Abrus precatorius Leaf Extract Reverses Alloxan/Nicotinamide-Induced Diabetes Mellitus in Rats through Hormonal (Insulin, GLP-1, and Glucagon) and Enzymatic (α-Amylase/α-Glucosidase) Modulation.

BACKGROUND: Abrus precatorius is used in folk medicine across Afro-Asian regions of the world. Earlier, glucose lowering and pancreato-protective effects of Abrus precatorius leaf extract (APLE) was confirmed experimentally in STZ/nicotinamide-induced diabetic rats; however, the underlying mechanism of antidiabetic effect and pancreato-protection remained unknown. OBJECTIVE: This study elucidated antidiabetic mechanisms and pancreato-protective effects of APLE in diabetic rats. MATERIALS AND METHODS: APLE was prepared by ethanol/Soxhlet extraction method. Total phenols and flavonoids were quantified calorimetrically after initial phytochemical screening. Diabetes mellitus (DM) was established in adult Sprague-Dawley rats (weighing 120-180 g) of both sexes by daily sequential injection of nicotinamide (48 mg/kg; ip) and Alloxan (120 mg/kg; ip) over a period of 7 days. Except control rats which had fasting blood glucose (FBG) of 4.60 mmol/L, rats having stable FBG (16-21 mmol/L) 7 days post-nicotinamide/Alloxan injection were considered diabetic and were randomly reassigned to one of the following groups (model, APLE (100, 200, and 400 mg/kg, respectively; po) and metformin (300 mg/kg; po)) and treated daily for 18 days. Bodyweight and FBG were measured every 72 hours for 18 days. On day 18, rats were sacrificed under deep anesthesia; organs (kidney, liver, pancreas, and spleen) were isolated and weighed. Blood was collected for estimation of serum insulin, glucagon, and GLP-1 using a rat-specific ELISA kit. The pancreas was processed, sectioned, and H&E-stained for histological examination. Effect of APLE on enzymatic activity of alpha (α)-amylase and α-glucosidase was assessed. Antioxidant and free radical scavenging properties of APLE were assessed using standard methods. RESULTS: APLE dose-dependently decreased the initial FBG by 68.67%, 31.07%, and 4.39% compared to model (4.34%) and metformin (43.63%). APLE (100 mg/kg) treatment restored weight loss relative to model. APLE increased serum insulin and GLP-1 but decreased serum glucagon relative to model. APLE increased both the number and median crosssectional area (×106 µm2) of pancreatic islets compared to that of model. APLE produced concentration-dependent inhibition of α-amylase and α-glucosidase relative to acarbose. APLE concentration dependently scavenged DPPH and nitric oxide (NO) radicals and demonstrated increased ferric reducing antioxidant capacity (FRAC) relative to standards. CONCLUSION: Antidiabetic effect of APLE is mediated through modulation of insulin and GLP-1 inversely with glucagon, noncompetitive inhibition of α-amylase and α-glucosidase, free radical scavenging, and recovery of damaged/necro-apoptosized pancreatic ß-cells.

Potential for Gut Peptide-Based Therapy in Postprandial Hypotension.

Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pooling. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose-dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH.

Grape-Seed Proanthocyanidin Extract Reverts Obesity-Related Metabolic Derangements in Aged Female Rats.

Obesity and ageing are current issues of global concern. Adaptive homeostasis is compromised in the elderly, who are more likely to suffer age-related health issues, such as obesity, metabolic syndrome, and cardiovascular disease. The current worldwide prevalence of obesity and higher life expectancy call for new strategies for treating metabolic disorders. Grape-seed proanthocyanidin extract (GSPE) is reported to be effective in ameliorating these pathologies, especially in young animal models. In this study, we aimed to test the effectiveness of GSPE in modulating obesity-related pathologies in aged rats fed an obesogenic diet. To do so, 21-month-old rats were fed a high-fat/high-sucrose diet (cafeteria diet) for 11 weeks. Two time points for GSPE administration (500 mg/kg body weight), i.e., a 10-day preventive GSPE treatment prior to cafeteria diet intervention and a simultaneous GSPE treatment with the cafeteria diet, were assayed. Body weight, metabolic parameters, liver steatosis, and systemic inflammation were analysed. GSPE administered simultaneously with the cafeteria diet was effective in reducing body weight, total adiposity, and liver steatosis. However, the preventive treatment was effective in reducing only mesenteric adiposity in these obese, aged rats. Our results confirm that the simultaneous administration of GSPE improves metabolic disruptions caused by the cafeteria diet also in aged rats.

