Acute Glucose-lowering Effect Research Articles

Black bean (Phaseolus vulgaris L.) protein hydrolysates reduce acute postprandial glucose levels in adults with prediabetes and normal glucose tolerance

This study evaluated the acute effect of black bean protein hydrolysate (BPH) on postprandial glucose and insulin levels in adults with normal glucose tolerance (NGT) or prediabetes. First, an in silico predictive digestion was performed on twenty peptides identified in BPH. Then, 28 adults with NGT or prediabetes were randomized to a parallel double-blind, placebo-controlled trial. Following consent, participants were randomly assigned to one of two groups, placebo, or 5 g of BPH. To evaluate the acute effects of BPH, an oral glucose tolerance test was administered, and blood samples were collected at 60, 120, and 150 min. In the 5 g BPH group, the area under the curve for glucose, and glucose levels at 120 min were statistically lower compared to the placebo group (p = 0.04, p = 0.02). In this study, BPH had an acute glucose lowering effect after an oral glucose tolerance test in subjects with NGT or prediabetes.

Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice

The mitochondrial pyruvate carrier (MPC) is an inner mitochondrial membrane complex that plays a critical role in intermediary metabolism. Inhibition of the MPC, especially in liver, may have efficacy for treating type 2 diabetes mellitus. Herein, we examined the antidiabetic effects of zaprinast and 7ACC2, small molecules which have been reported to act as MPC inhibitors. Both compounds activated a bioluminescence resonance energy transfer–based MPC reporter assay (reporter sensitive to pyruvate) and potently inhibited pyruvate-mediated respiration in isolated mitochondria. Furthermore, zaprinast and 7ACC2 acutely improved glucose tolerance in diet-induced obese mice in vivo. Although some findings were suggestive of improved insulin sensitivity, hyperinsulinemic–euglycemic clamp studies did not detect enhanced insulin action in response to 7ACC2 treatment. Rather, our data suggest acute glucose-lowering effects of MPC inhibition may be due to suppressed hepatic gluconeogenesis. Finally, we used reporter sensitive to pyruvate to screen a chemical library of drugs and identified 35 potentially novel MPC modulators. Using available evidence, we generated a pharmacophore model to prioritize which hits to pursue. Our analysis revealed carsalam and six quinolone antibiotics, as well as 7ACC1, share a common pharmacophore with 7ACC2. We validated that these compounds are novel inhibitors of the MPC and suppress hepatocyte glucose production and demonstrated that one quinolone (nalidixic acid) improved glucose tolerance in obese mice. In conclusion, these data demonstrate the feasibility of therapeutic targeting of the MPC for treating diabetes and provide scaffolds that can be used to develop potent and novel classes of MPC inhibitors.

Exendin 4-Hapten Conjugate Capable of Binding with Endogenous Antibodies for Peptide Half-life Extension and Exerting Long-Acting Hypoglycemic Activity.

Hapten-specific endogenous antibodies are naturally occurring antibodies present in human blood. Herein, we investigated a new strategy in which small-molecule haptens were utilized as naturally occurring antibody binders for peptide half-life extension. The glucagon-like peptide 1 receptor agonist exendin 4 was site-specifically functionalized with the dinitrophenyl (DNP) hapten at the C-terminus via sortase A-mediated ligation. The resulting Ex4-DNP conjugates retained GLP-1 receptor activation potency in vitro and had a similar in vivo acute glucose-lowering effect comparable to that of native Ex4. Pharmacokinetic studies and hypoglycemic duration tests demonstrated that the Ex4-DNP conjugates displayed significantly elongated half-lives and improved long-acting antidiabetic activity in the presence of endogenous anti-DNP antibodies. In chronic treatment studies, once-daily administration of optimal conjugate 7 demonstrated more beneficial effects without prominent toxicity compared with Ex4. This strategy provides a new approach and represents an alternative to the well-established peptide-Fc fusion strategy to improve the peptide half-life and the therapeutic efficacy.

Boarfish (Capros aper) protein hydrolysate has potent insulinotropic and GLP‐1 secretory activity in vitro and acute glucose lowering effects in mice

SummaryThe anti‐diabetic actions of a boarfish protein hydrolysate (BPH) were investigated in cultured cells and mice. A boarfish (Capros aper) muscle protein hydrolysate was generated using the enzymes Alcalase 2.4 L and Flavourzyme 500 L. Furthermore, the BPH was subjected to simulated gastrointestinal digestion (SGID). BPH and SGID samples (0.01–2.5 mg mL−1) were tested in vitro for DPP‐IV inhibition and insulin and GLP‐1 secretory activity from BRIN‐BD11 and GLUTag cells, respectively. The BPH and SGID samples, caused a dose‐dependent increase (4.2 to 5.3‐fold, P < 0.001) in insulin secretion from BRIN‐BD11 cells and inhibited DPP‐IV activity (IC50 1.18 ± 0.04 and 1.21 ± 0.04 mg mL−1), respectively. The SGID sample produced a 1.3‐fold (P < 0.01) increase in GLP‐1 secretion. An oral glucose tolerance test (OGTT) was conducted in healthy mice (n = 8), with or without BPH (50 mg/kg bodyweight). BPH mediated an increase in plasma insulin levels (AUC(0–120 min), P < 0.05) and a consequent reduction in blood glucose concentration (P < 0.01), after OGTT in mice versus controls. The BPH showed potent anti‐diabetic actions in cells and improved glucose tolerance in mice.

