Lower Blood Glucose Concentrations Research Articles

The glucagon-like peptide-1 and other endocrine responses to alcohol ingestion in women with versus without metabolic surgery.

Glucagon-like peptide-1 (GLP-1)-based therapies, effective in treating obesity and type 2 diabetes, hold potential for reducing alcohol-seeking behaviour. However, the understanding of how alcohol consumption affects endogenous GLP-1 responses-important for understanding GLP-1-based therapies' potential in addressing alcohol misuse-is limited, given the absence of placebo-controlled studies examining these effects. This study aimed to determine the acute effects of alcohol ingestion on GLP-1 and other peptides and evaluate whether metabolic surgery, which increases GLP-1 responses, blood alcohol concentrations (BAC) and alcohol misuse risk, influences this effect. Additionally, we assessed the acute effects of alcohol on plasma glucose and insulin concentrations. Using a placebo-controlled crossover study, we examined hormonal and glucose responses after oral alcohol consumption (0.5g/kg of fat-free mass) versus placebo drinks in 18 women who underwent metabolic surgery <5years ago and in 14 non-operated controls (equivalent in age, body mass index [BMI], race and alcohol consumption patterns). Women had a mean (SD) age of 41 (10) years and a BMI of 33 (5) kg/m2. Compared with the control group, the surgery group exhibited a higher peak BAC (0.99 [0.20] g/L vs. 0.75 [0.16] g/L; P < 0.005). Alcohol decreased GLP-1 by 34% (95% CI, 16%-52%) in both groups and decreased ghrelin more in the control (27%) than in the surgery group (13%). Alcohol modestly decreased plasma glucose and transiently increased insulin secretion in both groups (P < 0.05). However, alcohol lowered blood glucose concentrations to the hypoglycaemic range in 28% of the women in the surgery group versus none in the control group. These findings provide compelling evidence that acute alcohol consumption decreases GLP-1, a satiation signal, elucidating alcohol's 'apéritif' effect. This study also highlights the potential increase in alcohol-related hypoglycaemic effects after metabolic surgery.

Effects of Sargassum Glaucescens Algae on Blood Glucose Level in Diabetic Rats With a High-Fat Diet and Streptozotocin

Background: Diabetes medications can have dramatic effects on controlling the disease and achieving the therapeutic goals of people with diabetes, but most of them have side effects. Given the role of brown algae in maintaining blood glucose levels, their investigation can provide valuable information for the control and treatment of type 2 diabetes (T2D). Accordingly, this study investigated the effect of Sargassum glaucescens on blood glucose levels in diabetic rats. Materials and Methods: Forty-six randomly selected rats were assigned to five groups. The control group was fed the normal diet, and diabetic rats were induced by streptozotocin (STZ) and a high-fat diet (HFD). The other groups included the diabetes+low dose insulin group, diabetes+high dose insulin, and diabetic rats that received Sargassum Glaucescens 20% alga powder added to fatty food. Weekly blood glucose, hemoglobin A1c (HbA1c), the amount of drinking water, food consumed, urine volume, glucose tolerance test (GTT), and insulin tolerance test (ITT) underwent measurement. Results: The mean of ITT in the diabetic group was significantly higher than in the control group (P=0.001), which indicates insulin resistance in these groups. The lowest blood glucose concentration was in the high-dose insulin group; weekly blood glucose, GTT, ITT, and HbA1c in the alga group did not change compared to diabetes. However, some indicators, such as HbA1c, were better in the group receiving algae than in the low-dose insulin group. The weight of the group receiving algae increased until the third week, but it decreased after that, and at the end of the study, it was lower in this group than in the control group (P&lt;0.001). Conclusion: The study findings revealed that Sargassum Glaucescens algae had no significant effect on serum glucose, GTT, ITT, or HbA1c in the studied rats.

Ketone monoester attenuates declines in cognitive performance and oxygen saturation during acute severe hypoxic exposure under resting conditions.

