Novel Triterpenoids from Cassia fistula Stem Bark Depreciates STZ-Induced Detrimental Changes in IRS-1/Akt-Mediated Insulin Signaling Mechanisms in Type-1 Diabetic Rats.

Here, we identified the mechanisms of action of antidiabetic activity of novel compounds isolated from Cassia fistula stem bark in STZ-diabetic animals. Novel triterpenoid compounds (C1, C2 and C3) were treated to STZ-administered diabetic animals at a concentration of 20mg/kg body weight orally for 60 days to assess their effects on plasma glucose, plasma insulin/C-peptide, serum lipid markers and the enzymes of carbohydrate metabolism, glucose oxidation and insulin signaling molecules. Oral administration of novel triterpenoid compounds to STZ-diabetic animals significantly decreased (p < 0.05) the plasma glucose concentration on the 7th, 15th, 30th, 45th and 60th daysin a duration-dependent manner (p < 0.05). Plasma insulin (p < 0.0001)/C-peptide (p < 0.0006), tissue glycogen (p < 0.0034), glycogen phosphorylase (p < 0.005), glucose 6-phosphatase (p < 0.0001) and lipid markers were significantly increased (p < 0.0001) in diabetic rats, whereas glucokinase (p < 0.0047), glycogen synthase (p < 0.003), glucose oxidation (p < 0.001), GLUT4 mRNA (p < 0.0463), GLUT4 protein (p < 0.0475) and the insulin-signaling molecules IR mRNA (p < 0.0195), IR protein (p < 0.0001), IRS-1 mRNA (p < 0.0478), p-IRS-1Tyr612 (p < 0.0185), Akt mRNA (p < 0.0394), p-AktSer473 (p < 0.0162), GLUT4 mRNA (p < 0.0463) and GLUT4 (p < 0.0475) were decreased in the gastrocnemius muscle. In silico analysis of C1-C3 with IRK and PPAR-γ protein coincided with in vivo findings. C1-C3 possessed promising antidiabetic activity by regulating insulin signaling mechanisms and carbohydrate metabolic enzymes.

Maternal C-Peptide and Insulin Sensitivity, but Not BMI, Associate with Fatty Acids in the First Trimester of Pregnancy.

Maternal obesity in pregnancy is a pro-inflammatory condition exposing the fetus to an adverse environment. Here, we tested associations of maternal obesity (primary exposures: BMI, leptin) and metabolic parameters (secondary exposures: glucose, C-peptide, and insulin sensitivity) with total serum concentrations of fatty acids in the first trimester of human pregnancy. This cross-sectional study included 123 non-smoking women with singleton pregnancy. In maternal serum, cotinine, leptin, and C-peptide (ELISA), glucose (hexokinase-based test) and fatty acids (gas chromatography) were quantified, and the insulin sensitivity index (ISHOMA) was calculated. Concentrations of fatty acid classes and total fatty acids did not differ between BMI or leptin categories. However, n-3 polyunsaturated fatty acids (PUFA) were decreased in the category with the highest C-peptide concentration (n-3 PUFA: CI -35.82--6.28, p < 0.006) and in the lowest ISHOMA category (n-3 PUFA: CI -36.48--5.61, p < 0.008). In a subcohort, in which fetal sex was determined (RT-qPCR of placental tissue), C-peptide was significantly associated with docosahexaenoic acid (DHA) in mothers bearing a female (n = 46), but not male (n = 37) fetus. In conclusion, pregnant women with high fasting C-peptide and low ISHOMA had decreased n-3 PUFA, and DHA was lower with higher C-peptide only in mothers bearing a female fetus.

The Postprandial Glycaemic and Hormonal Responses Following the Ingestion of a Novel, Ready-to-Drink Shot Containing a Low Dose of Whey Protein in Centrally Obese and Lean Adult Males: A Randomised Controlled Trial.

