Lysophosphatidylcholine Activates Adipocyte Glucose Uptake and Lowers Blood Glucose Levels in Murine Models of Diabetes

Abstract

Glucose homeostasis is maintained by the orchestration of peripheral glucose utilization and hepatic glucose production, mainly by insulin. In this study, we found by utilizing a combined parallel chromatography mass profiling approach that lysophosphatidylcholine (LPC) regulates glucose levels. LPC was found to stimulate glucose uptake in 3T3-L1 adipocytes dose- and time-dependently, and this activity was found to be sensitive to variations in acyl chain lengths and to polar head group types in LPC. Treatment with LPC resulted in a significant increase in the level of GLUT4 at the plasma membranes of 3T3-L1 adipocytes. Moreover, LPC did not affect IRS-1 and AKT2 phosphorylations, and LPC-induced glucose uptake was not influenced by pretreatment with the PI 3-kinase inhibitor LY294002. However, glucose uptake stimulation by LPC was abrogated both by rottlerin (a protein kinase Cδ inhibitor) and by the adenoviral expression of dominant negative protein kinase Cδ. In line with its determined cellular functions, LPC was found to lower blood glucose levels in normal mice. Furthermore, LPC improved blood glucose levels in mouse models of type 1 and 2 diabetes. These results suggest that an understanding of the mode of action of LPC may provide a new perspective of glucose homeostasis. Glucose homeostasis is maintained by the orchestration of peripheral glucose utilization and hepatic glucose production, mainly by insulin. In this study, we found by utilizing a combined parallel chromatography mass profiling approach that lysophosphatidylcholine (LPC) regulates glucose levels. LPC was found to stimulate glucose uptake in 3T3-L1 adipocytes dose- and time-dependently, and this activity was found to be sensitive to variations in acyl chain lengths and to polar head group types in LPC. Treatment with LPC resulted in a significant increase in the level of GLUT4 at the plasma membranes of 3T3-L1 adipocytes. Moreover, LPC did not affect IRS-1 and AKT2 phosphorylations, and LPC-induced glucose uptake was not influenced by pretreatment with the PI 3-kinase inhibitor LY294002. However, glucose uptake stimulation by LPC was abrogated both by rottlerin (a protein kinase Cδ inhibitor) and by the adenoviral expression of dominant negative protein kinase Cδ. In line with its determined cellular functions, LPC was found to lower blood glucose levels in normal mice. Furthermore, LPC improved blood glucose levels in mouse models of type 1 and 2 diabetes. These results suggest that an understanding of the mode of action of LPC may provide a new perspective of glucose homeostasis. IntroductionGlucose is the most important metabolic fuel, and glucose homeostasis is maintained predominantly by insulin by balancing peripheral glucose uptake and hepatic glucose production (1.Saltiel A.R. Kahn C.R. Nature. 2001; 414: 799-806Crossref PubMed Scopus (3849) Google Scholar, 2.Chiasson J.L. Rabasa-Lhoret R. Diabetes. 2004; 53: fp>S34-S38Crossref Scopus (131) Google Scholar). However, if whole body glucose homeostasis is disrupted, hyperglycemia and various physiopathologies associated with metabolic disturbances may occur. The removal of excess glucose from the circulation involves the stimulation of glucose transport into metabolic tissues, and it has become clear that glucose intolerance in type 2 diabetes is manifested by defects in glucose transport into these metabolic tissues (3.Moller D.E. Nature. 2001; 414: 821-827Crossref PubMed Scopus (881) Google Scholar). Moreover, for many years, adipose tissue was believed to play key roles in glucose homeostasis (4.Hespel P. Vergauwen L. Vandenberghe K. Richter E.A. Diabetes. 