Activation of PI3K/Akt Signaling Pathway in Rat Hypothalamus Induced by an Acute Oral Administration of D-Pinitol.

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.

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/.

Whey protein preload enhances the active GLP-1 response and reduces circulating glucose in women with polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) increases risk for development of type 2 diabetes. Whey protein ingestion before a carbohydrate load attenuates blood glucose. For our exploratory, case-control study design, we hypothesized that 35 g whey protein isolate (WPI) preloading would increase postprandial incretins and reduce hyperglycemia in women with PCOS. Twenty-nine age-matched women (PCO = 14 and CON = 15) completed oral glycemic tolerance tests (OGTT) following baseline (Day 0) as well as 35 g WPI acute (Day 1) and short-term supplementation (Day 7). Eight venous samples were collected during each test for quantification of glucose, and enteropancreatic hormones and to calculate area under the curve (AUC). Data was analyzed via repeated measures ANCOVA with significance set at P< .05. "Day x time x group" significantly influenced glucose (P = .01) and insulin changes (P = .03). In both groups, AUCglu were significantly lower on Day 7 than Day 0 (P< .05). Postprandial glucose excursions were lower on Days 1 and 7 than Day 0 in PCO and CON. Both, PCO and CON exhibited greater insulin changes on Days 1 and 7 compared to Day 0 (P< .05). AUCglucagon were higher on Days 1 and 7 than on Day 0 (P< .05). Changes in active GLP-1 were higher on Day 1 than Day 0 (P= .03). Overall, we showed that WPI preloading augmented insulin release and consequently lowered circulating glucose in women with and without PCOS. This insulinogenic effect can be attributed to enhanced active GLP-1 levels. We concluded that the incretin-mimetic effect of WPI may aid women with PCOS in achieving glycemic homeostasis.

Glucagon Shows Higher Sensitivity than Insulin to Grapeseed Proanthocyanidin Extract (GSPE) Treatment in Cafeteria-Fed Rats.

The endocrine pancreas plays a key role in metabolism. Procyanidins (GSPE) targets ß-cells and glucagon-like peptide-1 (GLP-1)-producing cells; however, there is no information on the effects of GSPE on glucagon. We performed GSPE preventive treatments administered to Wistar rats before or at the same time as they were fed a cafeteria diet during 12 or 17 weeks. We then measured the pancreatic function and GLP-1 production. We found that glucagonemia remains modified by GSPE pre-treatment several weeks after the treatment has finished. The animals showed a higher GLP-1 response to glucose stimulation, together with a trend towards a higher GLP-1 receptor expression in the pancreas. When the GSPE treatment was administered every second week, the endocrine pancreas behaved differently. We show here that glucagon is a more sensitive parameter than insulin to GSPE treatments, with a secretion that is highly linked to GLP-1 ileal functionality and dependent on the type of treatment.

Role of zonulin and GLP-1/DPP-IV in alleviation of diabetes mellitus by peptide/polypeptide fraction of Aloe vera in streptozotocin- induced diabetic wistar rats.

ETHNO-PHARMACOLOGICAL RELEVANCE: The genus Aloe has a long history of usage in medicine. Aloe barbadensis Miller, commonly known as Aloe vera, is said to possess anti-diabetic, anti-inflammatory, anti-cancer, anti-microbial, immunomodulation, wound healing properties. AIM OF THE STUDY: In diabetes mellitus, loss in intestinal permeability is observed with high levels of zonulin and low levels of glucagon-like peptide-1 (GLP-1) leading to hyperglycemia. The aim of the study was to understand the role of peptide/polypeptide fraction (PPF) of Aloe vera in the alleviation of diabetes through maintaining the intestinal permeability by regulating the zonulin and GLP-1 levels. MATERIALS AND METHODS: The PPF of Aloe vera was obtained through trichloroacetic acid precipitation. The anti-diabetic potential of the PPF was tested through DPP-IV inhibition, glucose diffusion assay, and by using Rin-m5F cells. The anti-diabetic potential of the PPF was tested at a dose of 0.450 mg/kg bw in vivo using streptozotocin-induced diabetic Wistar rats. The effect of PPF on fasting plasma glucose, insulin, glucagon, Zonulin, GLP-1, DPP-IV, levels were studied in diabetic rats. The histopathological studies of the pancreas, small intestine, and liver were carried out for organ-specific effects. RESULTS: PPF has the ability to reduce fasting plasma glucose levels with concomitant increase in insulin levels in streptozotocin-induced diabetic rats. It was also observed that increase in GLP-1 levels with a decrease in DPP-IV and zonulin levels thereby mitigating the loss of intestinal permeability. These findings correlate with the small intestine's histopathological observation where the excessive proliferation of epithelium in the small intestine of diabetic rats was reduced after PPF treatment. CONCLUSION: These results suggest that the PPF of Aloe vera alleviates diabetes through islet cell rejuvenation via GLP-1/DPP-IV pathway and thereby suggesting the usage of PPF as an alternate medicine for diabetes mellitus with the possibility to reduce the intestinal permeability and zonulin levels.

