Chromium Improves Glucose Uptake and Metabolism Through Upregulating the mRNA Levels of IR,GLUT4, GS,and UCP3 in Skeletal Muscle Cells

The aim of this study was to evaluate the impact of three different chromium forms as chromic chloride (CrCl), chromium picolinate (CrPic), and a newly synthesized complex of chromium chelated with small peptides (CrSP) on glucose uptake and metabolism in vitro. In cultured skeletal muscle cells, chromium augmented insulin-stimulated glucose uptake and metabolism as assessed by a reduced glucose concentration of culture medium. At the molecular level, insulin significantly increased the mRNA levels of insulin receptor (IR), glucose transporter 4 (GLUT4), glycogen synthase (GS), and uncoupling protein-3 (UCP3), and these impacts can be enhanced by the addition of chromium, especially in the form of CrSP. Collectively, results of this study demonstrate that chromium improves glucose uptake and metabolism through upregulating the mRNA levels of IR, GLUT4, GS, and UCP3 in skeletal muscle cells, and CrSP has higher efficacy on glucose uptake and metabolism compared to the forms of CrCl and CrPic.     

Insulin-like growth factor 1 (IGF-1)-induced twist expression is involved in the anti-apoptotic effects of the IGF-1 receptor

In this study we investigated the molecular mechanisms whereby insulin-like growth factor 1 (IGF-1) induced Twist gene expression and the role of Twist in the anti-apoptotic actions of the IGF-1 receptor. In NIH-3T3 fibroblasts overexpressing the human IGF-1 receptor (NWTb3), treatment with IGF-1 (10(-8) m) for 1 and 4 h increased the level of Twist mRNA as well as protein by 3-fold. In contrast, insulin at physiological concentrations did not stimulate Twist expression in NIH-3T3 fibroblasts overexpressing the human insulin receptor. The IGF-1 effect was specific for the IGF-1 receptor since, in cells overexpressing a dominant negative IGF-1 receptor, IGF-1 failed to increase Twist expression. Pre-incubation with the ERK1/2 inhibitor U0126 or expression of a dominant negative MEK-1 abolished the effect of IGF-1 on Twist mRNA expression in NWTb3 cells, suggesting that Twist induction by IGF-1 occurs via the mitogen-activated protein kinase signaling pathway. In vivo, IGF-1 injection increased the mRNA level of Twist in mouse skeletal muscle, the major site of Twist expression. Finally, using an antisense strategy, we demonstrated that a reduction of 40% in Twist expression decreased significantly the ability of IGF-1 to rescue NWTb3 cells from etoposide-induced apoptosis. Taken together, these results define Twist as an important factor involved in the anti-apoptotic actions of the IGF-1 receptor.     

Effect of different doses of chromium picolinate on protein metabolism in infant rats.

This 12-day study was conducted to evaluate the effects of three different levels of dietary chromium (100, 200, and 500 microg/day) in the form of chromium picolinate (CrPic) on growth and protein use in weaned rats. No significant effect of CrPic on body weight gain, food intake, or food conversion rate was observed. Elevated doses of CrPic seemed to increase muscle mass, either by stimulating protein anabolism by activation of insulin by chromium or by lowering protein degradation. However, these effects had no repercussions on overall growth, suggesting that any anabolic effect of chromium due to the action of insulin was probably marginal.     

Chromium enhances insulin responsiveness via AMPK

Trivalent chromium (Cr³⁺) is known to improve glucose homeostasis. Cr³⁺ has been shown to improve plasma membrane-based aspects of glucose transporter GLUT4 regulation and increase activity of the cellular energy sensor 5’ AMP-activated protein kinase (AMPK). However, the mechanism(s) by which Cr³⁺ improves insulin responsiveness and whether AMPK mediates this action is not known. In this study we tested if Cr³⁺ protected against physiological hyperinsulinemia-induced plasma membrane cholesterol accumulation, cortical filamentous actin (F-actin) loss and insulin resistance in L6 skeletal muscle myotubes. In addition, we performed mechanistic studies to test our hypothesis that AMPK mediates the effects of Cr³⁺ on GLUT4 and glucose transport regulation. Hyperinsulinemia-induced insulin-resistant L6 myotubes displayed excess membrane cholesterol and diminished cortical F-actin essential for effective glucose transport regulation. These membrane and cytoskeletal abnormalities were associated with defects in insulin-stimulated GLUT4 translocation and glucose transport. Supplementing the culture medium with pharmacologically relevant doses of Cr³⁺ in the picolinate form (CrPic) protected against membrane cholesterol accumulation, F-actin loss, GLUT4 dysregulation and glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemic conditions nor enhanced by CrPic, whereas CrPic increased AMPK signaling. Mechanistically, siRNA-mediated depletion of AMPK abolished the protective effects of CrPic against GLUT4 and glucose transport dysregulation. Together these findings suggest that the micronutrient Cr³⁺, via increasing AMPK activity, positively impacts skeletal muscle cell insulin sensitivity and glucose transport regulation.     