1996; 45: S99-S104Crossref PubMed Google Scholar).In addition to insulin, various hormones and physiological conditions are capable of stimulating glucose uptake (5.Elmendorf J.S. J. Membr. Biol. 2002; 190: 167-174Crossref PubMed Scopus (36) Google Scholar, 6.Hutchinson D.S. Bengtsson T. Diabetes. 2006; 55: 682-690Crossref PubMed Scopus (65) Google Scholar, 7.Perrini S. Natalicchio A. Laviola L. Belsanti G. Montrone C. Cignarelli A. Minielli V. Grano M. De Pergola G. Giorgino R. Giorgino F. Diabetes. 2004; 53: 41-52Crossref PubMed Scopus (96) Google Scholar, 8.Kishi K. Muromoto N. Nakaya Y. Miyata I. Hagi A. Hayashi H. Ebina Y. Diabetes. 1998; 47: 550-558Crossref PubMed Scopus (148) Google Scholar, 9.Tanishita T. Shimizu Y. Minokoshi Y. Shimazu T. J. Biochem. 1997; 122: 90-95Crossref PubMed Scopus (37) Google Scholar, 10.Richter E.A. Derave W. Wojtaszewski J.F. J. Physiol. 2001; 535: 313-322Crossref PubMed Scopus (185) Google Scholar). For example, the activation of α1-adrenergic or endothelinA receptors results in enhanced glucose uptake rates independently of insulin levels, and physical exercise also plays an important role in the metabolism of glucose by skeletal muscle (10.Richter E.A. Derave W. Wojtaszewski J.F. J. Physiol. 2001; 535: 313-322Crossref PubMed Scopus (185) Google Scholar, 11.Kemppainen J. Fujimoto T. Kalliokoski K.K. Viljanen T. Nuutila P. Knuuti J. J. Physiol. 2002; 542: 403-412Crossref PubMed Scopus (100) Google Scholar, 12.Ryder J.W. Chibalin A.V. Zierath J.R. Acta Physiol. Scand. 2001; 171: 249-257Crossref PubMed Google Scholar, 13.Ishibashi K. Imamura T. Sharma P.M. Ugi S. Olefsky J.M. Endocrinology. 2000; 141: 4623-4628Crossref PubMed Scopus (28) Google Scholar). Furthermore, some of the signaling mechanisms that mediate these metabolic responses are similar to those utilized by insulin, whereas others are clearly distinct (5.Elmendorf J.S. J. Membr. Biol. 2002; 190: 167-174Crossref PubMed Scopus (36) Google Scholar). The above-mentioned processes illustrate that glucose regulation is not a simple event wholly attributable to insulin but rather a complex process that involves many glucose regulators. However, although the significance of insulin-independent glucose regulation has been recognized, no systematic search has been conducted to identify novel glucose regulators.Over the past few years, lysophospholipids have been increasingly recognized to be important cell signaling molecules (14.Xu Y. Biochim. Biophys. Acta. 2002; 1582: 81-88Crossref PubMed Scopus (196) Google Scholar), and one of these, lysophosphatidylcholine (LPC), 2The abbreviations used are: LPClysophosphatidylcholineDNdominant negativePKCprotein kinase CHPLChigh pressure liquid chromatographySTZstreptozotocinMS/MStandem mass spectrometryESIelectrospray ionizationDMEMDulbecco's modified Eagle's mediumAdVadenovirusPMplasma membraneSCXcation exchangeIRSinsulin receptor substratePIphosphoinositideLPAlysophosphatidic acid. which is produced during both physiological and pathological conditions, has been shown to be involved in many cellular processes (15.Xu Y. Fang X.J. Casey G. Mills G.B. Biochem. J. 1995; 309: 933-940Crossref PubMed Scopus (251) Google Scholar, 16.Xing F. Liu J. Mo Y. Liu Z. Qin Q. Wang J. Fan Z. Long Y. Liu N. Zhao K. Jiang Y. J. Cell Mol Med. 2008; 13: 1136-1148Crossref PubMed Scopus (19) Google Scholar, 17.Murugesan G. Sandhya Rani M.R. Gerber C.E. Mukhopadhyay C. Ransohoff R.M. Chisolm G.M. Kottke-Marchant K. J. Mol. Cell. Cardiol. 