Purpose: Elevated postprandial glycaemia [PPG] increases the risk of cardiometabolic complications in insulin-resistant, centrally obese individuals. Therefore, strategies that improve PPG are of importance for this population. Consuming large doses of whey protein [WP] before meals reduces PPG by delaying gastric emptying and stimulating the secretion of the incretin peptides, glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide 1 [GLP-1]. It is unclear if these effects are observed after smaller amounts of WP and what impact central adiposity has on these gastrointestinal processes. Methods: In a randomised-crossover design, 12 lean and 12 centrally obese adult males performed two 240 min mixed-meal tests, ~5-10 d apart. After an overnight fast, participants consumed a novel, ready-to-drink WP shot (15 g) or volume-matched water (100 ml; PLA) 10 min before a mixed-nutrient meal. Gastric emptying was estimated by oral acetaminophen absorbance. Interval blood samples were collected to measure glucose, insulin, GIP, GLP-1, and acetaminophen. Results: WP reduced PPG area under the curve [AUC0-60] by 13 and 18.2% in the centrally obese and lean cohorts, respectively (both p <0.001). In both groups, the reduction in PPG was accompanied by a two-three-fold increase in GLP-1 and delayed gastric emptying. Despite similar GLP-1 responses during PLA, GLP-1 secretion during the WP trial was ~27% lower in centrally obese individuals compared to lean (p = 0.001). In lean participants, WP increased the GLP-1ACTIVE/TOTAL ratio comparative to PLA (p = 0.004), indicative of reduced GLP-1 degradation. Conversely, no treatment effects for GLP-1ACTIVE/TOTAL were seen in obese subjects. Conclusion: Pre-meal ingestion of a novel, ready-to-drink WP shot containing just 15 g of dietary protein reduced PPG in lean and centrally obese males. However, an attenuated GLP-1 response to mealtime WP and increased incretin degradation might impact the efficacy of nutritional strategies utilising the actions of GLP-1 to regulate PPG in centrally obese populations. Whether these defects are caused by an individual's insulin resistance, their obese state, or other obesity-related ailments needs further investigation. Clinical Trial Registration: ISRCTN.com, identifier [ISRCTN95281775]. https://www.isrctn.com/.

A high potency multi-strain probiotic improves glycemic control in children with new-onset type 1 diabetes mellitus: A randomized, double-blind, and placebo-controlled pilot study.

BACKGROUND: Studies in animal models and humans with type 1 diabetes mellitus (T1DM) have shown that probiotic supplementation leads to decreased pro-inflammatory cytokines (responsible for damaging ß-cells of the pancreas), improved gut barrier function, and induction of immune tolerance. OBJECTIVE: To study the effect of supplementation of probiotics in children with T1DM on glycemic control, insulin dose, and plasma C-peptide levels. METHODS: A single-centered, double-blinded, and randomized placebo-controlled pilot trial was conducted in children (2-12 years) with new-onset T1DM. Ninety-six children were randomized and allocated to Placebo or Intervention groups. The intervention included high dose (112.5 billion viable lyophilized bacteria per capsule) multi-strain probiotic De Simone formulation (manufactured by Danisco-Dupont) sold as Visbiome® in India. The probiotic was supplemented for 3 months and HbA1c, fasting C-peptide, blood sugar records, and insulin dose was recorded at baseline and 3 months. RESULTS: A total of 90 patients (45 in each group) were analyzed for outcome parameters. We found a significant decrease in HbA1c (5.1 vs. 3.8; p = 0.021) and a significant decline in total and bolus insulin dose (U/kg/day; p = 0.037 and 0.018, respectively) in the intervention group when compared with the placebo group. A significantly higher (p = 0.023) number of children achieved remission in the treatment group. We did not notice adverse effects in either of the study groups. CONCLUSION: Children with newly diagnosed T1DM managed with standard treatment along with probiotics showed better glycemic control and a decrease in insulin requirements; however, more extensive studies are further warranted.

Analysis of the clinical characteristics of insulin autoimmune syndrome induced by alpha-lipoic acid.

WHAT IS KNOWN AND OBJECTIVE: Alpha-lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA-induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention. METHODS: We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English. RESULTS AND DISCUSSION: The median age of 37 patients (28 females and 9 males) was 61 years (range 32-82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09-3.52), the insulin concentration was ≥100 µIU/ml (94.6%), and the C-peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2-36). Follow-up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1-36). WHAT IS NEW AND CONCLUSION: ALA-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly.

Circulating fatty acids and risk of gestational diabetes mellitus: prospective analyses in China.