Insulin and Chromium Picolinate Induce Translocation of CD36 to the Plasma Membrane Through Different Signaling Pathways in 3T3-L1 Adipocytes,and with a Differential Functionality of the CD36

Chromium picolinate (CrPic) has been indicated to activate glucose transporter 4 (GLUT4) trafficking to the plasma membrane (PM) to enhance glucose uptake in 3T3-L1 adipocytes. In skeletal and heart muscle cells, insulin directs the intracellular trafficking of the fatty acid translocase/CD36 to induce the uptake of cellular long-chain fatty acid (LCFA). The current study describes the effects of CrPic and insulin on the translocation of CD36 from intracellular storage pools to the PM in 3T3-L1 adipocytes in comparison with that of GLUT4. Immunofluorescence microscopy and immunoblotting revealed that both CD36 and GLUT4 were expressed and primarily located intracellularly in 3T3-L1 adipocytes. Upon insulin or CrPic stimulation, PM expression of CD36 increased in a similar manner as that for GLUT4; the CrPic-stimulated PM expression was less strong than that of insulin. The increase in PM localization for these two proteins by insulin paralleled LCFA ([1-¹⁴C]palmitate) or [³H]deoxyglucose uptake in 3T3-L1 adipocytes. The induction of the PM expression of GLUT4, but not CD36, or substrate uptake by insulin and CrPic appears to be additive in adipocytes. Furthermore, wortmannin completely inhibited the insulin-stimulated translocation of GLUT4 or CD36 and prevented the increased uptake of glucose or LCFA in these cells. Taken together, for the first time, these findings suggest that both insulin and CrPic induce CD36 translocation to the PM in 3T3-L1 adipocytes and that their translocation-inducing effects are not additive. The signaling pathway inducing the translocations is different, apparently resulting in a differential activity of CD36.     

Effects of chromium picolinate on glucose uptake in insulin-resistant 3T3-L1 adipocytes involve activation of p38 MAPK

Chromium picolinate (CrPic) has been discovered as a supplemental or alternative medication for type 2 diabetes, but its mechanism of action is not well understood. The purpose of this study was to explore the possible anti-diabetic mechanisms of CrPic in insulin-resistant 3T3-L1 adipocytes; the insulin resistance was induced by treatment with high glucose and insulin for 24 h. The effects of CrPic on glucose metabolism and the glucose uptake-inducing activity of CrPic were investigated. Meanwhile, the effects of CrPic on glucose transporter 4 (GLUT4) translocation were visualized by immonofluorescence microscopy. In addition, its effects on insulin signaling pathways and mitogen-activated protein kinase (MAPK) signaling cascades were assessed by immunoblotting analysis and real-time PCR. The results showed that CrPic induced glucose metabolism and uptake, as well as GLUT4 translocation to plasma membrane (PM) in both control and insulin-resistant 3T3-L1 adipocytes without any changes in insulin receptor β (IR-β), protein kinase B (AKt), c-Cbl, extracellular signal-regulated kinase (ERK), c-Jun phosphorylation and c-Cbl-associated protein (CAP) mRNA levels. Interestingly, CrPic was able to increase the basal and insulin-stimulated levels of p38 MAPK activation in the control and insulin-resistant cells. Pretreatment with the specific p38 MAPK inhibitor SB203580 partially inhibited the CrPic-induced glucose transport, but CrPic-activated translocation of GLUT4 was not inhibited by SB203580. This study provides an experimental evidence of the effects of CrPic on glucose uptake through the activation of p38 MAPK and it is independent of the effect on GLUT4 translocation. The findings also suggest exciting new insights into the role of p38 MAPK in glucose uptake and GLUT4 translocation.     