2003; 35: 1375-1384Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). For example, it is known that LPC is a major plasma lipid component that transports fatty acids and choline to tissues (18.Croset M. Brossard N. Polette A. Lagarde M. Biochem. J. 2000; 345: 61-67Crossref PubMed Scopus (211) Google Scholar). Moreover, although the mechanisms of LPC synthesis are not completely understood, the hydrolysis of phosphatidylcholine by plasma lecithin-cholesterol acyltransferase is a possible mechanism of the in vivo synthesis of LPC (14.Xu Y. Biochim. Biophys. Acta. 2002; 1582: 81-88Crossref PubMed Scopus (196) Google Scholar). LPC exhibits diverse biological functions and has been reported to be involved in cellular proliferation, tumor cell invasiveness, and inflammation (14.Xu Y. Biochim. Biophys. Acta. 2002; 1582: 81-88Crossref PubMed Scopus (196) Google Scholar, 19.Wang L. Radu C.G. Yang L.V. Bentolila L.A. Riedinger M. Witte O.N. Mol. Biol. Cell. 2005; 16: 2234-2247Crossref PubMed Scopus (69) Google Scholar). However, little is known of the direct involvement of LPC in the metabolism of glucose. To identify novel serum factors that stimulate glucose uptake in 3T3-L1 adipocytes, we developed a new analytical technique based on parallel HPLC, protease digestion, and mass spectrometry. Using this modality, we found that LPC activates glucose uptake and effectively lowers blood glucose levels in mouse models of Type 1 and 2 diabetes.DISCUSSIONThe present study provides evidence that LPC is a blood-derived factor involved in glucose homeostasis. 3T3-L1 adipocytes treated with LPC were found to uptake glucose rapidly via PI 3-kinase-independent PKCδ activation. Furthermore, when acute intravenous LPC was administered to mouse models of type 1 and 2 diabetes, the blood glucose levels were significantly lowered. Accordingly, we suggest that LPC represents a novel insulin-independent signal that can regulate blood glucose levels in normal and diseased mouse models. Furthermore, our findings suggest that an understanding of the role played by LPC in glucose regulation would enhance our understanding of glucose metabolism.The stimulation of glucose uptake by 3T3-L1 adipocytes and the blood glucose lowering effect of LPC in mice were found to be sensitive to variations in LPC acyl chain length, i.e. whereas the palmitoyl and myristoyl LPC derivatives (16:0 and 14:0, respectively) enhanced glucose uptake by 3T3-L1 adipocytes, stearoyl, oleoyl, and arachidoyl LPC (18:0, 18:1, and 20:0, respectively) were ineffective. However, when 3T3-L1 adipocytes were treated with several lysophospholipids that differed structurally only in terms of the polar head group of palmitoyl LPC, glucose uptake by adipocytes was not increased (this structural specificity was also confirmed by our mouse model of type 1 and 2 diabetes). These findings suggest that both acyl chain length and the choline head group of LPC are critical for stimulating glucose uptake by 3T3-L1 adipocytes and for lowering blood glucose levels in mice. Based on the rapid onset and structural specificity of LPC, we speculate that the biological activity of LPC is possibly due to binding between LPC and a specific cell surface receptor. Several lysophospholipids have been reported to bind to G protein-coupled receptor family members (26.Contos J.J. Ishii I. Chun J. Mol. Pharmacol. 2000; 58: 1188-1196Crossref PubMed Scopus (366) Google Scholar, 27.Sugo T. Tachimoto H. Chikatsu T. Murakami Y. Kikukawa Y. Sato S. Kikuchi K. Nagi T. Harada M. Ogi K. Ebisawa M. Mori M. Biochem. Biophys. Res. Commun. 2006; 341: 1078-1087Crossref PubMed Scopus (117) Google Scholar, 28.Bandoh K. Aoki J. Hosono H. Kobayashi S. Kobayashi T. Murakami-Murofushi K. Tsujimoto M. Arai H. Inoue K. J. Biol. Chem. 1999; 274: 27776-27785Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar, 29.An S. Bleu T. Hallmark O.G. Goetzl E.J. J. Biol. Chem. 1998; 273: 7906-7910Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar). However, recently it was reported that LPC activates these receptors via a mechanism that does not involve direct binding (19.Wang L. Radu C.G. Yang L.V. Bentolila L.A. Riedinger M. Witte O.N. Mol. Biol. Cell. 2005; 16: 2234-2247Crossref PubMed Scopus (69) Google Scholar), although earlier reports concluded that LPC binds directly to and activates G2A and GPR4. Thus, it remains an open question as to whether LPC stimulates glucose