Exogenous ketone supplements are a potential augmentation strategy for cognitive resilience during acute hypoxic exposure due to their capacity to attenuate the decline in oxygen (O2) availability, and by providing an alternative substrate for cerebral metabolism. Utilizing a single-blind randomized crossover design, 16 male military personnel (age, 25.3±2.4year, body mass, 86.2±9.3kg) performed tests of cognitive performance at rest in three environments: room air (baseline), normoxia (20min; 0m; 20.9% O2) and hypoxia (20min; 6096m, 9.7% O2) using a reduced O2 breathing device (ROBD). (R)-3-Hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-βHB) ketone monoester (KME; 650mg/kg, split dose given at 30min prior to each exposure) or taste-matched placebo (PLA) was ingested prior to normoxia and hypoxic exposure. Blood R-βHB and glucose concentrations, cognitive performance and O2 saturation ( ) were collected throughout. KME ingestion increased blood R-βHB concentration, which was rapid and sustained (>4mM 30min post; P<0.001) and accompanied by lower blood glucose concentration (∼20mg/dL; P<0.01) compared to PLA. Declines in cognitive performance during hypoxic exposure, assessed as cognitive efficiency during a Defense Automated Neurobehavioral Assessment (DANA) code substitution task, were attenuated with KME leading to 6.8 (95% CL: 1.0, 12.6) more correct responses per minute compared to PLA (P=0.018). The decline in during hypoxic exposure was attenuated (6.40% ; 95% CL: 0.04, 12.75; P=0.049) in KME compared to PLA (KME, 76.8±6.4% ; PLA, 70.4±7.4% ). Acute ingestion of KME attenuated the decline in cognitive performance during acute severe hypoxic exposure, which coincided with attenuation of declines in O2 saturation.

Effect of adding &lt;i&gt;fenugreek&lt;/i&gt; and &lt;i&gt;Nigella sativa&lt;/i&gt; to white rice on postprandial glycemic and appetite responses in healthy individuals

White rice is a high glycemic index food, and therefore different approaches are adopted to reduce its glycemic effect. The present study investigated the effect of adding fenugreek and Nigella sativa seed powder to white rice on glycemia, appetite, palatability, and gastrointestinal clinical manifestations in healthy subjects. In a randomized crossover design, 16 healthy subjects consumed white rice alone (control group), white rice with 2-g fenugreek seed powder, or white rice with 4-g nigella seed powder on different occasions. Each test meal provided 50 g of available carbohydrates. Blood glucose, subjective appetite, and gastrointestinal manifestations were measured at fasting and postprandially for 2 h. Palatability of the test meals was also measured using a 9-point hedonic scale. The nigella meal resulted in significantly lower blood glucose concentration (31.25 mg/dL) at 30 min (p = 0.022), compared to the control meal (43.88 mg/dL) whereas fenugreek meal showed no significant effect. Moreover, the nigella meal significantly increased satiety ratings at 30 and 90 min (p = 0.035 and 0.018, respectively). The results demonstrated that the addition of nigella powder to white rice reduced its glycemic response and increased satiety, compared to the control meal. All test meals were judged as acceptable by the subjects and their consumption didn’t cause any gastrointestinal discomfort. Results of the current study demonstrated promising implications for reducing glycemic response of white rice, a commonly consumed high-glycemic index food.

Trends in Presentation and Management of Endogenous Hyperinsulinaemic Hypoglycaemia Over the Last Three Decades at a Tertiary Care Centre (1992-2022).

Endogenous hyperinsulinaemic hypoglycaemia (EHH) is characterized by inappropriate insulin secretion from pancreatic beta cells despite low blood glucose concentrations. We aimed to evaluate the secular changes in presentation and management of EHH due to insulinoma/non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) at our centre. This was a single-centre ambispective study (2014-2022). The clinical, biochemical, hormonal and radiological parameters (n = 63) collected as part of this study were compared with our earlier studies (1992-2005, n = 31; and 2006-2013, n = 35) and with other centres across the world. A total of 63 patients (39 males) with a preoperative diagnosis of EHH (insulinoma, n = 58; and NIPHS, n = 5) and a mean age of 40.7 years were studied. The mean lag time from the onset of symptoms to diagnosis decreased from 4.6 years during the first study period to 1.9 years during this study period. However, the majority presented with fasting hypoglycaemia of 98.4%, and both fasting and postprandial hypoglycaemia of 32%. Exclusive postprandial hypoglycaemia was present in 1.7% of insulinoma. A histopathological diagnosis of insulinoma was made in 52 patients and nesidioblastosis in two patients. Intraoperative ultrasonography (IOUS) and intraoperative palpation (IOP) yielded 100% sensitivity, while endoscopic ultrasonography (EUS) and 68Ga-DOTA-Exendin-4 positron emission tomography/computed tomography (PET/CT) yielded sensitivity of 86% and 85%, respectively, for localizing insulinoma. Resolution of hypoglycaemia was noted in 53 of 57 (93%) patients who underwent surgery with a preoperative diagnosis of insulinoma. We observed a trend towards earlier diagnosis of EHH, increased patient numbers and availability of nuclear imaging techniques for preoperative localization in the last decade compared to earlier.

