Increased Muscle Glucose Uptake Research Articles

Oral Glutamine Supplementation Reduces Obesity, Pro-Inflammatory Markers, and Improves Insulin Sensitivity in DIO Wistar Rats and Reduces Waist Circumference in Overweight and Obese Humans.

In the present study, we aimed to investigate whether chronic oral glutamine (Gln) supplementation may alter metabolic parameters and the inflammatory profile in overweight and obese humans as well as whether Gln may modulate molecular pathways in key tissues linked to the insulin action in rats. Thirty-nine overweight/obese volunteers received 30 g of Gln or alanine (Ala-control) for 14 days. Body weight (BW), waist circumference (WC), hormones, and pro-inflammatory markers were evaluated. To investigate molecular mechanisms, Gln or Ala was given to Wistar rats on a high-fat diet (HFD), and metabolic parameters, euglycemic hyperinsulinemic clamp with tracers, and Western blot were done. Gln reduced WC and serum lipopolysaccharide (LPS) in overweight volunteers. In the obese group, Gln diminished WC and serum insulin. There was a positive correlation between the reduction on WC and LPS. In rats on HFD, Gln reduced adiposity, improved insulin action and signaling, and reversed both defects in glucose metabolism in the liver and muscle. Gln supplementation increased muscle glucose uptake and reversed the increased hepatic glucose production, in parallel with a reduced glucose uptake in adipose tissue. This insulin resistance in AT was accompanied by enhanced IRS1 O-linked-glycosamine association in this tissue, but not in the liver and muscle. These data suggest that Gln supplementation leads to insulin resistance specifically in adipose tissue via the hexosamine pathway and reduces adipose mass, which is associated with improvement in the systemic insulin action. Thus, further investigation with Gln supplementation should be performed for longer periods in humans before prescribing as a beneficial therapeutic approach for individuals who are overweight and obese.

Attenuation of Free Fatty Acid-Induced Muscle Insulin Resistance by Rosemary Extract

Elevated blood free fatty acids (FFAs), as seen in obesity, impair muscle insulin action leading to insulin resistance and Type 2 diabetes mellitus. Serine phosphorylation of the insulin receptor substrate (IRS) is linked to insulin resistance and a number of serine/threonine kinases including JNK, mTOR and p70 S6K have been implicated in this process. Activation of the energy sensor AMP-activated protein kinase (AMPK) increases muscle glucose uptake, and in recent years AMPK has been viewed as an important target to counteract insulin resistance. We reported recently that rosemary extract (RE) increased muscle cell glucose uptake and activated AMPK. However, the effect of RE on FFA-induced muscle insulin resistance has never been examined. In the current study, we investigated the effect of RE in palmitate-induced insulin resistant L6 myotubes. Exposure of myotubes to palmitate reduced the insulin-stimulated glucose uptake, increased serine phosphorylation of IRS-1, and decreased the insulin-stimulated phosphorylation of Akt. Importantly, exposure to RE abolished these effects and the insulin-stimulated glucose uptake was restored. Treatment with palmitate increased the phosphorylation/activation of JNK, mTOR and p70 S6K whereas RE completely abolished these effects. RE increased the phosphorylation of AMPK even in the presence of palmitate. Our data indicate that rosemary extract has the potential to counteract the palmitate-induced muscle cell insulin resistance and further studies are required to explore its antidiabetic properties.

Phaseolus lunatus(lima beans) abates Fe2+‐induced hepatic redox imbalance; inhibits intestinal glucose absorption and major carbohydrate catabolic enzymes; and modulates muscle glucose uptake