OBJECTIVE: We aimed to examine prospective associations between circulating fatty acids in early pregnancy and incident gestational diabetes mellitus (GDM) among Chinese pregnant women. METHODS: Analyses were based on two prospective nested case-control studies conducted in western China (336 GDM cases and 672 matched controls) and central China (305 cases and 305 matched controls). Fasting plasma fatty acids in early pregnancy (gestational age at enrollment: 10.4 weeks(s.d., 2.0)) and 13.2 weeks (1.0), respectively) were determined by gas chromatography-mass spectrometry, and GDM was diagnosed based on the International Association of Diabetes in Pregnancy Study Groups criteria during 24-28 weeks of gestation. Multiple metabolic biomarkers (HOMA-IR (homeostatic model assessment for insulin resistance), HbA1c, c-peptide, high-sensitivity C-reactive protein, adiponectin, leptin, and blood lipids) were additionally measured among 672 non-GDM controls at enrollment. RESULTS: Higher levels of saturated fatty acids (SFAs) 14:0 (pooled odds ratio, 1.41 for each 1-s.d. increase; 95% CI: 1.25, 1.59) and 16:0 (1.19; 1.05, 1.35) were associated with higher odds of GDM. Higher levels of n-6 polyunsaturated fatty acid (PUFA) 18:2n-6 were strongly associated with lower odds of GDM (0.69; 0.60, 0.80). In non-GDM pregnant women, higher SFAs 14:0 and 16:0 but lower n-6 PUFA 18:2n-6 were generally correlated with unfavorable metabolic profiles. CONCLUSIONS: We documented adverse associations of 14:0 and 16:0 but a protective association of 18:2n-6 with GDM among Chinese pregnant women. Our findings highlight the distinct roles of specific fatty acids in the onset of GDM.

Hypoglycemic and hypolipidemic effects of total glycosides of Cistanche tubulosa in diet/streptozotocin-induced diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche tubulosa (Schrenk) R. Wight (Orobanchaceae) is a frequently prescribed component in many traditional herbal prescriptions which are used to treat diabetes in China. In recent studies, the antidiabetic activity of Cistanche tubulosa extracts have been confirmed. However, no systematic investigation has been reported on the total glycosides of Cistatnche tubulosa (TGCT). AIM OF THE STUDY: The present study aimed to investigate the hypoglycemic and hypolipidemic effects of TGCT and the potential mechanisms in diet/streptozotocin (STZ)-induced diabetic rats, and to chemically characterize the main constituents of TGCT. MATERIALS AND METHODS: The major constituents of TGCT were characterized by HPLC/Q-TOF-MS and the analytical quantification was performed with HPLC-DAD. Type 2 diabetic rats were induced by high-fat high-sucrose diet (HFSD) and a single injection of STZ (30 mg/kg). TGCT (50 mg/kg, 100 mg/kg and 200 mg/kg) or metformin (200 mg/kg) were orally administered for 6 weeks. Body weight and calorie intake were monitored throughout the experiment. Fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), area under curve of glucose (AUC-G), glycosylated hemoglobin (HbA1c), fasting insulin, serum C-peptide, glycogen content and insulin sensitivity index were tested. The levels of phosphorylated protein kinase B and phosphorylated glycogen synthase kinase 3ß, the activities of hexokinase and pyruvate kinase were assayed. Meanwhile, the changes in serum lipid profiles, superoxide dismutase, glutathione peroxidase, malondialdehyde and inflammatory factors were measured. Histological of pancreas were also evaluated by haematoxylin-eosin stain. RESULTS: Our investigation revealed the presence of phenylethanoid glycosides (PhGs): echinacoside (500.19 ± 11.52 mg/g), acteoside (19.13 ± 1.44 mg/g) and isoacteoside (141.82 ± 5.78 mg/g) in TGCT. Pharmacological tests indicated that TGCT significantly reversed STZ-induced weight loss (11.1%, 200 mg/kg); decreased FPG (56.4%, 200 mg/kg) and HbA1c (37.4%, 200 mg/kg); ameliorated the OGTT, AUC-G and insulin sensitivity; increased glycogen content (40.8% in liver and 52.6% in muscle, 200 mg/kg) and the activities of carbohydrate metabolizing enzymes; regulated lipid profile changes and the activities of antioxidant enzymes; diminished serum markers of oxidative stress and inflammation in a dose-dependent manner (p < 0.05). CONCLUSIONS: This study confirmed that TGCT was an effective nutritional agent for ameliorating hyperglycemia and hyperlipidemia in diet/STZ-induced diabetic rats, which might be largely attributed to the activities of TGCT on inhibitions of oxidative stress and inflammation.