Effects of electrical stimulation of the lower extremities on postprandial hyperglycemia and arterial stiffness.

To compare the acute effects of electrical stimulation (ES) of the lower extremities on postprandial hyperglycemia and arterial stiffness during oral glucose tolerance testing (OGTT). In a randomized crossover study, eight healthy young men completed three experimental trials in which they underwent ES for 30 min, starting 60 min before (Before) or 30 min after (After) ingesting 75 g of glucose; ES was not performed in the control trial (Control). The subjects' blood glucose levels and brachial-ankle pulse wave velocity (baPWV) were measured as an index of arterial stiffness at baseline and 30, 60, and 120 min after glucose ingestion. Serum insulin levels were measured at baseline and 60 min after glucose ingestion. The subjects' glucose intake led to an increase in their blood glucose concentration in all trials, however, in the After trial, ES resulted in significantly lower blood glucose concentrations at 60 min post glucose ingestion compared to the Control and Before trials. The area under the curve (AUC) of serum insulin concentrations during the OGTT in the After trial was significantly lower than that in the other two trials. Moreover, glucose ingestion did not increase the baPWV, however, 30 min of ES during the postprandial state acutely reduced the baPWV. These results suggest that ES is most effective in reducing postprandial hyperglycemia when administered after a meal. Thus, lower extremity ES may be an alternative exercise method to activate postprandial glucose metabolism in healthy individuals.

Ketone Monoester Followed by Carbohydrate Ingestion after Glycogen-Lowering Exercise Does Not Improve Subsequent Endurance Cycle Time Trial Performance.

Relative to carbohydrate (CHO) alone, exogenous ketones followed by CHO supplementation during recovery from glycogen-lowering exercise have been shown to increase muscle glycogen resynthesis. However, whether this strategy improves subsequent exercise performance is unknown. The objective of this study was to assess the efficacy of ketone monoester (KME) followed by CHO ingestion after glycogen-lowering exercise on subsequent 20 km (TT20km) and 5 km (TT5km) best-effort time trials. Nine recreationally active men (175.6 ± 5.3 cm, 72.9 ± 7.7 kg, 28 ± 5 y, 12.2 ± 3.2% body fat, VO2max = 56.2 ± 5.8 mL· kg BM-1·min-1; mean ± SD) completed a glycogen-lowering exercise session, followed by 4 h of recovery and subsequent TT20km and TT5km. During the first 2 h of recovery, participants ingested either KME (25 g) followed by CHO at a rate of 1.2 g·kg-1·h-1 (KME + CHO) or an iso-energetic placebo (dextrose) followed by CHO (PLAC + CHO). Blood metabolites during recovery and performance during the subsequent two-time trials were measured. In comparison to PLAC + CHO, KME + CHO displayed greater (p < 0.05) blood beta-hydroxybutyrate concentration during the first 2 h, lower (p < 0.05) blood glucose concentrations at 30 and 60 min, as well as greater (p < 0.05) blood insulin concentration 2 h following ingestion. However, no treatment differences (p > 0.05) in power output nor time to complete either time trial were observed vs. PLAC + CHO. These data indicate that the metabolic changes induced by KME + CHO ingestion following glycogen-lowering exercise are insufficient to enhance subsequent endurance time trial performance.

Differential effects of fish-oil and cocoa-butter based high-fat/high-sucrose diets on endocrine pancreas morphology and function in mice.