The antioxidative and antidiabetic effects of the aqueous extract of Phaseolus lunatus were investigated in vitro and ex vivo. The seeds were subjected to aqueous extraction, after defatting with n-hexane. The extract (15, 30, 60, 120, 240 µg/ml) showed significant (p < 0.05) free radical scavenging and enzyme inhibitory activities in vitro. It significantly (p < 0.05) elevated glutathione level with concomitant depletion of malondialdehyde level as well as increased superoxide dismutase and catalase activities in rat liver. Fe2+-induced hepatic DNA fragmentation was also significantly (p < 0.05) suppressed. The extract significantly inhibited intestinal glucose absorption and increased muscle glucose uptake with and without insulin. The inhibitory activities and reversion of hepatic redox imbalance, as well as inhibition of intestinal glucose absorption and increased muscle glucose uptake by P. lunatus suggest an antihyperglycemic and antioxidative effect. These can be ascribed to the synergistic effect of the phytochemicals and amino acids identified in the extract. Practical applications Lima beans (Phaseolus lunatus) is among the many underutilized legumes with reported nutritional benefits. It is utilized locally in Nigeria in treating and managing diabetes and its complications, but without any scientific proof. The ability of the legume to inhibit digestive enzymes linked to postprandial blood glucose spike, as well as inhibition of intestinal glucose absorption and increased muscle glucose uptake substantiates its antidiabetic folkloric uses. The amino acid constituents also indicate its nutritional properties. These findings will promote its utilization not only as an antidiabetic functional food but also as a nutritional meal.

Passive stretch regulates skeletal muscle glucose uptake independent of nitric oxide synthase.

Skeletal muscle contraction increases glucose uptake via an insulin-independent mechanism. Signaling pathways arising from mechanical strain are activated during muscle contractions, and mechanical strain in the form of passive stretching stimulates glucose uptake. However, the exact mechanisms regulating stretch-stimulated glucose uptake are not known. Since nitric oxide synthase (NOS) has been implicated in the regulation of glucose uptake during ex vivo and in situ muscle contractions and during exercise, and NO is increased with stretch, we examined whether the increase in muscle glucose uptake during stretching involves NOS. We passively stretched isolated extensor digitorum longus muscles (15 min at ~100-130 mN) from control mice and mice lacking either neuronal NOSµ (nNOSµ) or endothelial NOS (eNOS) isoforms, as well as used pharmacological inhibitors of NOS. Stretch significantly increased muscle glucose uptake appoximately twofold ( P < 0.05), and this was unaffected by the presence of the NOS inhibitors NG-monomethyl-l-arginine (100 µM) or NG-nitro-l-arginine methyl ester (100 µM). Similarly, stretch-stimulated glucose uptake was not attenuated by deletion of either eNOS or nNOSµ isoforms. Furthermore, stretching failed to increase skeletal muscle NOS enzymatic activity above resting levels. These data clearly demonstrate that stretch-stimulated skeletal muscle glucose uptake is not dependent on NOS. NEW & NOTEWORTHY Passive stretching is known to activate muscle glucose uptake through mechanisms that partially overlap with contraction. We report that genetic knockout of endothelial nitric oxide synthase (NOS) or neuronal NOS or pharmacological NOS inhibition does not affect stretch-stimulated glucose uptake. Passive stretch failed to increase NOS activity above resting levels. This information is important for the study of signaling pathways that regulate stretch-stimulated glucose uptake and indicate that NOS should be excluded as a potential signaling factor in this regard.

Overload Alters Skeletal Muscle Glucose Utilization but not Glucose Uptake or Hypertrophy in Insulin-Resistant Mice