Acute Nutritional Ketosis and Its Implications for Plasma Glucose and Glucoregulatory Peptides in Adults with Prediabetes: A Crossover Placebo-Controlled Randomized Trial.

BACKGROUND: The potential of a ketone monoester (ß-hydroxybutyrate; KEßHB) supplement to rapidly mimic a state of nutritional ketosis offers a new therapeutic possibility for diabetes prevention and management. While KEßHB supplementation has a glucose-lowering effect in adults with obesity, its impact on glucose control in other insulin-resistant states is unknown. OBJECTIVES: The primary objective was to investigate the effect of KEßHB-supplemented drink on plasma glucose in adults with prediabetes. The secondary objective was to determine its impact on plasma glucoregulatory peptides. METHODS: This randomized controlled trial [called CETUS (Cross-over randomizEd Trial of ß-hydroxybUtyrate in prediabeteS)] included 18 adults [67% men, mean age = 55 y, mean BMI (kg/m2) = 28.4] with prediabetes (glycated hemoglobin between 5.7% and 6.4% and/or fasting plasma glucose between 100 and 125 mg/dL). Participants were randomly assigned to receive KEßHB-supplemented and placebo drinks in a crossover sequence (washout period of 7-10 d between the drinks). Blood samples were collected from 0 to 150 min, at intervals of 30 min. Paired-samples t tests were used to investigate the change in the outcome variables [ß-hydroxybutyrate (ßHB), glucose, and glucoregulatory peptides] after both drinks. Repeated measures analyses were conducted to determine the change in concentrations of the prespecified outcomes over time. RESULTS: Blood ßHB concentrations increased to 3.5 mmol/L within 30 minutes after KEßHB supplementation. Plasma glucose AUC was significantly lower after KEßHB supplementation than after the placebo [mean difference (95% CI): -59 (-85.3, -32.3) mmol/L × min]. Compared with the placebo, KEßHB supplementation led to significantly greater AUCs for plasma insulin [0.237 (0.044, 0.429) nmol/L × min], C-peptide [0.259 (0.114, 0.403) nmol/L × min], and glucose-dependent insulinotropic peptide [0.243 (0.085, 0.401) nmol/L × min], with no significant differences in the AUCs for amylin, glucagon, and glucagon-like peptide 1. CONCLUSIONS: Ingestion of the KEßHB-supplemented drink acutely increased the blood ßHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes. Further research is needed to investigate the dynamics of repeated ingestions of a KEßHB supplement by individuals with prediabetes, with a view to preventing new-onset diabetes. This trial was registered at www.clinicaltrials.gov as NCT03889210.

Effect of inorganic nitrate on metabolic parameters in patients with type 2 diabetes: A 24-week randomized double-blind placebo-controlled clinical trial.

AIM: In this randomized placebo-controlled clinical trial, effect of oral inorganic nitrate (NO3-) on metabolic parameters was assessed in patients with type 2 diabetes mellitus (T2DM). METHODS: Seventy-four eligible patients with T2DM were randomly assigned to NO3--rich beetroot powder (5 g/d contains ~250 mg NO3-) and placebo groups to complete intervention over a 24-week period. Blood HbA1c, fasting serum glucose, insulin, C-peptide, as well as lipid profile were assessed at baseline and again at weeks 4, 12, and 24; indices of insulin resistance were also calculated. To assess safety of long-term oral NO3-, liver and renal function tests were measured. An intention-to-treat approach was used for data analysis. To compare effect of intervention over time between the groups (time×group), repeated measures generalized estimating equation (GEE) linear regression models were used. RESULTS: Mean age of the participants was 54.0 ± 8.5 (47.9% were male) and mean duration of diabetes was 8.5 ± 6.1 years. A total of 64 patients (n = 35 in beetroot group and n = 29 in placebo group) completed at least two visits and were included in the analyses. No significant difference was observed between the groups for glycemic and lipid parameters over time. Liver and renal function tests, as safety outcome measures, showed no undesirable changes during the study follow-up. CONCLUSION: Supplementation with inorganic NO3- had no effect on metabolic parameters in patients with T2DM.