A high-fat/high-sucrose diet leads to adverse metabolic changes that affect insulin sensitivity, function, and secretion. The source of fat in the diet might inhibit or increase this adverse effect. Fish oil and cocoa butter are a significant part of our diets. Yet comparisons of these commonly used fat sources with high sucrose on pancreas morphology and function are not made. This study investigated the comparative effects of a fish oil-based high-fat/high-sucrose diet (Fish-HFDS) versus a cocoa butter-based high-fat/high-sucrose diet (Cocoa-HFDS) on endocrine pancreas morphology and function in mice. C57BL/6 male mice (n=12) were randomly assigned to dietary intervention either Fish-HFDS (n=6) or Cocoa-HFDS (n=6) for 22 weeks. Intraperitoneal glucose and insulin tolerance tests (IP-GTT and IP-ITT) were performed after 20-21 weeks of dietary intervention. Plasma concentrations of c-peptide, insulin, glucagon, GLP-1, and leptin were measured by Milliplex kit. Pancreatic tissues were collected for immunohistochemistry to measure islet number and composition. Tissues were multi-labelled with antibodies against insulin and glucagon, also including expression on Pdx1-positive cells. Fish-HFDS-fed mice showed significantly reduced food intake and body weight gain compared to Cocoa-HFDS-fed mice. Fish-HFDS group had lower fasting blood glucose concentration and area under the curve (AUC) for both GTT and ITT. Plasma c-peptide, insulin, glucagon, and GLP-1 concentrations were increased in the Fish-HFDS group. Interestingly, mice fed the Fish-HFDS diet displayed higher plasma leptin concentration. Histochemical analysis revealed a significant increase in endocrine pancreas β-cells and islet numbers in mice fed Fish-HFDS compared to the Cocoa-HFDS group. Taken together, these findings suggest that in a high-fat/high-sucrose dietary setting, the source of the fat, especially fish oil, can ameliorate the effect of sucrose on glucose homeostasis and endocrine pancreas morphology and function.

A four-week dietary intervention with mycoprotein-containing food products reduces serum cholesterol concentrations in community-dwelling, overweight adults: A randomised controlled trial

BackgroundSubstituting dietary meat and fish for mycoprotein, a fungal-derived food source rich in protein and fibre, decreases circulating cholesterol concentrations in laboratory-controlled studies. However, whether these findings can be translated to a home-based setting, and to decrease cholesterol concentrations in overweight and hypercholesterolemic individuals, remains to be established. ObjectiveWe investigated whether a remotely-delivered, home-based dietary intervention of mycoprotein-containing food products would affect various circulating cholesterol moieties and other markers of cardio-metabolic health in overweight (BMI >27.5 kg·m-2) and hypercholesterolaemic (>5.0 mmol·L-1) adults. MethodsSeventy-two participants were randomized into a controlled, parallel-group trial conducted in a free-living setting, in which they received home deliveries of either meat/fish control products (CON; n=39; BMI 33±1 kg·m-2; 13 males, 26 females) or mycoprotein-containing food products (MYC; n=33; BMI 32±1 kg·m-2; 13 males, 20 females) for 4 weeks. Fingertip blood samples were collected and sent via postal service before and after the dietary intervention period and analysed for concentrations of serum lipids, blood glucose and c-peptide. ResultsSerum total cholesterol concentrations were unchanged throughout the intervention in CON, but decreased by 5±2% in MYC (from 5.4±0.2 to 5.1±0.2 mmol·L-1; P<0.05). Serum low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol concentrations were also unchanged in CON, but decreased in MYC by 10±3% and 6±2% (both by 0.3±0.1 mmol·L-1; P<0.05). Serum high-density lipoprotein cholesterol and free triglyceride concentrations were unaffected in CON or MYC. Post-intervention, MYC displayed lower mean blood glucose (3.7±0.2 versus 4.3±0.2 mmol·L-1) and c-peptide (779±76 vs. 1064±86 pmol·L-1) concentrations (P<0.05) vs. CON. ConclusionsWe show that a home-based dietary intervention of mycoprotein-containing food products effectively lowers circulating cholesterol concentrations in overweight, hypercholesterolemic adults. This demonstrates that mycoprotein consumption is a feasible and ecologically valid dietary strategy to improve markers of cardio-metabolic health in an at-risk population under free living conditions. Clinical trial registrationNCT04773483 (https://classic.clinicaltrials.gov/ct2/show/NCT04773483)

Effect of 100% Orange Juice and a Volume-Matched Sugar-Sweetened Drink on Subjective Appetite, Food Intake, and Glycemic Response in Adults.