Resistance exercise training/chronic muscle loading induces skeletal muscle hypertrophy and improves systemic glucose homeostasis in individuals with type 2 diabetes. Surprisingly, it is presently unknown if the improvement in glycemic control is due to an increase in muscle glucose uptake. PURPOSE: To determine if chronic muscle loading (overload)-induced muscle glucose uptake is impaired by insulin resistance. METHODS & RESULTS: Male C57BL/6J mice (6 wks old) were fed a low fat diet (LFD) or a 60%kcal high fat diet (HFD) for 12 wks to induce insulin resistance. Plantaris muscle overload was elicited by unilateral ablation of the distal 2/3 of the gastrocnemius and soleus. The contralateral leg was sham-operated. Muscles were weighed 5 days later. Overload increased muscle mass ~40% in both LFD and HFD mice. To assess glucose uptake, muscles were incubated in [3H]-2-deoxyglucose. Overload increased muscle glucose uptake ~80% in both LFD [Sham: 0.52±0.02; Overload: 0.91±0.04 (μmol/g muscle/h)] and HFD mice [Sham: 0.49±0.04; Overload: 0.86±0.09 (μmol/g muscle/h)], showing that overload stimulates glucose uptake independent of insulin resistance. To determine if this effect is due to increased glucose transporter (GLUT) or hexokinase levels, immunoblots were performed. Overload did not alter GLUT4 or hexokinase. In contrast, overload increased GLUT1 ~70%, but only in insulin resistant muscles. Decreased glycogen enhances glucose uptake. To determine if overload lowered glycogen levels, glycogen content was measured using a hexokinase-based reagent. Overload increased muscle glycogen ~26% in LFD (Sham: 29.0±1.6; Overload: 36.1±1.5 nmol/mg muscle), and ~40% in HFD mice (Sham: 31.2 ±2.1; Overload: 42.3±1.7 nmol/mg muscle). To determine if overload-induced glucose uptake is dependent on glucose utilization, muscles were incubated in [5-3H]-glucose to assess glycolytic flux, and immunoblots performed to assess the rate limiting enzyme of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD). Overload did not alter muscle glycolytic flux. In contrast overload increased muscle G6PD ~140% in LFD, and ~82% in HFD mice. CONCLUSION: Insulin resistance does not impair overload-induced muscle hypertrophy or glucose uptake, but does alter glucose utilization. SUPPORT: NIH R01 DK103562

Carnosol Increases Skeletal Muscle Cell Glucose Uptake via AMPK-Dependent GLUT4 Glucose Transporter Translocation.

Skeletal muscle is a major insulin-target tissue and plays an important role in glucose homeostasis. Insulin action in muscle activates the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway causing the translocation of intracellularly stored GLUT4 glucose transporters to the plasma membrane and increased glucose uptake. Impaired insulin action in muscle results in insulin resistance and type 2 diabetes mellitus (T2DM). Activation of the energy sensor AMP-activated kinase (AMPK) increases muscle glucose uptake and the use of AMPK activators is viewed as an effective strategy to combat insulin resistance. Rosemary extract (RE) has been shown to stimulate muscle AMPK and glucose uptake, but the exact components responsible for these effects are unknown. In the current study, we investigated the effect of carnosol, a RE polyphenol, in L6 rat muscle cells. Carnosol stimulated glucose uptake in L6 myotubes in a dose- and time-dependent manner, did not affect Akt, increased AMPK phosphorylation and plasma membrane GLUT4 levels. The carnosol-stimulated glucose uptake and GLUT4 translocation was significantly reduced by the AMPK inhibitor compound C (CC). Our study is the first to show an AMPK-dependent increase in muscle glucose uptake by carnosol. Carnosol has potential as a glucose homeostasis regulating agent and deserves further study.

Carnosol increases skeletal muscle cell glucose uptake via AMPK‐dependent GLUT 4 glucose transporter translocation

Skeletal muscle is highly important in glucose homeostasis since it is quantitatively a major insulin‐target tissue. Insulin action in muscle cells activates the phosphatidylinositol‐3 kinase (PI3K)/Akt signaling pathway causing the translocation of intracellularly stored GLUT4 glucose transporters to the plasma membrane leading to increased glucose uptake. Impaired insulin action in muscle leads to insulin resistance and type 2 diabetes mellitus (T2DM).AMP‐activated kinase (AMPK) is a cellular energy sensor and its activation increases glucose uptake by skeletal muscle cells. Finding AMPK activators is viewed as an effective approach to combat insulin resistance and T2DM. Rosemary extract (RE) has been shown to increase muscle glucose uptake and AMPK activity but the components responsible for these effects have not been identified yet. In the current study, we investigated the effect of carnosol, a polyphenol found in high concentrations in RE. L6 rat muscle cells were used to measure uptake of [3H]‐2‐deoxy‐D‐glucose and the signaling molecules involved were investigated by immunoblotting. Carnosol stimulated glucose uptake in L6 myotubes in a dose‐ and time‐dependent manner. A response comparable to maximum insulin stimulation (196±9.2 % of control) was seen with 50μM of carnosol (2h) (182±7.8 % of control). Carnosol did not affect Akt phosphorylation while it significantly increased AMPK phosphorylation. Furthermore, the increase in glucose uptake in the presence of carnosol was significantly reduced by the AMPK inhibitor compound C (CC) while it was not affected by the PI3K inhibitor wortmannin. Carnosol increased plasma membrane GLUT4 glucose transporter levels in GLUT4myc overexpressing L6 cells and this response was abolished by the AMPK inhibitor CC. Our study is the first to show a significant increase in muscle glucose uptake by carnosol via a mechanism that involves AMPK.Support or Funding InformationSupported by a Natural Sciences and Engineering Research Council of Canada (NSERC) grant to ET.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Attenuation of High Glucose/High Insulin‐Induced Muscle Insulin Resistance by Rosemary Extract