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.

Effects of colostrum instead of formula feeding for the first 2 days postnatum on whole-body energy metabolism and its endocrine control in neonatal calves.

Colostrum provides high amounts of nutritive and non-nutritive substrates, which are essential for calf nutrition and passive immunization. Colostral growth factors and hormones have beneficial effects on postnatal maturation and may affect substrate utilization and energy expenditure in neonatal calves. We tested the hypothesis that energy metabolism and its endocrine regulation differ during the first 10 d of life in calves fed either colostrum or a milk-based formula with a similar nutrient composition to colostrum, but largely depleted of bioactive substances, for the first 2 d postnatum. Male Holstein calves (n = 18) were fed either pooled colostrum (COL; n = 9) or a milk-based formula (FOR; n = 9) for the first 2 d of life. From d 3 on, all calves received same milk replacer. On d 2 and 7 of life, calves were placed in a respiration chamber for indirect calorimetric measurements to calculate heat production, fat (FOX) and carbohydrate oxidation (COX), as well as respiratory quotient. Blood was sampled on d 1 before first colostrum intake and on d 2, 3, 7, 8, 9, and 10 before morning feeding, to measure plasma concentrations of immunoglobulins, metabolites, and hormones. Additional postprandial blood samples were taken on d 1 and 9 at 30, 60, 120, 240, and 420 min after milk feeding. Liver samples were collected on d 10 of life to determine gene expression related to energy metabolism. Formula-fed calves showed lower plasma concentrations of total protein, immunoglobulins, haptoglobin, leptin, adiponectin, and insulin-like growth factor (IGF) binding protein (IGFBP)-4 during the whole study but temporarily higher plasma concentrations of urea, insulin, glucagon, triglyceride, and cholesterol on the first day after feeding, compared with concentrations in COL. The temporary increase in glucagon, triglyceride, and cholesterol on d 1 reversed on d 2 or 3, showing higher concentrations in COL than in FOR calves. In FOR, IGF-I, IGFBP-2, and IGFBP-3 were lower on d 3 than in COL. Interestingly, FOR calves had higher heat production during respiratory measurements on d 2 and higher body temperature on d 2, 3, and 5 than those of COL. The hepatic mRNA abundance of cytosolic phosphoenolpyruvate carboxykinase was higher in FOR than in COL. Our results indicate that first milk feeding after birth influenced whole-body energy expenditure but not FOX and COX in neonatal calves, and the absorption of colostral leptin and adiponectin might affect insulin sensitivity on d 1 of life.

A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial.

BACKGROUND: Exogenous ketones make it possible to reach a state of ketosis that may improve metabolic control in humans. OBJECTIVES: The main objective of this study was to determine whether the ingestion of a ketone monoester (KE) drink before a 2-h oral-glucose-tolerance test (OGTT) would lower blood glucose concentrations. Secondary objectives were to determine the impact of KE on nonesterified fatty acid (NEFA) concentration and glucoregulatory hormones. METHODS: We conducted a randomized controlled crossover experiment in 15 individuals with obesity (mean ± SD age: 47 ± 10 y; BMI: 34 ± 5 kg/m2). After an overnight fast, participants consumed a KE drink [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 0.45 mL/kg body weight] or taste-matched control drink 30 min before completing a 75-g OGTT. Participants and study personnel performing laboratory analyses were blinded to each condition. RESULTS: The KE increased d-ß-hydroxybutyrate to a maximum of ∼3.4 mM (P < 0.001) during the OGTT. Compared with the control drink, KE reduced glucose (-11%, P = 0.002), NEFA (-21%, P = 0.009), and glucagon-like peptide 1 (-31%, P = 0.001) areas under the curve (AUCs), whereas glucagon AUC increased (+11%, P = 0.030). No differences in triglyceride, C-peptide, and insulin AUCs were observed after the KE drink. Mean arterial blood pressure decreased and heart rate increased after the KE drink (both P < 0.01). CONCLUSIONS: A KE drink consumed before an OGTT lowered glucose and NEFA AUCs with no increase in circulating insulin. Our results suggest that a single drink of KE may acutely improve metabolic control in individuals with obesity. Future research is warranted to examine whether KE could be used safely to have longer-term effects on metabolic control. This trial was registered at clinicaltrials.gov as NCT03461068.