uptake by directly binding G2A and GPR4 or whether it does so indirectly via an as yet unknown mechanism.The involvement of conventional or atypical PKC activation in the promotion of glucose uptake by adipocytes and muscle cells is well established (30.Bandyopadhyay G. Standaert M.L. Zhao L. Yu B. Avignon A. Galloway L. Karnam P. Moscat J. Farese R.V. J. Biol. Chem. 1997; 272: 2551-2558Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar), but the activation of novel PKCs, especially of PKCδ, also controls glucose uptake. Stimulation of the translocation of GLUT4 to the plasma membrane and glucose uptake by insulin were found to be inhibited by rottlerin in rat skeletal muscle cells, and the overexpression of PKCδ induced by GLUT4 translocation to the plasma membrane was found to increase basal glucose uptake to levels attained by insulin (31.Braiman L. Alt A. Kuroki T. Ohba M. Bak A. Tennenbaum T. Sampson S.R. Mol. Endocrinol. 1999; 13: 2002-2012PubMed Google Scholar). In the present study, LPC-induced glucose uptake was found to be significantly blocked by rottlerin and by the overexpression of DN-PKCδ. In contrast, pretreatment with Gö6976 (a conventional PKC inhibitor) and the expression of DN-PKCζ were found to have no effect on LPC-induced glucose uptake. These findings suggest that only PKCδ is required for LPC-induced glucose transport in 3T3-L1 adipocytes. However, it has not been established whether PKCδ is downstream of LPC receptors like G2A or GPR4, and thus, additional work is needed to further elucidate the natures of the signal mechanisms that trigger specific PKCδs to participate in LPC-induced glucose transport.The induction of insulin secretion from pancreatic β-cells is a physiological function of LPC (32.Soga T. Ohishi T. Matsui T. Saito T. Matsumoto M. Takasaki J. Matsumoto S. Kamohara M. Hiyama H. Yoshida S. Momose K. Ueda Y. Matsushime H. Kobori M. Furuichi K. Biochem. Biophys. Res. Commun. 2005; 326: 744-751Crossref PubMed Scopus (282) Google Scholar). Recently, Suga et al. found that LPC induced insulin secretion by a pancreatic β-cell line (NIT-1) and by perfused rat pancreas under high glucose conditions (16.6 mm), but not under low glucose (2.8 mm) conditions (32.Soga T. Ohishi T. Matsui T. Saito T. Matsumoto M. Takasaki J. Matsumoto S. Kamohara M. Hiyama H. Yoshida S. Momose K. Ueda Y. Matsushime H. Kobori M. Furuichi K. Biochem. Biophys. Res. Commun. 2005; 326: 744-751Crossref PubMed Scopus (282) Google Scholar). In the present study, we measured serum insulin levels in fasted mice with blood glucose concentrations of 3–5 mm after LPC administration and found that LPC had no effect. On the other hand, we found that LPC had a blood glucose lowering effect in STZ-treated insulin-deficient mice. Thus, these results obtained in our study potentially support that LPC can directly affect glucose lowering in mice.It is well known that LPA can be produced abundantly from LPC by autotoxin, which has lysophospholipase D activity (33.van Meeteren L.A. Moolenaar W.H. Prog. Lipid Res. 2007; 46: 145-160Crossref PubMed Scopus (295) Google Scholar), and recently, it was reported that LPA has a glucose regulatory function (34.Yea K. Kim J. Lim S. Park H.S. Park K.S. Suh P.G. Ryu S.H. J. Mol. Med. 2008; 86: 211-220Crossref PubMed Scopus (37) Google Scholar). Furthermore, it has been reported that LPA can associate with four types of LPA receptors, enhance glucose uptake by 3T3-L1 adipocytes, and reduce blood glucose levels by interacting with LPA1 or LPA3 receptors (34.Yea K. Kim J. Lim S. Park H.S. Park K.S. Suh P.G. Ryu S.H. J. Mol. Med. 2008; 86: 211-220Crossref PubMed Scopus (37) Google Scholar, 35.Goetzl E.J. An S. FASEB J. 1998; 12: 1589-1598Crossref PubMed Scopus (490) Google Scholar). In addition, the authors showed that blood glucose reductions by LPA were significantly inhibited by Ki16425 (a selective LPA1 and LPA3 