Decreased plasma n6 : n3 polyunsaturated fatty acids ratio interacting with high C-peptide promotes non-alcoholic fatty liver disease in type 2 diabetes patients.

AIMS/INTRODUCTION: To explore relationships between polyunsaturated fatty acids (PUFA) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes, and whether insulin action has an interactive effect with PUFA on NAFLD progression. MATERIALS AND METHODS: We extracted clinical and omics data of 482 type 2 diabetes patients from a tertiary hospital consecutively from April 2018 to April 2019. NAFLD was estimated by ultrasound at admission. Plasma fasting n3 and n6 fatty acids were quantified by liquid chromatography-tandem mass spectrometry analysis. Restricted cubic spline nested in binary logistic regression was used to select the cut-off point, and estimate odds ratios and 95% confidence intervals. Additive interactions of the n6 : n3 ratio with insulin action for NAFLD were estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Relative excess risk due to interaction >0, attributable proportion due to interaction >0 or synergy index >1 indicates biological interaction. Spearman correlation analysis was used to obtain partial correlation coefficients between PUFA and hallmarks of NAFLD. RESULTS: Of 482 patients, 313 were with and 169 were without NAFLD. N3 ≥800 and n6 PUFA ≥8,100 µmol/L were independently associated with increased NAFLD risk; n6 : n3 ratio ≤10 was associated with NAFLD (odds ratio 1.80, 95% confidence interval 1.20-2.71), and the effect size was amplified by high C-peptide (odds ratio 8.89, 95% confidence interval 4.48-17.7) with significant interaction. The additive interaction of the n6 : n3 ratio and fasting insulin was not significant. CONCLUSION: Decreased n6 : n3 ratio was associated with increased NAFLD risk in type 2 diabetes patients, and the effect was only significant and amplified when there was the co-presence of high C-peptide.

Acute effects of delayed-release hydrolyzed pine nut oil on glucose tolerance, incretins, ghrelin and appetite in healthy humans.

BACGROUND & AIM: Pinolenic acid, a major component (~20%) of pine nut oil, is a dual agonist of the free fatty acid receptors, FFA1 and FFA4, which may regulate release of incretins and ghrelin from the gut. Here, we investigated the acute effects of hydrolyzed pine nut oil (PNO-FFA), delivered to the small intestine by delayed-release capsules, on glucose tolerance, insulin, incretin and ghrelin secretion, and appetite. METHODS: In two cross-over studies, we evaluated 3 g unhydrolyzed pine nut oil (PNO-TG) or 3 g PNO-FFA versus no oil in eight healthy, non-obese subjects (study 1), and 3 g PNO-FFA or 6 g PNO-FFA versus no oil in ten healthy, overweight/obese subjects (study 2) in both studies given in delayed-release capsules 30 min prior to a 4-h-oral glucose tolerance test (OGTT). Outcomes were circulating levels of glucose, insulin, GLP-1, GIP, ghrelin, appetite and gastrointestinal tolerability during OGTT. RESULTS: Both 3 g PNO-FFA in study 1 and 6 g PNO-FFA in study 2 markedly increased GLP-1 levels (p < 0.001) and attenuated ghrelin levels (p < 0.001) during the last 2 h of the OGTT compared with no oil. In study 2, these effects of PNO-FFA were accompanied by an increased satiety and fullness (p < 0.03), and decreased prospective food consumption (p < 0.05). PNO-FFA caused only small reductions in glucose and insulin levels during the first 2 h of the OGTT. CONCLUSIONS: Our results provide evidence that PNO-FFA delivered to the small intestine by delayed-release capsules may reduce appetite by augmenting GLP-1 release and attenuating ghrelin secretion in the late postprandial state. CLINICAL TRIAL REGISTRY NUMBERS: NCT03062592 and NCT03305367.

Safety and tolerability of a novel oral nutritional supplement in healthy volunteers.