Insulin is a key hormone affecting metabolism and plays a major role in the regulation of glucose homeostasis. Skeletal muscle accounts for ~80% of postprandial glucose disposal and is thus the major organ of glucose uptake. Insulin increases muscle glucose uptake by increasing the translocation of intracellularly stored GLUT4 glucose transporters to the plasma membrane through the phosphatidylinositol‐3 kinase (PI3K)/Akt signaling pathway. Impaired PI3K/Akt signaling is associated with insulin resistance (IR) in skeletal muscle, leading to chronically elevated blood glucose levels and followed by a compensatory rise in insulin levels. The elevated glucose and insulin levels, in turn, exacerbate IR. Polyphenols are phytochemicals derived from natural plant sources that were found to have antioxidant, anti‐inflammatory, anti‐cancer and anti‐diabetic effects.Rosemary extract (RE), rich in polyphenols, contains carnosic acid (CA), carnosol (COH) and rosmarinic acid (RA), which have been shown to counteract insulin resistance in both in vitro and in vivo animal models. However, the mechanisms involved are not known. Therefore, the aim of this study is to investigate the effects of RE on high glucose (HG)/high insulin (HI)‐induced skeletal muscle insulin resistance and the molecular mechanisms involved. Glucose uptake was assessed using [3 H]‐2‐deoxy‐d‐glucose. Total and phosphorylated levels of Akt and IRS‐1 were measured by immunoblotting. Exposure of L6 myotubes to 25mM glucose/100nM insulin for 24 h, to mimic hyperglycemia/hyperinsulinemia, abolished the acute insulin‐stimulated glucose uptake (I: 180±10.43, HG/HI + I: 108 % of basal). In addition, HG/HI attenuated the insulin‐stimulated Akt phosphorylation, while increased IRS‐1 Ser 636/639 phosphorylation indicating insulin resistance. Importantly, treatment with RE (5 μg/ml, 24 h) significantly restored the insulin‐stimulated glucose uptake (HG/HI + RE + I: 184%). Our data indicate a potential of RE to counteract muscle insulin resistance. The focus of our research is to investigate the mechanism involved in mediating this effect of RE.Support or Funding InformationSupported by a Natural Sciences and Engineering Research Council of Canada (NSERC) grant to ETThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Recombinant Uncarboxylated Osteocalcin Per Se Enhances Mouse Skeletal Muscle Glucose Uptake in both Extensor Digitorum Longus and Soleus Muscles.