antagonist) (34.Yea K. Kim J. Lim S. Park H.S. Park K.S. Suh P.G. Ryu S.H. J. Mol. Med. 2008; 86: 211-220Crossref PubMed Scopus (37) Google Scholar). Therefore, we examined whether the blood glucose lowering effect of LPC is affected by Ki16425. However, although we found that the glucose lowering effect of LPA was blocked by Ki16425, it had no effect on the glucose reduction induced by LPC (Fig. 6d). Based on this result, we suggest that the LPC-induced glucose level reductions are not caused by LPA metabolized from LPC, but rather that these reductions are due to the direct effects of LPC.The physiologic concentrations of LPC in body fluids, such as blood and ascites, are substantial (5–180 μm) (14.Xu Y. Biochim. Biophys. Acta. 2002; 1582: 81-88Crossref PubMed Scopus (196) Google Scholar). The levels of LPC are elevated in many diseases related to inflammation (15.Xu Y. Fang X.J. Casey G. Mills G.B. Biochem. J. 1995; 309: 933-940Crossref PubMed Scopus (251) Google Scholar). More recently, elevated LPC levels (in particular, the ratios of palmitoyl-LPC to linoleoyl-LPC) have been reported in ovarian cancer and multiple myeloma. Nevertheless, the changes in LPC concentration by glucose or other metabolic stimuli have not been characterized. Therefore, additional work is required on the regulation of LPC secretion and to confirm the effect of LPC on glucose metabolism.The present study provides the first evidence that blood-borne LPC is intimately involved in glucose homeostasis. It is our hope that this finding generates interest in the physiological and pathological roles of LPC in glucose metabolism. Finally, we believe that an understanding of the mechanism responsible for the metabolic effects of LPC could lead to the development of a novel means of treating diabetes. IntroductionGlucose is the most important metabolic fuel, and glucose homeostasis is maintained predominantly by insulin by balancing peripheral glucose uptake and hepatic glucose production (1.Saltiel A.R. Kahn C.R. Nature. 2001; 414: 799-806Crossref PubMed Scopus (3849) Google Scholar, 2.Chiasson J.L. Rabasa-Lhoret R. Diabetes. 2004; 53: fp>S34-S38Crossref Scopus (131) Google Scholar). However, if whole body glucose homeostasis is disrupted, hyperglycemia and various physiopathologies associated with metabolic disturbances may occur. The removal of excess glucose from the circulation involves the stimulation of glucose transport into metabolic tissues, and it has become clear that glucose intolerance in type 2 diabetes is manifested by defects in glucose transport into these metabolic tissues (3.Moller D.E. Nature. 2001; 414: 821-827Crossref PubMed Scopus (881) Google Scholar). Moreover, for many years, adipose tissue was believed to play key roles in glucose homeostasis (4.Hespel P. Vergauwen L. Vandenberghe K. Richter E.A. Diabetes. 1996; 45: S99-S104Crossref PubMed Google Scholar).In addition to insulin, various hormones and physiological conditions are capable of stimulating glucose uptake (5.Elmendorf J.S. J. Membr. Biol. 2002; 190: 167-174Crossref PubMed Scopus (36) Google Scholar, 6.Hutchinson D.S. Bengtsson T. Diabetes. 2006; 55: 682-690Crossref PubMed Scopus (65) Google Scholar, 7.Perrini S. Natalicchio A. Laviola L. Belsanti G. Montrone C. Cignarelli A. Minielli V. Grano M. De Pergola G. Giorgino R. Giorgino F. Diabetes. 2004; 53: 41-52Crossref PubMed Scopus (96) Google Scholar, 8.Kishi K. Muromoto N. Nakaya Y. Miyata I. Hagi A. Hayashi H. Ebina Y. Diabetes. 1998; 47: 550-558Crossref PubMed Scopus (148) Google Scholar, 9.Tanishita T. Shimizu Y. Minokoshi Y. Shimazu T. J. Biochem. 1997; 122: 90-95Crossref PubMed Scopus (37) Google Scholar, 10.Richter E.A. Derave W. Wojtaszewski J.F. J. Physiol. 