BACKGROUND AND OBJECTIVE: Foods for Special Medical Purposes (FSMPs) are formulated to support the nutritional needs of subjects with impaired capacity to ingest, digest or absorb ordinary food or nutrients. Polglumyt® is a proprietary highly purified, high quality glycogen obtained from mussels. Here we report the results of a single-center, single dose, open label, single arm study carried out to investigate acceptance (i.e. gastrointestinal tolerance and palatability), metabolic profile and safety of a low osmolarity, high-density energy Polglumyt®-based drink (the investigational product, IP) as a novel FSMP. METHODS: Twelve healthy subjects received a single oral administration of the IP under fasting conditions. The study endpoints were: changes in gastrointestinal system tolerability at 3 h, 6 h and 24 h after IP intake; IP palatability evaluation; metabolic evaluation through the kinetic profile of circulating glucose, insulin and C-peptide from 0 h to 6 h after IP intake and changes from baseline in circulating triglycerides at 3 h and 6 h after IP intake. RESULTS: The IP showed a good gastrointestinal tolerability and an acceptable palatability. The IP did not affect the physiological glycemic profile and the triglycerides levels 6 h after the intake. The IP was well tolerated by study subjects, with no or minor adverse events. CONCLUSIONS: The study results encourage additional clinical investigations on the IP as a novel FSMP in patients with impaired digestion or gastrointestinal absorption, unable to assume an ordinary diet, e.g. patients undergoing invasive gastrointestinal surgery, elderly or oncological patients, even with certain metabolic disorders.

Antidiabetic Potency, Antioxidant Effects, and Mode of Actions of Citrus reticulata Fruit Peel Hydroethanolic Extract, Hesperidin, and Quercetin in Nicotinamide/Streptozotocin-Induced Wistar Diabetic Rats.

This study is aimed at assessing the antihyperglycemic, antihyperlipidemic, and antioxidant effects of Citrus reticulata (C. reticulata) fruit peel hydroethanolic extract and two flavonoids, hesperidin and quercetin, in nicotinamide (NA)/streptozotocin- (STZ-) induced type 2 diabetic rats. In addition, GC-MS and HPLC-MS analyses of the extract were performed and the results indicated the presence of multiple flavonoids including hesperidin, quercetin, naringin, and polymethoxylated flavones (nobiletin and tangeretin). To achieve the aim of the study, diabetic rats with NA/STZ-induced T2DM were orally treated with C. reticulata fruit peel hydroethanolic extract, hesperidin, and quercetin at a dose of 100 mg/kg b.w./day for four weeks. The treatments with C. reticulata fruit peel extract, hesperidin, and quercetin significantly ameliorated the impaired oral glucose tolerance; the elevated serum fructosamine level; the diminished serum insulin and C-peptide levels; the altered HOMA-IR, HOMA-IS, and HOMA-ß cell function; the decreased liver glycogen content; the increased liver glucose-6-phosphatase and glycogen phosphorylase activities; the deleteriously affected serum lipid profile; the elevated serum AST and ALT activities; and the raised serum creatinine and urea levels in the diabetic rats. The treatments also produced remarkable improvement in the antioxidant defense system manifested by a decrease in the elevated liver lipid peroxidation and an increase in the lowered glutathione content and GPx, GST, and SOD activities. Furthermore, the three treatments enhanced the mRNA expression of GLUT-4 and the insulin receptor ß-subunit, but only quercetin produced a significant increase in the expression of adiponectin in adipose tissue of diabetic rats. In conclusion, C. reticulata fruit peel hydroethanolic extract, hesperidin, and quercetin have potent antidiabetic effects which may be mediated through their insulinotropic effects and insulin-sensitizing actions. In addition, the alleviation of the antioxidant defense system by the extract, hesperidin, and naringin may have an important action to enhance the antidiabetic actions and to improve liver and kidney functions in NA/STZ-induced diabetic rats.

Oral D/L-3-Hydroxybutyrate Stimulates Cholecystokinin and Insulin Secretion and Slows Gastric Emptying in Healthy Males.

BACKGROUND: D-3-hydroxybutyrate (D-3-OHB) is a ketone body that serves as an alternative nutritional fuel but also as an important signaling metabolite. Oral ketone supplements containing D/L-3-OHB are becoming a popular approach to achieve ketosis. AIM: To explore the gut-derived effects of ketone supplements. METHODS: Eight healthy lean male volunteers were investigated on 2 separate occasions:An acetaminophen test was performed to evaluate gastric emptying and blood samples were obtained consecutively throughout the study period. RESULTS: We show that oral consumption of D/L-3-OHB stimulates cholecystokinin release (P = 0.02), elevates insulin (P = 0.03) and C-peptide (P < 0.001) concentrations, and slows gastric emptying (P = 0.01) compared with matched intravenous D/L-3-OHB administration. Measures of appetite and plasma concentrations of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were unaffected by interventions. CONCLUSION: Our findings show that D/L-3-OHB exert incretin effects and indicate luminal sensing in the gut endothelium. This adds to our understanding of ketones as signaling metabolites and displays the important difference between physiological ketosis and oral ketone supplements.

