Prediabetic Mice.

Background: The liver controls blood glucose levels via regulation of anabolic (glycogen synthesis and gluconeogenesis) and catabolic (glycolysis and glycogenolysis) processes through activation of the PI3K-AKT signalling pathway. The aim of this study was to assess the effect of aerobic training, green coffee, and chlorogenic acid supplementation on glucose metabolism-regulating pathways in prediabetic mice. Methods: C57BL/6 mice were exposed to a high-fat diet and physical activity limitation to induce a state of prediabetes. After 12 weeks, mice were fed a high-fat diet compared to the control mice. The prediabetic mice were further treated with either green coffee, chlorogenic acid, or training or combinations of the same for 10 weeks. At the end of the experimental period, metabolic data (FBG, GTT, HOMA for IR, plasma level of insulinfrom systematic, AST, and ALT assessed into blood), histopathologic, and analysis of gene and protein expressions were obtained for target tissues. Results: Training along with green coffee and chlorogenic acid supplementation improved complications of prediabetes including weight gain and elevated fasting blood glucose and plasma insulin levels. These effects were associated with the changes in mRNA levels of genes important in hepatic glycogen synthesis (GYS2), glucogenesis (PCK and G6PC2), and glycolysis (GK, PK, and PFKL). Conclusion: The training in conjunction with green coffee or chlorogenic acid is effective in the prevention of prediabetes in mice. As these interventions are relatively inexpensive and safe application to individuals with prediabetes appears warranted.

Chitosan oligosaccharide mitigates kidney injury in prediabetic rats by improving intestinal barrier and renal autophagy.

Consumption of a high-fat diet (HFD) not only increases the risk of metabolic syndrome but also initiates kidney injury. Lipid accumulation-induced systemic low-grade inflammation is an upstream mechanism of kidney injury associated with prediabetes. Chitosan oligosaccharide (COS) provides potent anti-obesity effects through several mechanisms including fecal lipid excretion. In this study, we investigated the effects of COS on the prevention of obesity-related complications and its ability to confer renoprotection in a prediabetic model. Rats fed on a HFD developed obesity, glucose intolerance and kidney dysfunction. COS intervention successfully ameliorated these conditions (p < 0.05) by attenuating intestinal lipid absorption and the renal inflammation-autophagy-apoptosis axis. A novel anti-inflammatory effect of COS had been demonstrated by the strengthening of intestinal barrier integrity via calcium-sensing receptor (p < 0.05). The use of COS as a supplement may be useful in reducing prediabetic complications especially renal injury and the risk of type 2 diabetes.

Marine Oil from C. finmarchicus Enhances Glucose Homeostasis and Liver Insulin Resistance in Obese Prediabetic Individuals.

The intermediate state between normal glucose tolerance and overt type 2 diabetes mellitus is associated with micro- and macrovascular diseases, requiring safe and cost-effective treatment measures interventions. A novel source of LC n-3 FAs is Calanus finmarchicus Oil, which showed promising effects on glucose homeostasis in preclinical studies due to anti-obesity effects and/or anti-inflammatory properties. In total, 43 obese patients (BMI: 31.7 ± 5.2 kg/m2) were allocated in the following two groups: (1) Calanus oil group (2 g CO/day) and (2) placebo group (2 g paraffin oil/day). Markers of glucose metabolism, body composition and energy intake were measured at the beginning (t0), after 12 weeks (t12) and 16 weeks (t16). Overall, parameters reflecting abnormal glucose homeostasis and insulin resistance in the liver, including fasting insulin (-2.9 mU/L ± 4.10, p < 0.05), HOMA-IR (-0.9 ± 1.28, p < 0.05) and hepatic insulin resistance index (-1.06 ± 1.72 × 106, p < 0.05) significantly enhanced after a 12-week CO-intervention, while no differences were observed in HbA1c, AUC0-2h Glucose, AUC0-2h Insulin, 2 h plasma glucose and muscle insulin sensitivity index. Our results indicate that Calanus oil causes beneficial effects on glucose metabolism and insulin resistance in obese patients, with clinical relevance to be verified in further studies. In addition, the possible active compounds and their mechanisms of action should be elucidated.