Dietary recommendations to reduce the consumption of free sugars often group 100% fruit juice with other sugar-containing beverages. The objective of this study was to determine the effect of consuming 100% orange juice compared to an orange drink on next-meal food intake (FI), glycemic response, average appetite, emotions, and sensory characteristics in normal-weight adults. Thirty-six normal-weight adults (age: 26.8 ± 0.9 years) consumed, in random order and at least 5 days apart, three 240 mL test beverages as follows: (a) 100% orange juice, (b) orange drink, or (c) water. Subjective sweetness and pleasantness were determined immediately after test beverage consumption. Glycemic response, average appetite, and subjective emotions were measured every 15 min for 60 min. Food intake was determined at a pizza lunch 60 min later. Rest-of-day glycemic response and energy intake (EI) were determined using a continuous glucose monitor and food record, respectively. Lunch FI (p = 0.054) and total EI (p = 0.01) were both lower after 100% orange juice compared with the orange drink. Caloric compensation was 84% after 100% orange juice and -25% after the orange drink (p = 0.047). Average appetite was not significantly different between the test beverages (p > 0.05). Blood glucose iAUC adjusted for available carbohydrate was lower after 100% orange juice compared with the orange drink (p < 0.001). Rest-of-day blood glucose concentrations were lower after 100% orange juice compared with the orange drink (p = 0.03) and water control (p < 0.001). In conclusion, consumption of 100% orange juice as a preload resulted in higher caloric compensation, lower total daily EI, and lower blood glucose concentrations compared to the orange drink.

Effects of green coffee aqueous extract supplementation on glycemic indices, lipid profile, CRP, and malondialdehyde in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

Studies have reported the health benefits of green coffee extract (GCE) in experimental models. In the current study, we aimed to determine whether supplementation with GCE improves glycemic indices, inflammation, and oxidative stress in patients with type 2 diabetes (T2D). This randomized, double-blind, placebo-controlled trial included 44 patients (26 male and 18 female) with T2D and overweight/obesity. After blocked randomization, patients received either capsules containing 400 mg GCE twice per day (n = 22) or a placebo (n = 22) and were followed for 10 weeks. In this study, glycemic indices, lipid profiles, anthropometric examinations, blood pressure, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were measured twice; at baseline and at the end of the study. After 10 weeks of supplementation, GCE supplementation significantly reduced body weight (p = 0.04) and body mass index (BMI) (p = 0.03) compared to the placebo. The intention-to-treat (ITT) analysis indicated patients in the GCE group had a lower fasting blood glucose (FBG) concentration compared to the placebo group; however, this decreasing was marginally significant (8.48 ± 8.41 vs. 1.70 ± 5.82 mg/dL, p = 0.05). There was no significant difference in insulin levels and HOMA-IR between the groups. At the end of the study, significant changes in systolic blood pressure (SBP) (p = 0.01), triglyceride (TG) level (p = 0.02), high-density lipoprotein (HDL) (p = 0.001), and TG-to-HDL ratio (p = 0.001) were found between the intervention and placebo groups. Our trial indicated GCE supplementation had no effect on diastolic blood pressure (DBP), low-density lipoprotein (LDL), or total cholesterol. During the supplementation period, the hs-CRP level significantly decreased in the GCE group compared to the placebo group (p = 0.02). No significant changes were observed in the MDA level between the two groups at the end of the study (p = 0.54). Our findings showed beneficial effects of GCE on SBP, TG, hs-CRP, and HDL levels in patients with T2D and overweight/obesity over a 10-week period of supplementation.Clinical trial registration:https://en.irct.ir/trial/48549, identifier [IRCT20090203001640N18].

Effect of oligosaccharides and aerobic training on hyperglycemia, growth and intestinal microbial diversity of diabetic rats