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1.

The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests. In vitro, in GPR120 overexpressing cells, both agonists signaled through Gαq, Gαs and the β-arrestin pathway. However, in mouse islets the signaling pathway was different since the agonists reduced cAMP production. The GPR120 agonists stimulated GLP-1 secretion both in vitro in STC-1 cells and in vivo following oral administration. In vivo GPR120 activation induced significant glucose lowering and increased insulin secretion after intravenous glucose administration in lean mice, while the agonists had no effect in GPR120 null mice. Exendin 9–39, a GLP-1 receptor antagonist, abolished the GPR120 induced effects on glucose and insulin following an intravenous glucose challenge. In conclusion, GLP-1 secretion is an important mechanism behind the acute glucose lowering effect following specific GPR120 activation.

The Diabeates Project: Perceptual, Affective and Psychophysiological Effects of Music and Music-Video in a Clinical Exercise Setting.

The purpose of this study was to examine the effects of music and music-video on perceptual (attentional focus, rated perceived exertion), affective (affective valence and enjoyment) and psychophysiological (blood glucose, heart rate) variables in outpatients attending a diabetes exercise clinic. Participants were 24 females (age = 66.0 ± 8.5 years) enrolled in a supervised exercise program for people with diabetes. They engaged in mixed-modality exercise sessions that included a standardized combination of flexibility, aerobic and resistance activities under conditions of music, music-video and control. Analyses revealed a main effect of condition on attentional focus and affect during aerobic exercise only. The music-video condition elicited the highest level of attentional dissociation, while affective valence was more positive in the 2 experimental conditions when compared to control. Rated perceived exertion and heart rate did not differ across conditions. Measures of exercise enjoyment indicated a main effect of condition wherein scores were higher with the music-video condition when compared to control. There was an acute glucose-lowering effect of exercise in all conditions. Results lend support to the notion that auditory and visual stimuli can enhance affective responses to exercise in a clinical setting. This may have meaningful implications for adherence, given the link between affective judgements and future behaviour in an exercise context.

OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition

TGR5 agonists stimulate intestinal glucagon-like peptide-1 (GLP-1) release, but systemic exposure causes unwanted side effects, such as gallbladder filling. In the present study, linagliptin, a DPP-4 inhibitor with a large molecular weight and polarity, and MN6, a previously described TGR5 agonist, were linked to produce OL3, a novel low-absorbed TGR5 agonist with reduced side-effects and dual function in lowering blood glucose by activation of TGR5 and inhibition of DPP-4. TGR5 activation was assayed in HEK293 cells stably expressing human or mouse TGR5 and a CRE-driven luciferase gene. DPP-4 inhibition was assessed based on the rate of hydrolysis of a surrogate substrate. GLP-1 secretion was measured in human enteroendocrine NCI-H716 cells. OL3 permeability was tested in Caco-2 cells. Acute glucose-lowering effects of OL3 were evaluated in ICR and diabetic ob/ob mice. OL3 activated human and mouse TGR5 with an EC50 of 86.24 and 17.36 nmol/L, respectively, and stimulated GLP-1 secretion in human enteroendocrine NCI-H716 cells (3-30 μmol/L). OL3 inhibited human and mouse DPP-4 with IC50 values of 18.44 and 69.98 μmol/L, respectively. Low permeability of OL3 was observed in Caco-2 cells. In ICR mice treated orally with OL3 (150 mg/kg), the serum OL3 concentration was 101.10 ng/mL at 1 h, and decreased to 13.38 ng/mL at 5.5 h post dose, confirming the low absorption of OL3 in vivo. In ICR mice and ob/ob mice, oral administration of OL3 significantly lowered the blood glucose levels, which was a synergic effect of activating TGR5 that stimulated GLP-1 secretion in the intestine and inhibiting DPP-4 that cleaved GLP-1 in the plasma. In ICR mice, oral administration of OL3 did not cause gallbladder filling. OL3 is a low-absorbed TGR5 agonist that lowers blood glucose without inducing gallbladder filling. This study presents a new strategy in the development of potent TGR5 agonists in treating type 2 diabetes, which target to the intestine to avoid systemic side effects.