Effects of Vitamin D Supplementation on Insulin Sensitivity and Secretion in Prediabetes.

CONTEXT: Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on ß-cell function remain unclear. OBJECTIVE: To investigate the effects of vitamin D3 supplementation on insulin sensitivity and ß-cell function. METHODS: This is a prespecified secondary analysis of the Vitamin D and Type 2 Diabetes study. Overweight/obese adults at high risk for type 2 diabetes (prediabetes) were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months. MAIN OUTCOME: Disposition index (DI), as an estimate of ß-cell function, was calculated as the product of Homeostasis Model Assessment 2 indices derived from C-peptide values (HOMA2%Scpep) and C-peptide response during the first 30 minutes of a 75-g oral glucose tolerance test (OGTT). RESULTS: Mean age was 60.5 ± 9.8 years and body mass index was 31.9 ± 4.4 kg/m2. Mean serum 25(OH)D level increased from 27.9 ± 10.3 ng/mL at baseline to 54.9 ng/mL at 2 years in the vitamin D group and was unchanged (28.5 ± 10.0 ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the 2 groups. Among participants with baseline 25(OH)D level <12 ng/mL, the mean percent differences for DI between the vitamin D and placebo groups was 8.5 (95% CI, 0.2-16.8). CONCLUSIONS: Supplementation with vitamin D3 for 24 months did not improve an OGTT-derived index of ß-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status.

Blueberry Counteracts Prediabetes in a Hypercaloric Diet-Induced Rat Model and Rescues Hepatic Mitochondrial Bioenergetics.

The paramount importance of a healthy diet in the prevention of type 2 diabetes is now well recognized. Blueberries (BBs) have been described as attractive functional fruits for this purpose. This study aimed to elucidate the cellular and molecular mechanisms pertaining to the protective impact of blueberry juice (BJ) on prediabetes. Using a hypercaloric diet-induced prediabetic rat model, we evaluated the effects of BJ on glucose, insulin, and lipid profiles; gut microbiota composition; intestinal barrier integrity; and metabolic endotoxemia, as well as on hepatic metabolic surrogates, including several related to mitochondria bioenergetics. BJ supplementation for 14 weeks counteracted diet-evoked metabolic deregulation, improving glucose tolerance, insulin sensitivity, and hypertriglyceridemia, along with systemic and hepatic antioxidant properties, without a significant impact on the gut microbiota composition and related mechanisms. In addition, BJ treatment effectively alleviated hepatic steatosis and mitochondrial dysfunction observed in the prediabetic animals, as suggested by the amelioration of bioenergetics parameters and key targets of inflammation, insulin signaling, ketogenesis, and fatty acids oxidation. In conclusion, the beneficial metabolic impact of BJ in prediabetes may be mainly explained by the rescue of hepatic mitochondrial bioenergetics. These findings pave the way to support the use of BJ in prediabetes to prevent diabetes and its complications.

The Beneficial Effects of Astaxanthin on Glucose Metabolism and Modified Low-Density Lipoprotein in Healthy Volunteers and Subjects with Prediabetes.

Astaxanthin (ASTX) is an antioxidant agent. Recently, its use has been focused on the prevention of diabetes and atherosclerosis. We examined the effects of astaxanthin supplementation for 12 weeks on glucose metabolism, glycemic control, insulin sensitivity, lipid profiles and anthropometric indices in healthy volunteers including subjects with prediabetes with a randomized, placebo-controlled trial. METHODS: We enrolled 53 subjects who met our inclusion criteria and administered them with 12 mg astaxanthin or a placebo once daily for 12 weeks. Subsequently, their HbA1c levels, lipid profiles and biochemical parameters were determined. The participants also underwent a 75 g oral glucose tolerance test (OGTT), vascular endothelial function test and measurement of the visceral fat area. RESULTS: After astaxanthin supplementation for 12 weeks, glucose levels after 120 min in a 75 g OGTT significantly decreased compared to those before supplementation. Furthermore, the levels of HbA1c (5.64 ± 0.33 vs. 5.57 ± 0.39%, p < 0.05), apo E (4.43 ± 1.29 vs. 4.13 ± 1.24 mg/dL, p < 0.05) and malondialdehyde-modified low-density lipoprotein (87.3 ± 28.6 vs. 76.3 ± 24.6 U/L, p < 0.05) were also reduced, whereas total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-C (HDL-C) levels were unaltered. The Matuda index, which is one of the parameters of insulin resistance, was improved in the ASTX group compared to that before supplementation. CONCLUSIONS: our results suggest that ASTX may have preventive effects against diabetes and atherosclerosis and may be a novel complementary treatment option for the prevention of diabetes in healthy volunteers, including subjects with prediabetes, without adverse effects.