Abstract Objectives Type 1 diabetes mellitus is a metabolic disease characterized by dysbiosis. Modulation of the gut microbiota by oligosaccharides and aerobic training are proposed mechanisms that ameliorate the disease through affecting host-microbiota interactions. Methods Seventy-two male Wistar rats were randomly divided into 8 groups – 5 with streptozotocin-induced diabetes and 3 healthy controls. The effect of two oligosaccharides – xylo- and galactooligosaccharides, and of aerobic training on the blood glucose concentration, growth and diversity of the gut microbiota was evaluated in the current study. Results The galactooligosaccharides positively affected the glycemic status of the experimental animals as the diabetic and healthy rats had lower blood glucose concentration after 6 weeks of treatment (diabetic rats: week 4 vs. week 8, p=0.047; healthy rats: week 2,4,6,10 vs. week 8, p=0.001, p=0.000, p=0.025 and p=0.001, respectively). A positive effect of the galactooligosaccharides on body weight was observed when administered to diabetic rats in comparison to the diabetic control (p=0.020). Similar results were observed for the aerobically trained diabetic rats (p=0.004). The identification of bacterial species showed preserved microbiota diversity and indicated Bifidobacterium indicum, Lactobacillus feritoshensis and E. coli as the most abundant species among the analyzed genera. Conclusions Prebiotic treatment beneficially affected the hyperglycemia and growth of type 1 diabetic rats. The most significant effect of the aerobic training was the improvement of the morphological parameters. Oligosaccharide administration and exercise did not affect the diversity of the bacterial species.

Comparison of Ultra-Short Race Pace and High-Intensity Interval Training in Age Group Competitive Swimmers.

The aim of this study was tο examine the acute responses to an Ultra-Short Race Pace Training (USRPT) and a High-Intensity Interval Training (HIIT), both oriented for the event of 100 m freestyle. Eighteen national-level swimmers (8 boys, 10 girls) aged 13.5 ± 0.1 years, with 8.0 ± 0.5 years of experience participated in the study. All participants completed a USRPT and a HIIT protocol consisting of 2 × 10 × 25 m (USRPT1 & USRPT2) and 5 × 50 m. Significantly higher swimming velocity (SV) were achieved in USRPT compared to HIIT (p < 0.001), while significantly lower distance per stroke (DPS) and stroke index (SI) were obtained (p = 0.007 and p < 0.001). Also, significantly lower blood lactate and glucose (BL & BG) concentrations were found after USRPT (p ≤ 0.001 and p = 0.037). Heart rate (HR) and rate of perceived exertion (RPE) were significantly lower after USRPT than HIIT (p < 0.001 and p = 0.015). According to the results, an USRPT swimming set consisting of 20 × 25 m at a 100 m pace seems to induce more specific responses in kinematic characteristics, biomarkers, HR and RPE compared to a 5 × 50 m HIIT set.

Hypoglycaemia Among Diabetes Patients: A Preventive Approach

Hypoglycaemia is a low blood glucose concentration and an indicator of diabetes mellitus, and are associated with physical and psychological morbidity. It is a common, potentially avoidable consequence of diabetes treatment, and a major barrier to better metabolic control in diabetes. It is due to overtreatment of diabetes patients with insulin or sulfonylureas or glinides or also consumption of too little food or unplanned excessive exercise or physical activity. It is the acute complication of diabetes and is associated with considerable morbidity and mortality. It is important of the early recognition, treatment, and prevention of hypoglycaemia. Immediate treatment of severe hypoglycaemia is needed to avoid life threatening complications of the diabetic patients. In this study an attempt has been taken to discuss the aspects of hypoglycaemia of diabetes mellitus patients.

Whey Protein Premeal Lowers Postprandial Glucose Concentrations in Adults Compared with Water—The Effect of Timing, Dose, and Metabolic Status: a Systematic Review and Meta-analysis

BackgroundServing whey protein before a meal in order to lower postprandial blood glucose concentrations is known as a premeal. The underlying mechanisms are only partly understood but may involve stimulation of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and insulin secretion together with a slower gastric emptying rate. ObjectivesThe objective of this systematic review and meta-analysis was to review all randomized clinical trials investigating premeals with whey protein in comparison with a nonactive comparator (control) that evaluated plasma glucose, GLP-1, GIP, insulin, and/or gastric emptying rate. Secondary aims included subgroup analyses on the timing and dose of the premeal together with the metabolic state of the participants [lean, obese, and type 2 diabetes mellitus (T2DM)]. MethodsWe searched EMBASE, CENTRAL, PUBMED, and clinicaltrials.gov and found 16 randomized crossover trials with a total of 244 individuals. The last search was performed on 9 August, 2022. ResultsWhey protein premeals lowered peak glucose concentration by −1.4 mmol/L [−1.9 mmol/L; −0.9 mmol/L], and the area under the curve for glucose was −0.9 standard deviation (SD) [−1.2 SD; −0.6 SD] compared with controls (high certainty). In association with these findings, whey protein premeals elevated GLP-1 (low certainty) and peak insulin (high certainty) concentrations and slowed gastric emptying rate (high certainty) compared with controls. Subgroup analyses showed a more pronounced and prolonged glucose-lowering effect in individuals with T2DM compared with participants without T2DM. The available evidence did not elucidate the role of GIP. The protein dose used varied between 4 and 55 g, and meta-regression analysis showed that the protein dose correlated with the glucose-lowering effects. ConclusionsIn conclusion, whey protein premeals lower postprandial blood glucose, reduce gastric emptying rate, and increase peak insulin. In addition, whey protein premeals may elevate plasma concentrations of GLP-1. Whey protein premeals may possess clinical potential, but the long-term effects await future clinical trials.