Valproate modulates glucose metabolism in patients with epilepsy after first exposure.

Valproate (VPA) treatment has been reported to be associated with weight gain and metabolic changes, such as hyperinsulinemia. The question of whether hyperinsulinemia and other metabolic changes are consequences of increased weight, or are instead direct results of VPA treatment, remains a matter of debate. The aim of the current study was to explore the influence of VPA treatment on glucose and insulin levels during the oral glucose tolerance test (OGTT) directly following the first intravenous (IV) administration. Sixteen patients (18-46 years old) with newly diagnosed epilepsy underwent an OGTT with 75 g glucose prior to the start of VPA treatment, as well as directly following the first IV VPA administration. We observed that plasma glucose levels during the 120 min of OGTT session following infusion of VPA were significantly lower than those measured during OGTT without VPA treatment (mean ± standard deviation [SD] 4.28 ± 0.94 mmol/l vs. 4.75 ± 1.09 mmol/l respectively, p = 0.038). However, blood concentrations of insulin and C-peptide did not differ significantly between the two measurements. This is the first study to show a potential acute glucose-lowering effect of VPA during OGTT in patients with newly diagnosed epilepsy.

An acute method to test leptin responsiveness in rats

Continuous subcutaneous administration of leptin normalizes blood glucose levels in rodent models of Type 1 and Type 2 diabetes independent of changes in food intake, body weight, and plasma insulin. We tested whether an acute intravenous leptin infusion changed blood glucose in normal and diet-induced leptin-resistant rats to determine whether this measure could be used as a marker of leptin sensitivity. Leptin-responsive chow-fed rats and diet-induced leptin-resistant male Sprague-Dawley rats were fitted with thoracic jugular vein catheters. Four days after surgery, conscious rats were infused intravenously with either saline for 32 min, low-dose (LD) leptin (1.9 μg·kg(-1)·min(-1)) followed by high-dose (HD) leptin (3.8 μg·kg(-1)·min(-1)) for 16 min each, or only HD leptin for 16 min. There was no change in blood glucose after an acute intravenous infusion of either LD leptin or HD leptin alone for 16 min. An intravenous infusion of LD followed by HD leptin for 16 min each significantly decreased serum glucose in leptin-responsive rats but not in leptin-resistant rats. Leptin infusions increased serum leptin in all rat groups but had no effect on plasma glucagon or 12-h weight gain and energy intake in any group of rats. These results show that leptin has an acute glucose-lowering effect that reflects the leptin responsiveness of the rat. This effect is consistent across controls and different leptin-resistant rat models, and the acute nonlethal test provides a novel method of testing leptin responsiveness in rats.

Mechanism of Metabolic Advantages After Bariatric Surgery

The acute glucose-lowering effect of certain bariatric procedures—before any significant weight loss has occurred—has been known for decades (1). In a comprehensive meta-analysis by Buchwald et al. (2), type 2 diabetes remission rates after the most common bariatric procedure, Roux-en-Y gastric bypass (RYGB), were reported to be 80%. Applying the 2009 consensus criteria for the definition of diabetes remission has been reported to show complete remission of diabetes in “only” 41% of 160 RYGB-treated obese patients with type 2 diabetes (3). Importantly, bariatric surgery seems to improve several components of the metabolic syndrome, and type 2 diabetes–specific mortality rates have been demonstrated to be up to 90% lower in RYGB-treated subjects compared with nontreated control subjects (2,4). In comparison with medical therapy alone, recent clinical trials have shown that RYGB or biliopancreatic diversion resulted in better glucose control (5), RYGB achieved glycemic control in significantly more patients (6), and sleeve gastrectomy resolved the diabetic state more effectively (7). Thus, it is well established that bariatric procedures improve glycemic control or even resolve the type 2 diabetic state. However, the mechanisms by which these operations bring about their glucose-lowering effects remain much debated. Obviously, the body weight–lowering effect of these operations contributes to the long-term improvements in glucose metabolism (primarily via increased hepatic and peripheral insulin sensitivity [8]), but it is striking that amelioration of hyperglycemia after bariatric surgery occurs within days of the surgery, pointing to immediate, weight loss–independent mechanisms possibly related to surgery-induced changes in food intake (caloric restriction), gastrointestinal (GI) anatomy, or transit of nutrients. The predominant hypotheses on the physiological background for the metabolic advantages (specifically, the glucose-lowering effects) after bariatric surgery include changed release of GI hormones (increased secretion of hormones with antidiabetes properties and reduced secretion of “diabetogenic” hormones) and surgery-induced …

The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes.