Effect of ß-hydroxybutyrate monoester on markers of iron metabolism in new-onset prediabetes: findings from a randomised placebo-controlled trial.

Background: People with prediabetes often have altered iron metabolism and may benefit from mild exogenous ketosis, which can now be successfully achieved thanks to recent developments in chemistry of food components. Objective: The objective was to investigate the effect of acute exogenous ketone monoester (ß-hydroxybutyrate) on plasma levels of markers of iron metabolism in people with prediabetes. Methods: Eighteen participants with new-onset prediabetes after acute pancreatitis aged 18 years or above took part in randomised controlled cross-over trial in Auckland, New Zealand. After an overnight fast, participants consumed the exogenous ketone supplement or placebo. Blood samples were collected in the fasted state (0 minutes) and then serially every 30 minutes for 150 minutes. Both participants and study personnel were blinded to the intervention/placebo allocation. Repeated measures analysis of variance was performed using total area under the curve to determine the change in hepcidin and ferritin over time after consumption of the exogenous ketone supplement and placebo. Results: Consumption of the exogenous ketone supplement significantly elevated blood levels of ß-hydroxybutyrate from 0.20 mmol L-1 at baseline to 3.50 mmol L-1 at 30 minutes (p < 0.05) and remained significantly elevated for the duration of the trial. The total area under the curve of hepcidin was 340.5 ± 121.1 ng mL-1 after the exogenous ketone supplementation as compared with 343.2 ± 119.6 ng mL-1 min-1 after the use of placebo (p = 0.91). The total area under the curve of ferritin was 786.7 ± 129.1 ng mL-1 min-1 after the exogenous ketone supplementation as compared with 776.9 ± 131.4 ng mL-1 min-1 after the use of placebo (p = 0.10). Conclusion: Acute supplementation of ß-hydroxybutyrate did not significantly affect the circulating levels of hepcidin or ferritin in people with prediabetes. Long-term effects of ß-hydroxybutyrate warrant investigations in the future.

Baicalein Enhances the Effect of Acarbose on the Improvement of Nonalcoholic Fatty Liver Disease Associated with Prediabetes via the Inhibition of De Novo Lipogenesis.

Prediabetes is a prevalent metabolic disorder with multiple complications, including nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the combinatorial effect of baicalein, a dietary flavonoid abundant in multiple edible plants, and acarbose on prediabetes-associated NAFLD. Baicalein and its metabolites inhibited de novo lipogenesis (DNL), thereby decreasing lipid accumulation and hepatokine secretion in oleic acid-induced hepatocytes. Carbohydrate restriction, which mimicked the effect of acarbose, led to comparable results. The combinatorial effect of baicalein and acarbose was further verified in prediabetic mice with NAFLD. Through the 16-week intervention, baicalein and acarbose inhibited DNL and improved glucose tolerance, oxidative stress, liver histology, and hepatokine secretion, thereby ameliorating insulin resistance and NAFLD. Our study demonstrated that baicalein enhanced the effect of acarbose on improving NAFLD and explored the underlying multitarget mechanism, laying a theoretical foundation for the development of flavonoid dietary supplements for the simultaneous improvement of NAFLD and prediabetes.

White Tea Intake Abrogates Markers of Streptozotocin-Induced Prediabetes Oxidative Stress in Rat Lungs'.