Chronic stimulation of glucose transporter gene expression in L6 myocytes mediated via the insulin-like growth factor-1 receptor

We have used differentiated L6 myocytes to investigate the regulation of glucose transporter gene expression by insulin and insulin-like growth factor-1 (IGF-1). Chronic exposure to insulin (1 microM) or IGF-1 (10 nm) resulted in a 2- to 5-fold stimulation of 3H-2-deoxy-D-glucose uptake and a corresponding increase in the expression of rat brain/HepG2-type glucose transporter mRNA (GTmRNA) and immunoreactive transporter protein. The dose responses to both insulin and IGF-1 for stimulation of glucose uptake were paralleled by the expression of GTmRNA. Glucose uptake and GTmRNA levels were half maximally stimulated by 350 and 100 nM insulin, respectively, or by 2 nM IGF-1. Comparison of receptor occupancy with stimulation of glucose uptake and GTmRNA expression suggests that insulin exerts its effects through the IGF-1 receptor. Fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, and phorbol ester had little or no effect on GTmRNA expression. These results demonstrate that the IGF-1 receptor mediates chronic regulation of transporter mRNA expression and protein synthesis and activity in cultured rat muscle cells.     

Acute effect of fatty acids on metabolism and mitochondrial coupling in skeletal muscle

Acute effects of free fatty acids (FFA) were investigated on: (1) glucose oxidation, and UCP-2 and -3 mRNA and protein levels in 1 h incubated rat soleus and extensor digitorium longus (EDL) muscles, (2) mitochondrial membrane potential in cultured skeletal muscle cells, (3) respiratory activity and transmembrane electrical potential in mitochondria isolated from rat skeletal muscle, and (4) oxygen consumption by anesthetized rats. Long-chain FFA increased both basal and insulin-stimulated glucose oxidation in incubated rat soleus and EDL muscles and reduced mitochondrial membrane potential in C2C12 myotubes and rat skeletal muscle cells. Caprylic, palmitic, oleic, and linoleic acid increased O₂ consumption and decreased electrical membrane potential in isolated mitochondria from rat skeletal muscles. FFA did not alter UCP-2 and -3 mRNA and protein levels in rat soleus and EDL muscles. Palmitic acid increased oxygen consumption by anesthetized rats. These results suggest that long-chain FFA acutely lead to mitochondrial uncoupling in skeletal muscle.     

Interleukin-15 stimulates adiponectin secretion by 3T3-L1 adipocytes: evidence for a skeletal muscle-to-fat signaling pathway

Interleukin-15 (IL-15) is a cytokine which is highly expressed in skeletal muscle tissue, and which has anabolic effects on skeletal muscle protein dynamics both in vivo and in vitro. Additionally, administration of IL-15 to rats and mice inhibits white adipose tissue deposition. To determine if the action of IL-15 on adipose tissue is direct, the capacity of cultured murine 3T3-L1 preadipocytes and adipocytes to respond to IL-15 was examined. IL-15 administration inhibited lipid accumulation in differentiating 3T3-L1 preadipocytes, and stimulated secretion of the adipocyte-specific hormone adiponectin by differentiated 3T3-L1 adipocytes. The latter observation constitutes the first report of a cytokine or growth factor which stimulates adiponectin production. IL-15 mRNA expression by cultured 3T3-L1 adipogenic cells and C2C12 murine skeletal myogenic cells was also examined. Quantitative real-time PCR indicated IL-15 mRNA was expressed by C2C12 skeletal myogenic cells, and was upregulated more than 10-fold in differentiated skeletal myotubes compared to undifferentiated myoblasts. In contrast, 3T3-L1 cells expressed little or no IL-15 mRNA at either the undifferentiated preadipocyte or differentiated adipocyte stages. These findings provide support for the hypothesis that IL-15 functions in a muscle-to-fat endocrine axis which modulates fat:lean body composition and insulin sensitivity.     

Chromium activates glucose transporter 4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism