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.

Characterisation and antidiabetic utility of a novel hybrid peptide, exendin-4/gastrin/xenin-8-Gln.

Enteroendocrine derived hormones such as glucagon-like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), gastrin and xenin are known to exert complementary beneficial metabolic effects in diabetes. This study has assessed the biological activity and therapeutic utility of a novel GLP-1/gastrin/xenin hybrid peptide, namely exendin-4/gastrin/xenin-8-Gln hybrid, both alone and in combination with the stable GIP mimetic, (DAla2)GIP. Exendin-4/gastrin/xenin-8-Gln increased in vitro insulin secretion to a similar or superior extent, as the parent peptides. Insulinotropic effects were mainly linked to modulation of GLP-1 and neurotensin receptors. Exendin-4/gastrin/xenin-8-Gln also augmented the insulinotropic actions of (DAla2)GIP. Acute administration of exendin-4/gastrin/xenin-8-Gln in mice induced significant appetite suppressive, glucose lowering and insulin secretory effects, with a duration of biological action beyond 8 h. Twice daily administration of exendin-4, exendin-4/gastrin/xenin-8-Gln, either alone or in combination with (DAla2)GIP, reduced circulating glucose, increased plasma insulin as well as improving glucose tolerance, insulin sensitivity and metabolic response to GIP in high fat fed mice. Body weight, food intake, circulating glucagon and amylase activity were unaltered. All hybrid peptide treated high fat mice exhibited marked reductions in LDL-cholesterol and body fat mass. Energy expenditure and locomotor activity were increased in mice treated with exendin-4/gastrin/xenin-8-Gln in combination with (DAla2)GIP. Interestingly, exendin-4 and exendin-4/gastrin/xenin-8-Gln treatment, but not exendin-4/gastrin/xenin-8-Gln in combination with (DAla2)GIP, reduced pancreatic islet and beta-cell area when compared to high fat controls. These studies confirm that unimolecular multi-agonist peptide hormones exert beneficial metabolic effects in diabetes, highlighting their potential as novel treatment strategies.

A novel role of the corticotrophin-releasing hormone regulating peptide, teneurin C-terminal associated peptide 1, on glucose uptake into the brain.

Teneurin C-terminal associated peptide (TCAP) is an ancient paracrine signalling agent that evolved via lateral gene transfer from prokaryotes into an early metazoan ancestor. Although it bears structural similarity to corticotrophin-releasing hormone (CRH), it inhibits the in vivo actions of CRH. The TCAPs are highly expressed in neurones, where they induce rapid cytoskeletal rearrangement and are neuroprotective. Because these processes are highly energy-dependent, this suggests that TCAP has the potential to regulate glucose uptake because glucose is the primary energy substrate in brain, and neurones require a steady supply to meet the high metabolic demands of neuronal communication. Therefore, the objective of the present study was to assess the effect of TCAP-mediated glucose uptake in the brain and in neuronal cell models. TCAP-mediated 18 F-deoxyglucose (FDG) uptake into brain tissue was assessed in male wild-type Wistar rats by functional positron emission tomography. TCAP-1 increased FDG uptake by over 40% into cortical regions of the brain, demonstrating that TCAP-1 can significantly enhance glucose supply. Importantly, a single nanomolar injection of TCAP-1 increased brain glucose after 3 days and decreased blood glucose after 1 week. This is corroborated by a decreased serum concentration of insulin and an increased serum concentration of glucagon. In immortalised hypothalamic neurones, TCAP-1 increased ATP production and enhanced glucose uptake by increasing glucose transporter recruitment to the plasma membrane likely via AKT and mitogen-activated protein kinase/ERK phosphorylation events. Taken together, these data demonstrate that TCAP-1 increases glucose metabolism in neurones, and may represent a peptide signalling agent that regulated glucose uptake before insulin and related peptides.