Emerging evidence suggests that undercarboxylated osteocalcin (ucOC) improves muscle glucose uptake in rodents. However, whether ucOC can directly increase glucose uptake in both glycolytic and oxidative muscles and the possible mechanisms of action still need further exploration. We tested the hypothesis that ucOC per se stimulates muscle glucose uptake via extracellular signal-regulated kinase (ERK), adenosine monophosphate-activated protein kinase (AMPK), and/or the mechanistic target of rapamycin complex 2 (mTORC2)-protein kinase B (AKT)-AKT substrate of 160 kDa (AS160) signaling cascade. Extensor digitorum longus (EDL) and soleus muscles from male C57BL/6 mice were isolated, divided into halves, and then incubated with ucOC with or without the pretreatment of ERK inhibitor U0126. ucOC increased muscle glucose uptake in both EDL and soleus. It also enhanced phosphorylation of ERK2 (Thr202/Tyr204) and AS160 (Thr642) in both muscle types and increased mTOR phosphorylation (Ser2481) in EDL only. ucOC had no significant effect on the phosphorylation of AMPKα (Thr172). The inhibition of ucOC-induced ERK phosphorylation had limited effect on ucOC-stimulated glucose uptake and AS160 phosphorylation in both muscle types, but appeared to inhibit the elevation in AKT phosphorylation only in EDL. Taken together, ucOC at the physiological range directly increased glucose uptake in both EDL and soleus muscles in mouse. The molecular mechanisms behind this ucOC effect on muscle glucose uptake seem to be muscle type-specific, involving enhanced phosphorylation of AS160 but limitedly modulated by ERK phosphorylation. Our study suggests that, since ucOC increases muscle glucose uptake without insulin, it could be considered as a potential agent to improve muscle glucose uptake in insulin resistant conditions.

Nitric oxide is required for the insulin sensitizing effects of contraction in mouse skeletal muscle.

People with insulin resistance or type 2 diabetes can substantially increase their skeletal muscle glucose uptake during exercise and insulin sensitivity after exercise. Skeletal muscle nitric oxide (NO) is important for glucose uptake during exercise, although how prior exercise increases insulin sensitivity is unclear. In the present study, we examined whether NO is necessary for normal increases in skeletal muscle insulin sensitivity after contraction ex vivo in mouse muscle. The present study uncovers, for the first time, a novel role for NO in the insulin sensitizing effects of ex vivo contraction, which is independent of blood flow. The factors regulating the increase in skeletal muscle insulin sensitivity after exercise are unclear. We examined whether nitric oxide (NO) is required for the increase in insulin sensitivity after ex vivo contractions. Isolated C57BL/6J mouse EDL muscles were contracted for 10min or remained at rest (basal) with or without the NO synthase (NOS) inhibition (NG -monomethyl-l-arginine; l-NMMA; 100μm). Then, 3.5h post contraction/basal, muscles were exposed to saline or insulin (120μUml-1 ) with or without l-NMMA during the last 30min. l-NMMA had no effect on basal skeletal muscle glucose uptake. The increase in muscle glucose uptake with insulin (57%) was significantly (P<0.05) greater after prior contraction (140% increase). NOS inhibition during the contractions had no effect on this insulin-sensitizing effect of contraction, whereas NOS inhibition during insulin prevented the increase in skeletal muscle insulin sensitivity post-contraction. Soluble guanylate cyclase inhibition, protein kinase G (PKG) inhibition or cyclic nucleotide phosphodiesterase inhibition each had no effect on the insulin-sensitizing effect of prior contraction. In conclusion, NO is required for increases in insulin sensitivity several hours after contraction of mouse skeletal muscle via a cGMP/PKG independent pathway.

Rosmarinic Acid, a Rosemary Extract Polyphenol, Increases Skeletal Muscle Cell Glucose Uptake and Activates AMPK.

Skeletal muscle is a major insulin-target tissue and plays an important role in glucose homeostasis. Impaired insulin action in muscles leads to insulin resistance and type 2 diabetes mellitus. 5′ AMP-activated kinase (AMPK) is an energy sensor, its activation increases glucose uptake in skeletal muscle and AMPK activators have been viewed as a targeted approach in combating insulin resistance. We previously reported AMPK activation and increased muscle glucose uptake by rosemary extract (RE). In the present study, we examined the effects and the mechanism of action of rosmarinic acid (RA), a major RE constituent, in L6 rat muscle cells. RA (5.0 µM) increased glucose uptake (186 ± 4.17% of control, p < 0.001) to levels comparable to maximum insulin (204 ± 10.73% of control, p < 0.001) and metformin (202 ± 14.37% of control, p < 0.001). Akt phosphorylation was not affected by RA, while AMPK phosphorylation was increased. The RA-stimulated glucose uptake was inhibited by the AMPK inhibitor compound C and was not affected by wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). The current study shows an effect of RA to increase muscle glucose uptake and AMPK phosphorylation. RA deserves further study as it shows potential to be used as an agent to regulate glucose homeostasis.