Evidence suggests that chromium supplementation may alleviate symptoms associated with diabetes, such as high blood glucose and lipid abnormalities, yet a molecular mechanism remains unclear. Here, we report that trivalent chromium in the chloride (CrCl3) or picolinate (CrPic) salt forms mobilize the glucose transporter, GLUT4, to the plasma membrane in 3T3-L1 adipocytes. Concomitant with an increase in GLUT4 at the plasma membrane, insulin-stimulated glucose transport was enhanced by chromium treatment. In contrast, the chromium-mobilized pool of transporters was not active in the absence of insulin. Microscopic analysis of an exofacially Myc-tagged enhanced green fluorescent protein-GLUT4 construct revealed that the chromium-induced accumulation of GLUT4-containing vesicles occurred adjacent to the inner cell surface membrane. With insulin these transporters physically incorporated into the plasma membrane. Regulation of GLUT4 translocation by chromium did not involve known insulin signaling proteins such as the insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, and Akt. Consistent with a reported effect of chromium on increasing membrane fluidity, we found that chromium treatment decreased plasma membrane cholesterol. Interestingly, cholesterol add-back to the plasma membrane prevented the beneficial effect of chromium on both GLUT4 mobilization and insulin-stimulated glucose transport. Furthermore, chromium action was absent in methyl-beta-cyclodextrin-pretreated cells already displaying reduced plasma membrane cholesterol and increased GLUT4 translocation. Together, these data reveal a novel mechanism by which chromium may enhance GLUT4 trafficking and insulin-stimulated glucose transport. Moreover, these findings at the level of the cell are consistent with in vivo observations of improved glucose tolerance and decreased circulating cholesterol levels after chromium supplementation.     

Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways

Coordination of skeletal muscle growth and metabolism with nutrient availability is critical for metabolic homeostasis. To establish the role of insulin-like signaling in this process, we used muscle creatine kinase (MCK)-Cre to disrupt expression of insulin receptor substrates Irs1 and Irs2 in mouse skeletal/cardiac muscle. In 2-week-old mice, skeletal muscle masses and insulin responses were slightly affected by Irs1, but not Irs2, deficiency. In contrast, the combined deficiency of Irs1 and Irs2 (MDKO mice) severely reduced skeletal muscle growth and Akt→mTOR signaling and caused death by 3 weeks of age. Autopsy of MDKO mice revealed dilated cardiomyopathy, reflecting the known requirement of insulin-like signaling for cardiac function (P. G. Laustsen et al., Mol. Cell. Biol. 27:1649-1664, 2007). Impaired growth and function of MDKO skeletal muscle were accompanied by increased Foxo-dependent atrogene expression and amino acid release. MDKO mice were resistant to injected insulin, and their isolated skeletal muscles showed decreased insulin-stimulated glucose uptake. Glucose utilization in MDKO mice and isolated skeletal muscles was shifted from oxidation to lactate production, accompanied by an elevated AMP/ATP ratio that increased AMP-activated protein kinase (AMPK)→acetyl coenzyme A carboxylase (ACC) phosphorylation and fatty acid oxidation. Thus, insulin-like signaling via Irs1/2 is essential to terminate skeletal muscle catabolic/fasting pathways in the presence of adequate nutrition.     

Insulin-like growth factors, IGF-1, IGF-2 and somatomedin C trigger cell proliferation in mammalian epithelial cells cultured in a serum-free medium

A single insulin-like growth factor which constitutes part of a defined serum-free medium is sufficient to stimulate DNA synthesis and mitosis in mammalian lens epithelial cells. Rabbit lenses were cultured in KEI-4, a medium which mimics rabbit aqueous humor, or in KEI-4 containing insulin growth factor I (IGF I), insulin growth factor II (IGF II) or somatomedin C. The magnitude of DNA synthesis and mitosis was evaluated on whole mount preparations of the epithelium at various times of culture. IGF I and II, the most highly purified of the insulin-like growth factors, and somatomedin C were equipotent lens mitogens, were active at the ng level, were more mitogenic toward lens epithelial cells than insulin, and initiated cell proliferation throughout the normally amitotic central region of the lens epithelium. The time course of the mitotic response elicited by the insulin-like growth factors was identical to that noted in lenses cultured in medium supplemented with serum or insulin. The present results, coupled with those of other investigators, suggest that insulin-like factors may regulate cell division in the mammalian lens in vivo.     

Differential regulation of glucose transporter activity and expression in red and white skeletal muscle.