1575-P: Glycerol Metabolism and Gluconeogenesis in Mice Lacking the Mitochondrial Pyruvate Carrier in Hepatocytes

Hepatic glucose production from glycogen breakdown and gluconeogenic substrates is an important physiologic adaptation, but uncontrolled glucose release by the liver contributes to hyperglycemia in diabetes. The liver can produce glucose from several substrates, including amino acids, lactate/pyruvate, and glycerol. Mitochondrial import of pyruvate by the mitochondrial pyruvate carrier (MPC) plays an important role in gluconeogenesis from lactate/pyruvate, but its role in gluconeogenesis from other substrates is less clear. For example, glycerol can be converted to glucose by two pathways; [1] a direct pathway involving the reversal of several steps in glycolysis and [2] a mitochondrial pathway requiring the import of pyruvate via the MPC. While prior work has shown that compared to wild-type (WT) mice, hepatocyte MPC-/- mice exhibit lower blood glucose concentrations after fasting 24 h, concentrations after fasting 18 h were not different between genotypes in the present study. To determine whether gluconeogenesis from glycerol was affected by MPC deficiency, we administered 13C-glycerol to overnight fasted WT and MPC knockout mice and found that loss of the MPC increased the incorporation of 13C into new glucose. Further analysis determined that MPC deletion reduced the incorporation of 13C into glucose derived from the mitochondrial pathway and hepatic TCA cycle metabolites, but actually increased glycerol-mediated gluconeogenesis via the direct pathway. Suppression of glycerol kinase or overexpression of glycerol-3-phosphate phosphatase markedly reduced glycerol-mediated glucose production from both the direct and mitochondrial pathways, but did not reduce glucose concentrations in fasted MPC knockout mice. These findings indicate that glycerol-mediated gluconeogenesis is not impaired in MPC-deficient hepatocytes and suggest that gluconeogenesis from other organs, likely kidney or intestine, compensates for loss of the hepatic MPC. Disclosure N.Yiew: None. G.J.Patti: None. S.C.Burgess: None. B.N.Finck: Advisory Panel; Cirius Therapeutics, Inc., Stock/Shareholder; Cirius Therapeutics, Inc. D.Ferguson: None. K.Cho: None. S.Deja: None. C.Jarasvaraparn: None. X.Fu: None. A.J.Lutkewitte: None. S.Mukherjee: None. J.M.Singer: None. Funding National Institutes of Health (R01DK104735, R01DK117657, T32DK007120, R35ES028365)

Liraglutide in Combination with Insulin Has a Superior Therapeutic Effect to Either Alone on Fracture Healing in Diabetic Rats.

Fractures in patients with type 2 diabetes mellitus are at a high risk of delayed union or non-union. Previous studies have shown a protective effect of liraglutide on bone. In the present study, we aimed to investigate the effects of a combination of liraglutide and insulin on fracture healing in a rat model of diabetes and the mechanisms involved. Closed femoral mid-shaft fractures were established in male Sprague-Dawley rats with or without diabetes mellitus, and the diabetic rats were administered insulin and/or liraglutide. Six weeks after femoral fracture, the femoral callus was evaluated by immunohistochemistry, histology, and micro-computed tomography. Additionally, the effects of liraglutide on high-glucose-stimulated MC3T3-E1 cells were analyzed by Western blotting. Micro-computed tomography and safranin O/fast green staining showed that fracture healing was delayed in the diabetic rats, and this was accompanied by much lower expression of osteogenic markers and greater osteoclast activity. However, treatment with insulin and/or liraglutide prevented these changes. Liraglutide in combination with insulin treatment resulted in lower blood glucose concentrations and significantly higher osteocalcin (OCN) and collagen I (Col I) expression six weeks following fracture. Western blot analysis showed that liraglutide prevented the low expression of the bone morphogenetic protein-2, osterix/SP7, OCN, Col I, and β-catenin in high-glucose-stimulated MC3T3-E1 cells. These results demonstrate that insulin and/or liraglutide promotes bone fracture healing in the DF model. The combination was more effective than either single treatment, which may be because of the two drugs' additive effects on the osteogenic ability of osteoblast precursors.