A randomized, double-blind, placebo-controlled crossover clinical trial to evaluate the anti-diabetic effects of Allium hookeri extract in the subjects with prediabetes.

BACKGROUND: Allium hookeri is widely consumed as a vegetable and herbal medicine in Asia. A. hookeri has been reported anti-inflammatory, anti-obesity, osteoblastic, anti-oxidant, and anti-diabetic effects in animal studies. We investigated the anti-diabetic effects of A. hookeri aqueous extract (AHE) in the Korean subjects. METHODS: Prediabetic subjects (100 ≤ fasting plasma glucose (FPG) < 126 mg/dL) who met the inclusion criteria were recruited for this study. The enrolled subjects (n = 30) were randomly divided into either an AHE (n = 15, 486 mg/day) or placebo (n = 15) group. Outcomes were measurements of FPG, glycemic response to an oral glucose tolerance test (OGTT), insulin, C-peptide, hemoglobin A1c (HbA1c), total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol. The t-test was used to assess differences between the groups. A p-value < 0.05 was considered statistically significant. RESULTS: Eight weeks after AHE supplementation, HbA1c level was significantly decreased in the AHE group compared with the placebo group. No clinically significant changes in any safety parameter were observed. CONCLUSION: The findings suggest that AHE can be effective in reducing HbA1c, indicating it as an adjunctive tool for improving glycemic control. TRIAL REGISTRATION: The study protocol was retrospectively registered at www.clinicaltrials.gov ( NCT03330366 , October 30, 2017).

Effect of nano yam polysaccharide on the blood glucose and blood lipid in rats.

Chinese yam is the dry rhizome of dioscoreaceae plant. Polysaccharide in yam is one of significant functional components, its pharmacological effects include glucose-lowering, lipid-lowering, anti-tumor, anti-oxidation and enhancing the immune. The effects of nano yam polysaccharide on the metabolism of blood glucose and blood lipid in model rats were systematically investigated in this study. The results showed that the diabetic rat model can been successfully induced by the peritoneal injection of 200mg/kg alloxan. The rats were fed with the high-fat diet for 30d, which could induce a model of hyperlipidemia rat successfully. After the model rats were fed with nano yam polysaccharide of 50mg/ml and 100mg/ml per day for 12d and 30d, respectively. For each nano yam polysaccharide group, the blood glucose level was significantly reduced, the glucose tolerance, glycogen and the content of C-peptide were improved in alloxan rats. Moreover, the symptom of one little and three more in diabetic rats was ameliorated and the contents of TC, TG and LDL-C in the serum for the high fat rats were significantly decreased.

Effect of Steamed Onion (ONIRO) Consumption on Body Fat and Metabolic Profiles in Overweight Subjects: A 12-Week Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Objective: The aim of the study is to investigate the effect of Jeju steamed onion (ONIRO) on body fat and metabolic profiles in overweight subjects.Methods: This randomized, double-blind, placebo-controlled clinical intervention was conducted and completed at one clinical research site. The subjects (n = 70) were randomly divided into placebo or test group and were instructed to take before each meal either the placebo or ONIRO capsule for 12 weeks. Anthropometric as well as serum and metabolic parameters, including triglycerides, cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, leptin, adiponectin, C-peptide, and aspartate aminotransferase (AST) were measured at baseline and after 12 weeks. Body composition was also measured by dual-energy x-ray absorptiometry (DEXA) and computed tomography (CT). This trial is registered under the trial registration code clinicaltrials.gov: NCT03645382 (https://register.clinicaltrials.gov).Results: Compared to the placebo, ONIRO supplementation for significantly reduced the percentage of body fat and fat mass as measured by DEXA (p = 0.028 and 0.022, respectively) with no significant effects on lean body mass. CT analyses at the L1 level showed a significant decrease in the areas of whole fat, visceral fat, and subcutaneous fat (p = 0.009, p = 0.039, p = 0.020, respectively), while CT scan of L4 resulted in a significant reduction of whole fat area and subcutaneous area (p = 0.006 and p = 0.012, respectively). The levels of triglycerides (TG) and C-peptide were significantly lower after 12 weeks of ONIRO treatment.Conclusions: These findings suggest that ONIRO supplementation reduces total body fat, notably abdominal visceral fat, with positive changes of the clinically relevant metabolic parameters serum TG and C-peptide.