Prediabetes (PrDM) is a prodromal stage of diabetes mellitus (DM) with an increasing prevalence worldwide. During DM progression, individuals gradually develop complications in various organs. However, lungs are suggested to be affected later than other organs, such as the eyes, heart or brain. In this work, we studied the effects of PrDM on male Wistar rats' lungs and whether the regular consumption of white tea (WTEA) for 2 months contributes to the improvement of the antioxidant profile of this tissue, namely through improved activity of the first line defense antioxidant enzymes, the total antioxidant capacity and the damages caused in proteins, lipids and histone H2A. Our data shows that PrDM induced a decrease in lung superoxide dismutase and glutathione peroxidase activities and histone H2A levels and an increase in protein nitration and lipid peroxidation. Remarkably, the regular WTEA intake improved lung antioxidant enzymes activity and total antioxidant capacity and re-established the values of protein nitration, lipid peroxidation and histone H2A. Overall, this is the first time that lung is reported as a major target for PrDM. Moreover, it is also the first report showing that WTEA possesses relevant chemical properties against PrDM-induced lung dysfunction.

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women.

In rodents, obesity and aging impair nicotinamide adenine dinucleotide (NAD+) biosynthesis, which contributes to metabolic dysfunction. Nicotinamide mononucleotide (NMN) availability is a rate-limiting factor in mammalian NAD+ biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese. Insulin-stimulated glucose disposal, assessed by using the hyperinsulinemic-euglycemic clamp, and skeletal muscle insulin signaling [phosphorylation of protein kinase AKT and mechanistic target of rapamycin (mTOR)] increased after NMN supplementation but did not change after placebo treatment. NMN supplementation up-regulated the expression of platelet-derived growth factor receptor ß and other genes related to muscle remodeling. These results demonstrate that NMN increases muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese (clinicaltrial.gov NCT03151239).

Neurotensin receptor 1 agonist provides neuroprotection in pre-diabetic rats.

Exogenous treatment of a neurotensin receptor 1 (NTR1) agonist exerted the neuroprotection in an obese and Alzheimer's model. However, the effects of NTR1 modulation on peripheral/hippocampal impairment and cognitive deficit following sustained HFD consumption are poorly understood. Forty rats received a normal diet (ND) or HFD for 16 weeks. At week 13, the ND group received a vehicle (n = 8). Thirty-two HFD-fed group were randomized into four subgroups (n = 8/subgroup) with a vehicle, 1 mg/kg of NTR1 agonist, 1 mg/kg of NTR antagonist, and combined treatment (NTR1 agonist-NTR antagonist) for 2 weeks, s.c. injection. Then, the cognitive tests and peripheral/hippocampal parameters were determined. Our findings demonstrated that NTR1 activator reversed obesity and attenuated metabolic impairment in pre-diabetic rats. It also alleviated hippocampal pathologies and synaptic dysplasticity, leading to deceleration or prevention of cognitive impairment progression. Therefore, NTR1 activation would be a possible novel therapy to decelerate or prevent progression of neuropathology and cognitive impairment in the pre-diabetes.

Effects of vitamin D supplementation on the glycemic control of pre-diabetic individuals: a systematic review.

INTRODUCTION: Introduction: research shows the potential effect of vitamin D supplementation with an improvement in the glycemic profile of pre-diabetic patients. Objective: this study evaluates the effects of vitamin D supplementation on glycemic control markers in pre-diabetic individuals. Methods: we analyzed studies published over the last ten years, and indexed in the Science Direct, PubMed, and LILACS databases. We searched studies using health descriptors related to vitamin D, pre-diabetes, and glycemic control markers. We considered randomized controlled trials eligible for inclusion. All phases of selection, data extraction, and risk of bias assessment were carried out by two independent evaluators. Results: we identified 309 articles, of which 4 met the inclusion criteria. Of these, 3 studies have shown that vitamin D supplementation does not alter glycemic control markers in pre-diabetic individuals. Only one study showed a positive effect after supplementation with 60,000 IU/month of vitamin D3 for 12 months, with a significant reduction in the concentrations of glycated hemoglobin, fasting glucose, and two-hour postprandial glucose. Conclusion: there is insufficient scientific evidence to confirm the beneficial effects of vitamin D supplementation on glycemic control markers in pre-diabetic individuals.