Insulin-stimulated glucose transport activity and GLUT4 glucose transporter protein expression in rat soleus, red-enriched, and white-enriched skeletal muscle were examined in streptozotocin (STZ)-induced insulin-deficient diabetes. Six days of STZ-diabetes resulted in a nearly complete inhibition of insulin-stimulated glucose transport activity in perfused soleus, red, and white muscle which recovered following insulin therapy. A specific decrease in the GLUT4 glucose transporter protein was observed in soleus (3-fold) and red (2-fold) muscle which also recovered to control values with insulin therapy. Similarly, cardiac muscle displayed a marked STZ-induced decrease in GLUT4 protein that was normalized by insulin therapy. White muscle displayed a small but statistically significant decrease in GLUT4 protein (23%), but this could not account for the marked inhibition of insulin-stimulated glucose transport activity observed in this tissue. In addition, GLUT4 mRNA was found to decrease in red muscle (2-fold) with no significant alteration in white muscle. The effect of STZ-induced diabetes was time-dependent with maximal inhibition of insulin-stimulated glucose transport activity at 24 h in both red and white skeletal muscle and half-maximal inhibition at approximately 8 h. In contrast, GLUT4 protein in red and white muscle remained unchanged until 4 and 7 days following STZ treatment, respectively. These data demonstrate that red skeletal muscle displays a more rapid hormonal/metabolic-dependent regulation of GLUT4 glucose transporter protein and mRNA expression than white skeletal muscle. In addition, the inhibition of insulin-stimulated glucose transport activity in both red and white muscle precedes the decrease in GLUT4 protein and mRNA levels. Thus, STZ treatment initially results in a rapid uncoupling of the insulin-mediated signaling of glucose transport activity which is independent of GLUT4 protein and mRNA levels.     

Role of tumor suppressor PTEN in tumor necrosis factor alpha-induced inhibition of insulin signaling in murine skeletal muscle C2C12 cells.

In an attempt to clarify the role of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in muscle insulin resistance, we investigated the effect of PTEN on phosphoinositide 3 (PI3)-kinase/Akt related insulin signaling pathway in skeletal muscle-like C2C12 cells damaged by tumor necrosis factor-alpha (TNFalpha). C2C12 cells cultured with TNFalpha (10 ng/ml) for 1 h displayed a marked decrease of insulin-stimulated 2-[14C]-deoxy-D-glucose (2-DG) uptake in parallel with an elevation of PTEN mRNA and protein levels. However, pretreatment of PTEN antisense oligonucleotide (AS) (1 micromol/l for 3 days) for specific inhibition of PTEN expression in C2C12 cells abolished the TNFalpha-induced changes in 2-DG uptake. Similar pretreatment with PTEN AS, but not with sense oligonucleotide (1 micromol/l for 3 days), eliminated the ability of TNFalpha to impair insulin-stimulated signals including p85 regulatory subunit of PI3-kinase expression and the degree of Akt serine phosphorylation as well as protein expression in glucose transporter subtype 4. Data taken from cultured C2C12 cells emphasize the negative regulatory of muscle PI3-kinase/Akt signaling pathways as the major substrate of PTEN but also support the concept that PTEN contributes to the development of insulin resistance in skeletal muscle.     

High-fat diet feeding impairs both the expression and activity of AMPKa in rats' skeletal muscle

OBJECTIVE: To investigate the effects of high-fat feeding on the expression and activity of AMPK in rats' skeletal muscle. METHODS: Total 40 male Wistar rats were randomly divided into three groups and received either a rat maintenance diet (Control group) or an isocaloric rich-fat diet (HF group and MET group) for five months. Metformin was administered orally with the daily dose of 300mg in MET group during the last month of high-fat feeding. Hyperinsulinemic-euglycemic clamp study was performed to estimate whole-body insulin sensitivity. The ability of insulin-stimulated glucose uptake in isolated skeletal muscle was detected just before execution. mRNA levels of AMPKa1, AMPKa2, and Glut4 of rats' skeletal muscle were determined using real-time PCR. Protein contents of AMPKa, P-AMPKa, P-ACC, and Glut4 in rats' skeletal muscle were measured using Western blot. RESULTS: (1) Hyperinsulinemic-euglycemic clamp study revealed a significantly impaired insulin action at the whole-body level after high-fat feeding (p<0.01). Also, both basal and insulin-stimulated glucose uptake in isolated skeletal muscle decreased after high-fat feeding (p<0.05), indicating onset of high-fat induced insulin resistance. (2) Five months of high-fat treatment induced a significant decrease of AMPKa protein contents and AMPKa2 mRNA levels in rats' skeletal muscles (p<0.05), while it did not alter AMPKa1 mRNA levels. Protein levels of P-AMPKa also decreased after high-fat feeding (p<0.01). These data suggest that high-fat exposure might impair AMPKa expression and activities. (3) P-ACC protein contents, mRNA and protein levels of Glut4 in rats' skeletal muscles also decreased after high-fat treatment (p<0.05). (4) Compared with HF group, although no significant alternations of AMPKa expression in rats' skeletal muscles were detected, P-AMPKa levels revealed a 162% increase after metformin treatment (p<0.05), demonstrating the AMPK-activating effect of metformin. Accompanied with activation of AMPKa, rats in MET group exhibited significantly elevated P-ACC contents, Glut4 mRNA and protein levels, and an obviously enhanced insulin sensitivity at both whole-body and skeletal muscle levels (p<0.05). CONCLUSIONS: High-fat feeding impaired both the expression and activities of AMPKa, while activating AMPKa by metformin obviously ameliorated high-fat induced insulin resistance, thus indicating a possible role of AMPKa in lipotoxicity.     