Zinc Supplementation Does Not Affect Glucagon Response to Intravenous Glucose and Insulin Infusion in Patients with Well-Controlled Type 2 Diabetes.

Glucagon dysregulation is an essential component in the pathophysiology of type 2 diabetes. Studies in vitro and in animal models have shown that zinc co-secreted with insulin suppresses glucagon secretion. Zinc supplementation improves blood glucose control in patients with type 2 diabetes, although there is little information about how zinc supplementation may affect glucagon secretion. The objective of this study was to evaluate the effect of 1-year zinc supplementation on fasting plasma glucagon concentration and in response to intravenous glucose and insulin infusion in patients with type 2 diabetes. A cross-sectional study was performed after 1-year of intervention with 30 mg/day zinc supplementation or a placebo on 28 patients with type 2 diabetes. Demographic, anthropometric, and biochemical parameters were determined. Fasting plasma glucagon and in response to intravenous glucose and insulin infusion were evaluated. Patients of both placebo and supplemented groups presented a well control of diabetes, with mean values of fasting blood glucose and glycated hemoglobin within the therapeutic goals established by ADA. No significant differences were observed in plasma glucagon concentration, glucagon/glucose ratio or glucagon/insulin ratio fasting, after glucose or after insulin infusions between placebo and supplemented groups. No significant effects of glucose or insulin infusions were observed on plasma glucagon concentration. One-year zinc supplementation did not affect fasting plasma glucagon nor response to intravenous glucose or insulin infusion in well-controlled type 2 diabetes patients with an adequate zinc status.

Dose-Dependent Effects of Randomized Intraduodenal Whey-Protein Loads on Glucose, Gut Hormone, and Amino Acid Concentrations in Healthy Older and Younger Men.

Protein-rich supplements are used widely for the prevention and management of malnutrition in older people. We have reported that healthy older, compared to younger, adults have less suppression of energy intake by whey-protein-effects on appetite-related hormones are unknown. The objective was to determine the effects of intraduodenally administered whey-protein on glucose, gut hormone, and amino acid concentrations, and their relation to subsequent ad libitum energy intake at a buffet meal, in healthy older and younger men. Hydrolyzed whey-protein (30 kcal, 90 kcal, and 180 kcal) and a saline control (~0 kcal) were infused intraduodenally for 60 min in 10 younger (19-29 years, 73 ± 2 kg, 22 ± 1 kg/m²) and 10 older (68-81 years, 79 ± 2 kg, 26 ± 1 kg/m²) healthy men in a randomized, double-blind fashion. Plasma insulin, glucagon, gastric inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY), and amino acid concentrations, but not blood glucose, increased, while ghrelin decreased during the whey-protein infusions. Plasma GIP concentrations were greater in older than younger men. Energy intake correlated positively with plasma ghrelin and negatively with insulin, glucagon, GIP, GLP-1, PYY, and amino acids concentrations (p < 0.05). In conclusion, intraduodenal whey-protein infusions resulted in increased GIP and comparable ghrelin, insulin, glucagon, GIP, GLP-1, PYY, and amino acid responses in healthy older and younger men, which correlated to subsequent energy intake.

Effect of Age on Blood Glucose and Plasma Insulin, Glucagon, Ghrelin, CCK, GIP, and GLP-1 Responses to Whey Protein Ingestion.

Protein-rich supplements are used widely to prevent and manage undernutrition in older people. We have previously shown that healthy older, compared to younger, adults have less suppression of energy intake by whey protein-although the effects of age on appetite-related gut hormones are largely unknown. The aim of this study was to determine and compare the acute effects of whey protein loads on blood glucose and plasma gut hormone concentrations in older and younger adults. Sixteen healthy older (eight men, eight women; mean ± SEM: age: 72 ± 1 years; body mass index: 25 ± 1 kg/m²) and 16 younger (eight men, eight women; 24 ± 1 years; 23 ± 0.4 kg/m²) adults were studied on three occasions in which they ingested 30 g (120 kcal) or 70 g (280 kcal) whey protein, or a flavored-water control drink (~2 kcal). At regular intervals over 180 min, blood glucose and plasma insulin, glucagon, ghrelin, cholecystokinin (CCK), gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were measured. Plasma ghrelin was dose-dependently suppressed and insulin, glucagon, CCK, GIP, and GLP-1 concentrations were dose-dependently increased by the whey protein ingestion, while blood glucose concentrations were comparable during all study days. The stimulation of plasma CCK and GIP concentrations was greater in older than younger adults. In conclusion, orally ingested whey protein resulted in load-dependent gut hormone responses, which were greater for plasma CCK and GIP in older compared to younger adults.