To examine the acute glucose-lowering effects of aerobic exercise in children and adolescents with type 1 diabetes. Fifty children and adolescents with type 1 diabetes (ages 10 to <18 years) were studied during exercise. The 75-min exercise session consisted of four 15-min periods of walking on a treadmill to a target heart rate of 140 bpm and three 5-min rest periods. Blood glucose and plasma glucagon, cortisol, growth hormone, and norepinephrine concentrations were measured before, during, and after exercise. In most subjects (83%), plasma glucose concentration dropped at least 25% from baseline, and 15 (30%) subjects became hypoglycemic (< or = 60 mg/dl) or were treated for low glucose either during or immediately following the exercise session. The incidence of hypoglycemia and/or treatment for low glucose varied significantly by baseline glucose, occurring in 86 vs. 13 vs. 6% of subjects with baseline values <120, 120-180, and >180 mg/dl, respectively (P < 0.001). Exercise-induced increases in growth hormone and norepinephrine concentrations were marginally higher in subjects whose glucose dropped < or = 70 mg/dl. Treatment of hypoglycemia with 15 g of oral glucose resulted in only about a 20-mg/dl rise in glucose concentrations. In youth with type 1 diabetes, prolonged moderate aerobic exercise results in a consistent reduction in plasma glucose and the frequent occurrence of hypoglycemia when preexercise glucose concentrations are <120 mg/dl. Moreover, treatment with 15 g of oral glucose is often insufficient to reliably treat hypoglycemia during exercise in these youngsters.

The Effects of Aerobic Exercise on Glucose and Counterregulatory Hormone Concentrations in Children With Type 1 Diabetes

OBJECTIVE—To examine the acute glucose-lowering effects of aerobic exercise in children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS—Fifty children and adolescents with type 1 diabetes (ages 10 to &amp;lt;18 years) were studied during exercise. The 75-min exercise session consisted of four 15-min periods of walking on a treadmill to a target heart rate of 140 bpm and three 5-min rest periods. Blood glucose and plasma glucagon, cortisol, growth hormone, and norepinephrine concentrations were measured before, during, and after exercise. RESULTS—In most subjects (83%), plasma glucose concentration dropped at least 25% from baseline, and 15 (30%) subjects became hypoglycemic (≤60 mg/dl) or were treated for low glucose either during or immediately following the exercise session. The incidence of hypoglycemia and/or treatment for low glucose varied significantly by baseline glucose, occurring in 86 vs. 13 vs. 6% of subjects with baseline values &amp;lt;120, 120–180, and &amp;gt;180 mg/dl, respectively (P &amp;lt; 0.001). Exercise-induced increases in growth hormone and norepinephrine concentrations were marginally higher in subjects whose glucose dropped ≤70 mg/dl. Treatment of hypoglycemia with 15 g of oral glucose resulted in only about a 20-mg/dl rise in glucose concentrations. CONCLUSIONS—In youth with type 1 diabetes, prolonged moderate aerobic exercise results in a consistent reduction in plasma glucose and the frequent occurrence of hypoglycemia when preexercise glucose concentrations are &amp;lt;120 mg/dl. Moreover, treatment with 15 g of oral glucose is often insufficient to reliably treat hypoglycemia during exercise in these youngsters.

Comparison of the acute and long-term effects of exercise on glucose control in type I diabetes.

To determine the long-term effect of exercise training on glucose control, 13 subjects with type I diabetes and 7 control subjects performed 45 min of cycle exercise three times per wk for 12 wk. The acute blood glucose response, the long-term effect on glucose control (glycosylated hemoglobin and fasting plasma glucose), and changes in nutrient intake were assessed. Fitness as measured by VO2 MAX increased in both control (33.8 +/- 1.7 to 43.2 +/- 3.5 ml/min/kg) and diabetic (38.7 +/- 3.3 to 46.5 +/- 3.6 ml/min/kg) (P less than 0.05) subjects although body weight remained unchanged. In the diabetic subjects, an acute glucose-lowering effect occurred with each exercise session throughout the 12-wk training period (225.8 +/- 16.1 to 148.5 +/- 16.8 mg/dl, P less than 0.001). However, fasting plasma glucose and glycosylated hemoglobin remained essentially unchanged (pretraining, 193.7 +/- 27.5 mg/dl and 10.7 +/- 0.3%; 6-wk training, 192.5 +/- 27.1 mg/dl and 10.7 +/- 0.03%; 12-wk training, 202 +/- 30.1 mg/dl and 10.3 +/- 0.8%). Total caloric intake as assessed by diet history increased significantly on exercising days (2569-2849 kcal, P less than 0.05). Although plasma glucose decreases acutely with exercise, increased caloric intake on exercising days obviates a long-term effect of training on glucose control. More precise guidelines and recommendations as to exercise timing and nutrient intake, likely based on self-monitoring of blood glucose, are required to achieve a beneficial effect of exercise training on metabolic control in type I diabetes.