Erythritol reduces small intestinal glucose absorption, increases muscle glucose uptake, improves glucose metabolic enzymes activities and increases expression of Glut-4 and IRS-1 in type 2 diabetic rats.

Studies have reported that erythritol, a lowor non-glycemic sugar alcohol possesses anti-hyperglycemic and anti-diabetic potentials but the underlying mode of actions is not clear. This study investigated the underlying mode of actions behind the anti-hyperglycemic and anti-diabetic potentials of erythritol using different experimental models (experiment 1, 2 and 3). Experiment 1 examined the effects of increasing concentrations (2.5-20%) of erythritol on glucose absorption and uptake in isolated rat jejunum and psoas muscle, respectively. Experiments 2 and 3 examined the effects of a single oral dose of erythritol (1g/kg bw) on intestinal glucose absorption, gastric emptying and postprandial blood glucose increase, glucose tolerance, serum insulin level, muscle/liver hexokinase and liver glucose-6 phosphatase activities, liver and muscle glycogen contents and mRNA and protein expression of muscle Glut-4 and IRS-1 in normal and type 2 diabetic animals. Experiment 1 revealed that erythritol dose dependently enhanced muscle glucose ex vivo. Experiment 2 demonstrated that erythritol feeding delayed gastric emptying and reduced small intestinal glucose absorption as well as postprandial blood glucose rise, especially in diabetic animals. Experiment 3 showed that erythritol feeding improved glucose tolerance, muscle/liver hexokinase and liver glucose-6 phosphatase activities, glycogen storage and also modulated expression of muscle Glut-4 and IRS-1 in diabetic animals. Data suggest that erythritol may exert anti-hyperglycemic effects not only via reducing small intestinal glucose absorption, but also by increasing muscle glucose uptake, improving glucose metabolic enzymes activity and modulating muscle Glut-4 and IRS-1 mRNA and protein expression. Hence, erythritol may be a useful dietary supplement for managing hyperglycemia, particularly for T2D.

Autophagy and Mitochondria in Obesity and Type 2 Diabetes.

Obesity and type 2 diabetes are growing health problems worldwide. The three principal diabetogenic factors are adiposity, insulin resistance in skeletal muscle, and decreased insulin production by pancreatic β cells. During recent years, macroautophagy (hereafter autophagy) - sequestration and lysosomal degradation of cellular components - has emerged as an important player in these processes, playing a protective role against development of insulin resistance and diabetes. Of particular importance is the removal of dysfunctional mitochondria via mitophagy, a form of macroautophagy selective for mitochondria. Both muscle insulin resistance and β-cell dysfunction largely depend on metabolic overload of mitochondria, which results in incomplete β-oxidation, oxidative stress, accumulation of toxic lipid intermediates, and mitochondrial damage. Mitophagy eliminates this vicious cycle of oxidative stress and mitochondrial damage, and thus counteracts pathogenic processes. Autophagy also mediates exercise-induced increases in muscle glucose uptake and protects β cells against ER stress in diabetogenic conditions. On the other hand, adipose tissue autophagy promotes adipocyte differentiation, possibly through its role in mitochondrial clearance. Being involved in many aspects, autophagy appears to be an attractive target for therapeutic interventions against obesity and diabetes. Here we explore the connections of autophagy with mitochondria in obesity and type 2 diabetes, and discuss its roles in diabetic complications. Understanding how autophagy protects against diabetes could help design new strategies against this growing epidemic.

Regulation of microvascular flow and metabolism: An overview.