INTRODUCCIÓN: Introducción: las investigaciones muestran el efecto potencial de la suplementación con vitamina D con una mejora del perfil glucémico de los pacientes prediabéticos. Objetivo: este estudio evalúa los efectos de la suplementación con vitamina D sobre los marcadores de control glucémico en personas prediabéticas. Métodos: analizamos los estudios publicados en los últimos diez años e indexados en las bases de datos Science Direct, PubMed y LILACS. Se realizaron búsquedas de estudios mediante descriptores de salud relacionados con la vitamina D, la prediabetes y los marcadores de control glucémico. Los ensayos controlados y aleatorizados se consideraron elegibles para su inclusión. Todas las fases de selección, extracción de datos y evaluación del riesgo de sesgos fueron realizadas por dos evaluadores independientes. Resultados: identificamos 309 artículos, de los que 4 cumplieron los criterios de inclusión. De estos, 3 estudios demostraron que la suplementación con vitamina D no altera los marcadores de control glucémico en las personas prediabéticas. Solo un estudio mostró un efecto positivo después de la suplementación de 60.000 UI/mes de vitamina D3 durante 12 meses, con una reducción significativa de las concentraciones de hemoglobina glucosilada, glucosa en ayunas y glucosa posprandial a las dos horas. Conclusión: no hay evidencia científica suficiente para confirmar los efectos beneficiosos de la suplementación de vitamina D sobre los marcadores de control glucémico en las personas prediabéticas.

Effects of α-Cyclodextrin on Cholesterol Control and Hydrolyzed Ginseng Extract on Glycemic Control in People With Prediabetes: A Randomized Clinical Trial.

Importance: Effective strategies for preventing type 2 diabetes are needed. Many people turn to complementary medicines, but there is little well-conducted scientific evidence to support their use. Objective: To assess the efficacy of α-cyclodextrin for cholesterol control and that of hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Design, Setting, and Participants: This 6-month double-blind, placebo-controlled, randomized clinical trial, with a 2 × 2 factorial design, was conducted between July 2015 and October 2018 at 2 locations in Sydney, Australia. Eligible participants were aged 18 years or older, had a body mass index (weight in kilograms divided by height in meters squared) of 25 or higher, and had prediabetes within 6 months of study entry according to the American Diabetes Association guidelines. Data analysis was performed from May to August 2019. Interventions: Participants were randomized to 1 of 4 groups to take active or placebo versions of each supplement (α-cyclodextrin plus hydrolyzed ginseng, α-cyclodextrin plus placebo, placebo plus hydrolyzed ginseng, or placebo plus placebo) for 6 months. All participants received dietetic advice for weight loss. Main Outcomes and Measures: The primary outcomes were the differences in total cholesterol and fasting plasma glucose between groups after 6 months. The primary analysis used the intention-to-treat principle. Multiple predetermined subsample analyses were conducted. Results: A total of 401 participants were eligible for the study (248 women [62%]; mean [SD] age, 53.5 [10.2] years; mean [SD] body mass index, 34.6 [6.2]). One hundred one patients were randomized to receive α-cyclodextrin plus hydrolyzed ginseng, 99 were randomized to receive α-cyclodextrin plus placebo, 101 were randomized to receive placebo plus hydrolyzed ginseng, and 100 were randomized to receive placebo plus placebo. For 200 participants taking α-cyclodextrin compared with 201 participants taking placebo, there was no difference in total cholesterol after 6 months (-1.5 mg/dL; 95% CI, -6.6 to 3.5 mg/dL; P = .51). For 202 participants taking hydrolyzed ginseng compared with 199 participants taking placebo, there was no difference in fasting plasma glucose after 6 months (0.0 mg/dL; 95% CI, -1.6 to 1.8 mg/dL; P = .95). Use of α-cyclodextrin was associated with constipation (16 participants vs 4 participants; P = .006) and cough (8 participants vs 1 participant; P = .02). Use of hydrolyzed ginseng was associated with rash and pruritus (13 participants vs 2 participants; P = .006). Only 37 of 401 participants (9.2%) experienced these adverse events. Conclusions and Relevance: Although they are safe for use, there was no benefit found for either α-cyclodextrin for cholesterol control or hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614001302640.