Detemir improves diabetic regulation in poorly controlled diabetic dogs with concurrent diseases.

This study evaluated the use of detemir for treating diabetic dogs with comorbidities that were poorly controlled with intermediate-acting insulins. 7 insulin-treated diabetic dogs. Retrospective pilot study. Dogs were treated with detemir for at least 3 months, and glycemia was assessed by the owners at home initially 2 to 4 times daily for 6 to 8 weeks and twice daily thereafter. Clinical evaluations occurred on days 7 to 14, day 30, and then every 60 to 90 days, and dosage adjustments of detemir occurred as needed to control glycemia. The mean, peak, nadir, morning, and evening preinsulin daily blood glucose concentrations were significantly lower after dosing with detemir for 1, 3, or 6 months and during the last month of treatment compared to the final month of treatment with intermediate-acting insulin. Intermediate-acting insulins resulted in significantly worse glycemic control than detemir in all 3 categories of control. The odds of a biochemical hypoglycemic measurement with detemir were not significantly different compared to intermediate-acting insulins. Clinical hypoglycemia did not occur following detemir treatment. When insulin was withheld because of low morning preinsulin blood glucose concentration < 6.7 mmol/L (≤ 120 mg/dL) and dogs were fed, mean blood glucose concentration was significantly higher 1 hour later. Glucose concentrations were also significantly higher 12 hours later on days when insulin was withheld in the morning or evening for either 1 or 12 hours. Detemir is useful in diabetic dogs with other comorbidities and can be considered an alternative treatment in poorly controlled diabetic dogs.

Fluoroquinolone-induced Glycaemic Aberrations: Could Quinolones be Repurposed to Serve as New Antidiabetic Agents?

Nalidixic acid is a synthetic antibiotic discovered in the 1960s during the synthesis of chloroquine, an effective drug for treating malaria. Nalidixic acid became the backbone for developing quinolones that are now widely used clinically for the treatment of various bacterial infections. The mechanism of action of quinolone involves the inhibition of topoisomerase II and topoisomerase IV. In attempts to improve the potency of fluoroquinolones, modifications were made; these modifications resulted in the emergence of newer generations of fluoroquinolones. Also, due to these modifications, several side effects were noted, including blood glucose control aberrations. Among fluoroquinolones that disrupt glucose homeostasis is gatifloxacin, which is in the third-generation category. Fluoroquinolones have been demonstrated to induce glycaemic aberrations by enhancing pancreatic cells' insulin secretion and interaction with antidiabetic agents via inhibition of cytochrome P450 enzymes. Considering their ability to induce hypoglycaemia, few studies have reported repurposing of quinolones as antidiabetic agents. Hyperglycaemia has also been reported to often precede hypoglycaemia. Due to the ability to decrease blood glucose, it is not surprising that some authors have reported novel quinolone derivates with antidiabetic properties in experimental studies. However, there is still a paucity of data regarding the effect of quinolones derivatives on glycaemic control. Understanding how fluoroquinolones lower blood glucose concentration could serve as the basis for developing novel quinolone derivatives with the sole purpose of lowering blood glucose concentrations. Although there are various conventional anti-hyperglycaemic agents, due to their associated shortfalls as well as an increase in the prevalence of diabetes, the discovery and development of new antidiabetics are warranted.

Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis

ObjectiveObesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function. MethodsWe first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR−/−) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR−/−) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR−/− mice. ResultseWAT from HFD-fed whole-body FXR−/− and Ad-FXR−/− mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR−/− mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR−/− mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter. ConclusionsThese results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.