Skeletal muscle is an important site for insulin to regulate blood glucose levels. It is estimated that skeletal muscle is responsible for ~80% of insulin-mediated glucose disposal in the post-prandial period. The classical action of insulin to increase muscle glucose uptake involves insulin binding to insulin receptors on myocytes to stimulate glucose transporter 4 (GLUT 4) translocation to the cell surface membrane, enhancing glucose uptake. However, an additional role of insulin that is often under-appreciated is its action to increase muscle perfusion thereby improving insulin and glucose delivery to myocytes. Either of these responses (myocyte and/or vascular) may be impaired in insulin resistance, and both impairments are apparent in type 2 diabetes, resulting in diminished glucose disposal by muscle. The aim of this review is to report on the growing body of literature suggesting that insulin-mediated control of skeletal muscle perfusion is an important regulator of muscle glucose uptake and that impairment of microvascular insulin action has important physiological consequences early in the pathogenesis of insulin resistance. This work was discussed at the 2015 Australian Physiological Society Symposium "Physiological mechanisms controlling microvascular flow and muscle metabolism".

Sorbitol increases muscle glucose uptake ex vivo and inhibits intestinal glucose absorption ex vivo and in normal and type 2 diabetic rats.

Previous studies have suggested that sorbitol, a known polyol sweetener, possesses glycemic control potentials. However, the effect of sorbitol on intestinal glucose absorption and muscle glucose uptake still remains elusive. The present study investigated the effects of sorbitol on intestinal glucose absorption and muscle glucose uptake as possible anti-hyperglycemic or glycemic control potentials using ex vivo and in vivo experimental models. Sorbitol (2.5% to 20%) inhibited glucose absorption in isolated rat jejuna (IC50 = 14.6% ± 4.6%) and increased glucose uptake in isolated rat psoas muscle with (GU50 = 3.5% ± 1.6%) or without insulin (GU50 = 7.0% ± 0.5%) in a concentration-dependent manner. Furthermore, sorbitol significantly delayed gastric emptying, accelerated digesta transit, inhibited intestinal glucose absorption, and reduced blood glucose increase in both normoglycemic and type 2 diabetic rats after 1 h of coingestion with glucose. Data of this study suggest that sorbitol exhibited anti-hyperglycemic potentials, possibly via increasing muscle glucose uptake ex vivo and reducing intestinal glucose absorption in normal and type 2 diabetic rats. Hence, sorbitol may be further investigated as a possible anti-hyperglycemic sweetener.

Myo-inositol inhibits intestinal glucose absorption and promotes muscle glucose uptake: a dual approach study.

The present study investigated the effects of myo-inositol on muscle glucose uptake and intestinal glucose absorption ex vivo as well as in normal and type 2 diabetes model of rats. In ex vivo study, both intestinal glucose absorption and muscle glucose uptake were studied in isolated rat jejunum and psoas muscle respectively in the presence of increasing concentrations (2.5% to 20%) of myo-inositol. In the in vivo study, the effect of a single bolus dose (1g/kg bw) of oral myo-inositol on intestinal glucose absorption, blood glucose, gastric emptying and digesta transit was investigated in normal and type 2 diabetic rats after 1h of co-administration with 2g/kg bw glucose, when phenol red was used as a recovery marker. Myo-inositol inhibited intestinal glucose absorption (IC50=28.23±6.01%) and increased muscle glucose uptake, with (GU50=2.68±0.75%) or without (GU50=8.61±0.55%) insulin. Additionally, oral myo-inositol not only inhibited duodenal glucose absorption and reduced blood glucose increase, but also delayed gastric emptying and accelerated digesta transit in both normal and diabetic animals. Results of this study suggest that dietary myo-inositol inhibits intestinal glucose absorption both in ex vivo and in normal or diabetic rats and also promotes muscle glucose uptake in ex vivo condition. Hence, myo-inositol may be further investigated as a possible anti-hyperglycaemic dietary supplement for diabetic foods and food products.

α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors

ObjectiveCentral melanocortin pathways are well-established regulators of energy balance. However, scant data exist about the role of systemic melanocortin peptides. We set out to determine if peripheral α-melanocyte stimulating hormone (α-MSH) plays a role in glucose homeostasis and tested the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting α-MSH. MethodsWe established glucose-stimulated α-MSH secretion using humans, non-human primates, and mouse models. Continuous α-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of α-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of α-MSH via the melanocortin 5 receptor (MC5R)–PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and α-MSH was adopted to restore glucose tolerance in obese mice. ResultsHere we demonstrate that pituitary secretion of α-MSH is increased by glucose. Peripheral α-MSH increases temperature in skeletal muscles, acts directly on soleus and gastrocnemius muscles to significantly increase glucose uptake, and enhances whole-body glucose clearance via the activation of muscle MC5R and protein kinase A. These actions are absent in obese mice, accompanied by a blunting of α-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores α-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice. ConclusionThese data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary α-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity.