Plasma and Urinary (Poly)phenolic Profiles after 4-Week Red Raspberry (Rubus idaeus L.) Intake with or without Fructo-Oligosaccharide Supplementation.

Red raspberries (RRB) are high in anthocyanin- and ellagitannin- type (poly)phenols. This study aimed to investigate the effect of 4-week RRB supplementation on (poly)phenolic metabolism in adults with prediabetes and insulin-resistance (PreDM-IR); and whether adding fructo-oligosaccharides (FOS), prebiotics, would augment the microbial metabolites of RRB (poly)phenols. In a randomized crossover clinical trial, subjects (n = 35: PreDM-IR, n = 25; healthy Reference group, n = 10) consumed 1 cup RRB (fresh weight equivalence) per day and RRB with 8 g FOS per day each for 4 weeks in random order separated by 4-week washout. Plasma and urinary (poly)phenolic metabolites were characterized after (0-24h) consuming a RRB-based test drink (2 cups RRB) at baseline/week 0 and again after 4-week supplementations. A total of 123 (poly)phenolic metabolites were quantified. After 4-week RRB supplementation, several metabolite groups were significantly increased (p < 0.05), including urolithins, phenyl-γ-valerolactones, and phenolic acids. Supplementing FOS with RRB for 4 weeks enhanced benzoic acid derivatives compared to the baseline (p < 0.05). Specific effects of supplementation by metabolic status indicated 4-week RRB supplementation significantly increased microbial metabolites that were lower in PreDM-IR group. Our results suggest alterations in the capacity of PreDM-IR group to metabolize and render bioavailable raspberry-derived (poly)phenols when consumed regularly.

Effects of the Lysulin™ supplementation on pre-diabetes: A randomized double-blind, placebo-controlled clinical trial.

BACKGROUND AND AIMS: Diabetes is a leading cause of morbidity and mortality worldwide. Recent studies have demonstrated that nutraceutical products have beneficial effects in diabetes. Present study aims to investigate whether a product (Lysulin™) containing amino acid lysine, micronutrient zinc and vitamin C will have beneficial effects in pre-diabetes. METHODS: A randomized, double-blind, placebo-controlled trial was conducted for a period of 6 months. The two parallel groups (1:1) were Lysulin™ (Interventional group-IG) and placebo (control group-CG). Evaluations were done at baseline, 1, 3 and 6 months. Primary outcome was defined as change in glycaemic control measured by HbA1c from baseline. Other outcomes included change in; fasting plasma glucose (FPG), 2-h OGTT plasma glucose and lipid profile from baseline. Three multiple regression analyses were performed, where change in FPG, 2-h OGTT, and HbA1c post intervention from baseline respectively were the continuous dependent variable with other independent variables. RESULTS: One hundred and ten participants were recruited, 50% (n = 55) were males and mean age (±SD) was 46.7 ± 9.9 years. A significantly higher percentage of participants in CG (25.4%, n = 14) developed diabetes in comparison to IG (7.3%, n = 4) (p = 0.018). FPG, 2-h OGTT and HbA1c significantly reduced in the IG only. Both total cholesterol and LDL cholesterol decreased significantly from baseline only in the IG. In all three regression models the best predictor of respective dependent variable was Lysulin™ treatment. CONCLUSIONS: Lysulin™ improved glycaemic control, with reduced progression to diabetes, in those with pre-diabetes. Treatment also showed a beneficial reduction in total and LDL cholesterol levels. TRIAL REGISTRATION: Sri Lanka Clinical Trials Registry, identifier: SLCTR/2018/022 (http://slctr.lk/trials/1290). Registered on 13th July 2018; Study protocol version 2.0 (23rd March 2018).