Epidermal growth factor and transforming growth factor alpha mimic the effects of insulin in human fat cells and augment downstream signaling in insulin resistance

The ability of the growth factors epidermal growth factor (EGF), transforming growth factor alpha, and platelet-derived growth factor to exert insulin-like effects on glucose transport and lipolysis were examined in human and rat fat cells. No effects were found in rat fat cells, whereas EGF (EC(50) for glucose transport approximately 0.02 nm) and transforming growth factor alpha (EC(50) approximately 0.2 nm), but not platelet-derived growth factor, mimicked the effects of insulin (EC(50) approximately 0.2 nm) on both pathways. EGF receptors, but not EGF, were abundantly expressed in human fat cells as well as in human skeletal muscle. EGF increased the tyrosine phosphorylation of several proteins (the EGF receptor, insulin receptor substrate (IRS)-1, IRS-2, and Grb2-associated binder 1), whereas Shc and Gab2 were only weakly and inconsistently phosphorylated. p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), was also found to associate with all of these docking molecules, showing that EGF activated PI 3-kinase pools that were additional to those of insulin. EGF and/or insulin increased protein kinase B/Akt serine phosphorylation to a similar extent, whereas mitogen-activated protein kinase phosphorylation was more pronounced for EGF than for insulin. The impaired insulin-stimulated downstream signaling, measured as protein kinase B/Akt serine phosphorylation, in insulin-resistant cells (Type 2 diabetes) was improved by the addition of EGF. Thus, EGF receptors, but not EGF, are abundantly expressed in human fat cells and skeletal muscle. EGF mimics the effects of insulin on both the metabolic and mitogenic pathways but utilize in part different signaling pathways. Both insulin and EGF increase the tyrosine phosphorylation and activation of IRS-1 and IRS-2, whereas EGF is also capable of activating additional PI 3-kinase pools and, thus, can augment the downstream signaling of insulin in insulin-resistant states like Type 2 diabetes.     

The Effects of Propionate and Valerate on Insulin Responsiveness for Glucose Uptake in 3T3-L1 Adipocytes and C2C12 Myotubes via G Protein-Coupled Receptor 41

Since insulin resistance can lead to hyperglycemia, improving glucose uptake into target tissues is critical for regulating blood glucose levels. Among the free fatty acid receptor (FFAR) family of G protein-coupled receptors, GPR41 is known to be the Gα_i/o-coupled receptor for short-chain fatty acids (SCFAs) such as propionic acid (C3) and valeric acid (C5). This study aimed to investigate the role of GPR41 in modulating basal and insulin-stimulated glucose uptake in insulin-sensitive cells including adipocytes and skeletal muscle cells. Expression of GPR41 mRNA and protein was increased with maximal expression at differentiation day 8 for 3T3-L1 adipocytes and day 6 for C2C12 myotubes. GPR41 protein was also expressed in adipose tissues and skeletal muscle. After analyzing dose-response relationship, 300 µM propionic acid or 500 µM valeric acid for 30 min incubation was used for the measurement of glucose uptake. Both propionic acid and valeric acid increased insulin-stimulated glucose uptake in 3T3-L1 adipocyte, which did not occur in cells transfected with siRNA for GPR41 (siGPR41). In C2C12 myotubes, these SCFAs increased basal glucose uptake, but did not potentiate insulin-stimulated glucose uptake, and siGPR41 treatment reduced valerate-stimulated basal glucose uptake. Therefore, these findings indicate that GPR41 plays a role in insulin responsiveness enhanced by both propionic and valeric acids on glucose uptake in 3T3-L1 adipocytes and C2C12 myotubes, and in valerate-induced increase in basal glucose uptake in C2C12 myotubes.