Effects of Nicotinamide Riboside on Endocrine Pancreatic Function and Incretin Hormones in Nondiabetic Men With Obesity.

OBJECTIVE: Augmenting nicotinamide adenine dinucleotide (NAD+) metabolism through dietary provision of NAD+ precursor vitamins translates to improved glucose handling in rodent models of obesity and diabetes. Preclinical evidence suggests that the NAD+/SIRT1 axis may be implicated in modulating important gut-related aspects of glucose regulation. We sought to test whether NAD+ precursor supplementation with nicotinamide riboside (NR) affects ß-cell function, α-cell function, and incretin hormone secretion as well as circulating bile acid levels in humans. DESIGN: A 12-week randomized, double-blind, placebo-controlled, parallel-group trial in 40 males with obesity and insulin resistance allocated to NR at 1000 mg twice daily (n = 20) or placebo (n = 20). Two-hour 75-g oral glucose tolerance tests were performed before and after the intervention, and plasma concentrations of glucose, insulin, C-peptide, glucagon, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were determined. ß-Cell function indices were calculated based on glucose, insulin, and C-peptide measurements. Fasting plasma concentrations of bile acids were determined. RESULTS: NR supplementation during 12 weeks did not affect fasting or postglucose challenge concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, or GIP, and ß-cell function did not respond to the intervention. Additionally, no changes in circulating adipsin or bile acids were observed following NR supplementation. CONCLUSION: The current study does not provide evidence to support that dietary supplementation with the NAD+ precursor NR serves to impact glucose tolerance, ß-cell secretory capacity, α-cell function, and incretin hormone secretion in nondiabetic males with obesity. Moreover, bile acid levels in plasma did not change in response to NR supplementation.

Development of a delayed-release nutrient for appetite control in adults with obesity and type 2 diabetes and initial clinical testing in a single dose randomized controlled trial.

BACKGROUND AND OBJECTIVES: Delivery of nutrients directly to the small intestine, either via enteral feeding tube or by gastric bypass surgery, is associated with increased levels of appetite-suppressing and glucoregulatory hormones, including GLP-1, and reduced appetite. Achieving these changes non-invasively using formulated foods may be of therapeutic benefit in individuals with obesity and related comorbidities. The aim of this pilot study was to determine the effect of a single dose of a novel delayed-release nutrient (DRN) on glucose, GLP-1, c-peptide, insulin, and appetite in adults with obesity and type 2 diabetes. SUBJECTS AND METHODS: We formulated an all-natural, generally recognized as safe ('GRAS") DRN and conducted a randomized prospective crossover trial. Nineteen adults with obesity and type 2 diabetes underwent paired 3-h meal tolerance tests (MTT) in randomized order 1-4 weeks apart. Subjects ingested a single dose of DRN and the same nutrients as unformulated powders (UN). RESULTS: For DRN compared with UN, the maximal concentration (Cmax) was significantly lower for glucose, c-peptide, and insulin, and the time of maximal concentration (Tmax) was significantly delayed. While Tmax for GLP-1 was also significantly delayed following DRN compared with UN (45 min later; p = 0.26), Cmax did not differ significantly. GLP-1 rose significantly during the last 90 min of the 3-h MTT (ß1 = 0.16 pg/mL/min, p = 0.025), while following UN it decreased (ß1 = -0.21 pg/mL/min, p = 0.0026) (p difference = 0.0003). There were minimal differences in seven measures of appetite and adverse symptoms between DRN and UN. CONCLUSIONS: We conclude that nutrient can be formulated using all-natural ingredients to induce a delayed rise in GLP-1. Further testing is needed to determine the amount and site of nutrient release, when maximum GLP-1 levels occur, and if modification of the formulation specifications and dose are associated with appetite and glucose control.