Wnt Signaling Genes in Adipose Tissue and Skeletal Muscle of Humans With Different Degrees of Insulin Sensitivity.

The β-catenin-dependent Wnt signaling plays a role in adipogenesis, myogenesis, and glucose homeostasis. The aim of this study was to assess adipose tissue and skeletal muscle expression of Wnt/β-catenin signaling genes in a young healthy population according to insulin sensitivity and its regulation by hyperinsulinemia and free fatty acids. We examined 117 male volunteers. The participants were divided into subgroups of high-insulin sensitivity (IS) and low-IS on the basis of a 2-hour euglycemic clamp. In 20 subjects, the clamp was prolonged to 6 hours. After 1 week, another 6-hour clamp, with Intralipid/heparin infusion, was performed. Tissue biopsies were performed before each clamp and after 6-hour clamps. Additionally, we collected muscle biopsies from another group of 16 male subjects for cell cultures. Myotubes were treated with insulin separately and in combination with palmitate. We found decreased adipose tissue WNT10B, FZD1/8, LRP5, DVL2, CTNN1B, TCF7L2, and AXIN2 and increased muscle WNT10B, FZD1/8, LRP6, DVL1, GSK3B, CTNNB1, TCF7L2, AXIN2, MYC, and CCND1 expression in the low-IS group. Hyperinsulinemia resulted in a decrease in adipose tissue FZD4, LRP5/6, TCF7L2, and AXIN2 and an increase in muscle FZD1/8, DVL1/2/3, TCF7L2, AXIN2, and MYC expression. These changes disappeared after free fatty acid elevation. In myotubes, insulin increased the expression of FZD1, DVL2, CTNNB1, and TCF7L2, whereas palmitate abolished these effects. The association of β-catenin-dependent Wnt signaling with insulin resistance is tissue specific. Observed changes might reflect a compensatory mechanism to increase muscle glucose uptake and to generate new fat cells in insulin-resistant conditions.

Apple cider vinegar for diabetes: Limited evidence, potential risks

action of vinegar and AVC, speci cally the acetic acid component, may involve delayed gastric emptying, increased satiety, and increased uptake of glucose, among other effects.3 One crossover study assessed ACV’s potential antiglycemic properties in healthy volunteers. Five participants without diabetes were tested four separate times, twice with placebo and twice with ACV, before ingesting a carbohydrate-rich meal. Glucose levels increased 20 to 100 minutes after meal ingestion, 0.44 mg/min when taking vinegar, and 0.40 mg/min when taking placebo.4 A 2015 crossover study of 11 patients with type 2 diabetes evaluated the effects of vinegar, focusing on acetic acid. The study showed that postprandial vinegar ingestion had statistically signi cant effects in reducing total blood glucose, decreasing postprandial hyperinsulinemia, and increasing muscle glucose uptake.5

Potential Benefit of Metformin as Treatment for Colon Cancer: the Evidence so Far.

Metformin is known as a hypoglycaemic agent that regulates glucose homeostasis by inhibiting liver glucose production and increasing muscle glucose uptake. Colorectal cancer (CRC) is one of the most common cancers worldwide, with about a million new cases diagnosed each year. The risk factors for CRC include advanced age, smoking, black race, obesity, low fibre diet, insulin resistance, and the metabolic syndrome. We have searched Medline for the metabolic syndrome and its relation to CRC, and metformin as a potential treatment of colorectal cancer. Administration of metformin alone or in combination with chemotherapy has been shown to suppress CRC. The mechanism that explains how insulin resistance is associated with CRC is complex and not fully understood. In this review we have summarised studies which showed an association with the metabolic syndrome as well as studies which tackled metformin as a potential treatment of CRC. In addition, we have also provided a summary of how metformin at the cellular level can induce changes that suppress the activity of cancer cells.