The effects of phenylalanine on exercise-induced fat oxidation: a preliminary, double-blind, placebo-controlled, crossover trial.

BACKGROUND: When combined with exercise, dietary amino acid (AA) supplementation is an effective method for accelerating fat mobilization. However, the effects of single AAs combined with exercise on fat oxidation remains unclear. We hypothesized that consumption of a specific amino acid, L- phenylalanine, may result in the secretion of glucagon, and when combined with exercise may promote fat oxidation. METHODS: Six healthy, active male volunteers were randomized in a crossover study to ingest either phenylalanine (3 g/dose) or placebo. Thirty minutes after ingestion each subject performed workload trials on a cycle ergometer for 1 h at 50% of maximal oxygen consumption. RESULTS: Oral intake of phenylalanine caused a significant increase in the concentrations of plasma glycerol and glucagon during exercise. The respiratory exchange ratio was also decreased significantly following ingestion of phenylalanine. CONCLUSION: These results suggested that pre-exercise supplementation of phenylalanine may stimulate whole body fat oxidation. No serious or study-related adverse events were observed. TRIAL REGISTRATION: UMIN000027502 Registered 26 May 2017. Restrospectively registered.

Curcumin reverses the depressive-like behavior and insulin resistance induced by chronic mild stress.

Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity. Serum parameters were detected using commercial kits. Real-time quantitative PCR was used to examine mRNA expression. CMS rats exhibited reduced sucrose consumption, increased serum glucose, insulin, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), non-esterified fatty acid (NEFA), glucagon, leptin, and corticosterone levels, as well as impaired insulin sensitivity. Curcumin upregulated the phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (Akt) in the liver, enhanced insulin sensitivity, and reversed the metabolic abnormalities and depressive-like behaviors mentioned above. Moreover, curcumin increased the hepatic glycogen content by inhibiting glycogen synthase kinase (GSK)-3ß and prevented gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These results suggest that curcumin not only exerted antidepressant-like effects, but also reversed the insulin resistance and metabolic abnormalities induced by CMS. These data may provide evidence to support the potential use of curcumin against depression and/or metabolic disorders.

Associations between changes in glucagon-like peptide-1 and bodyweight reduction in patients receiving acarbose or metformin treatment.

BACKGROUND: The present post hoc analysis investigated whether changes in endogenous glucagon-like peptide-1 (∆GLP-1) levels are associated with weight loss in newly diagnosed diabetes patients. METHODS: In all, 784 subjects from the Metformin and AcaRbose in Chinese as initial Hypoglycemic treatment (MARCH) study were stratified according to ∆GLP-1. Changes in clinical and physiological parameters were evaluated across ∆GLP-1 subgroups (low, medium, and high) to assess correlations between ∆GLP-1 and weight loss in acarbose- versus metformin-treated groups. RESULTS: After 24 weeks treatment, greater ∆GLP-1 was associated with significantly greater weight loss (-2 vs -1 kg in the medium/high vs low ∆GLP-1 groups, respectively) and reduction in body mass index (BMI; -0.88, -0.83, and -0.69 kg/m2 in the high, medium, and low ∆GLP-1 groups, respectively). In the acarbose-treated group, there was a significant association between ∆GLP-1 and BMI reductions, and greater ∆GLP-1 across the high, medium, and low ∆GLP-1 groups was correlated with greater weight loss (-2.8, -2.1, and -1.9 kg, respectively) and reductions in fasting plasma glucose (-1.57, -1.28, and -1.02 mmol/L, respectively) at Week 24. No significant differences were found across ∆GLP-1 subgroups in metformin-treated patients (P > 0.05). Multivariate linear regression analysis revealed that gender, baseline BMI, and ∆GLP-1 at Week 24 were associated with weight loss. Baseline BMI and ∆GLP-1 in the acarbose-treated group and baseline BMI in the metformin-treated group predicted weight loss at Week 24. CONCLUSION: Changes in GLP-1 levels are associated with weight loss in newly diagnosed Chinese diabetes patients receiving acarbose.