2001; 535: 313-322Crossref PubMed Scopus (185) Google Scholar). For example, the activation of α1-adrenergic or endothelinA receptors results in enhanced glucose uptake rates independently of insulin levels, and physical exercise also plays an important role in the metabolism of glucose by skeletal muscle (10.Richter E.A. Derave W. Wojtaszewski J.F. J. Physiol. 2001; 535: 313-322Crossref PubMed Scopus (185) Google Scholar, 11.Kemppainen J. Fujimoto T. Kalliokoski K.K. Viljanen T. Nuutila P. Knuuti J. J. Physiol. 2002; 542: 403-412Crossref PubMed Scopus (100) Google Scholar, 12.Ryder J.W. Chibalin A.V. Zierath J.R. Acta Physiol. Scand. 2001; 171: 249-257Crossref PubMed Google Scholar, 13.Ishibashi K. Imamura T. Sharma P.M. Ugi S. Olefsky J.M. Endocrinology. 2000; 141: 4623-4628Crossref PubMed Scopus (28) Google Scholar). Furthermore, some of the signaling mechanisms that mediate these metabolic responses are similar to those utilized by insulin, whereas others are clearly distinct (5.Elmendorf J.S. J. Membr. Biol. 2002; 190: 167-174Crossref PubMed Scopus (36) Google Scholar). The above-mentioned processes illustrate that glucose regulation is not a simple event wholly attributable to insulin but rather a complex process that involves many glucose regulators. However, although the significance of insulin-independent glucose regulation has been recognized, no systematic search has been conducted to identify novel glucose regulators.Over the past few years, lysophospholipids have been increasingly recognized to be important cell signaling molecules (14.Xu Y. Biochim. Biophys. Acta. 2002; 1582: 81-88Crossref PubMed Scopus (196) Google Scholar), and one of these, lysophosphatidylcholine (LPC), 2The abbreviations used are: LPClysophosphatidylcholineDNdominant negativePKCprotein kinase CHPLChigh pressure liquid chromatographySTZstreptozotocinMS/MStandem mass spectrometryESIelectrospray ionizationDMEMDulbecco's modified Eagle's mediumAdVadenovirusPMplasma membraneSCXcation exchangeIRSinsulin receptor substratePIphosphoinositideLPAlysophosphatidic acid. which is produced during both physiological and pathological conditions, has been shown to be involved in many cellular processes (15.Xu Y. Fang X.J. Casey G. Mills G.B. Biochem. J. 1995; 309: 933-940Crossref PubMed Scopus (251) Google Scholar, 16.Xing F. Liu J. Mo Y. Liu Z. Qin Q. Wang J. Fan Z. Long Y. Liu N. Zhao K. Jiang Y. J. Cell Mol Med. 2008; 13: 1136-1148Crossref PubMed Scopus (19) Google Scholar, 17.Murugesan G. Sandhya Rani M.R. Gerber C.E. Mukhopadhyay C. Ransohoff R.M. Chisolm G.M. Kottke-Marchant K. J. Mol. Cell. Cardiol. 2003; 35: 1375-1384Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). For example, it is known that LPC is a major plasma lipid component that transports fatty acids and choline to tissues (18.Croset M. Brossard N. Polette A. Lagarde M. Biochem. J. 2000; 345: 61-67Crossref PubMed Scopus (211) Google Scholar). Moreover, although the mechanisms of LPC synthesis are not completely understood, the hydrolysis of phosphatidylcholine by plasma lecithin-cholesterol acyltransferase is a possible mechanism of the in vivo synthesis of LPC (14.Xu Y. Biochim. Biophys. Acta. 2002; 1582: 81-88Crossref PubMed Scopus (196) Google Scholar). LPC exhibits diverse biological functions and has been reported to be involved in cellular proliferation, tumor cell invasiveness, and inflammation (14.Xu Y. Biochim. Biophys. Acta. 2002; 1582: 81-88Crossref PubMed Scopus (196) Google Scholar, 19.Wang L. Radu C.G. Yang L.V. Bentolila L.A. Riedinger M. Witte O.N. Mol. Biol. Cell. 2005; 16: 2234-2247Crossref PubMed Scopus (69) Google Scholar). However, little is known of the direct involvement of LPC in the metabolism of glucose. To identify novel serum factors that stimulate glucose uptake in 3T3-L1 adipocytes, we developed a new analytical technique based on parallel HPLC, protease digestion, and mass spectrometry. Using this modality, we found that LPC activates glucose uptake and effectively lowers blood glucose levels in mouse models of Type 1 and 2 diabetes.