Suppression of hepatic glucose production by human neutrophil alpha-defensins through a signaling pathway distinct from insulin

In this study, we tested the hypothesis that human neutrophil alpha-defensins (HNPs) inhibit hepatic glucose production through a signaling pathway distinct from insulin. The effect of HNP-1 on fasting blood glucose levels and the expression of hepatic gluconeogenic genes was first examined. Using hyperinsulinemic-euglycemic clamps, we determined the effect of HNP-1 on endogenous glucose production, hepatic expression of key gluconeogenic genes and glucose uptake in skeletal muscle in Zucker diabetic fatty rats. In isolated primary hepatocytes, we studied the effect of HNP-1 and -2 on glucose production, expression of gluconeogenic genes, and phosphorylation of Akt, c-Src, and FoxO1. Our results show that HNP-1 reduced blood glucose levels of both normal mice and Zucker diabetic fatty rats predominantly through suppression of hepatic glucose production. HNPs inhibited glycogenolysis and gluconeogenesis in isolated hepatocytes. HNPs also suppressed expression of key gluconeogenic genes including phosphoenoylpyruvate carboxyl kinase and glucose-6-phosphatase. To investigate the mechanism, we found that HNPs stimulated phosphorylation of Akt and FoxO1 without activating IRS1. Nevertheless, HNPs activated c-Src. Blockade of c-Src activity with either a chemical inhibitor PP2 or an alternative inhibitor CSK prevented the inhibitory effect of HNPs on gluconeogenesis. Together, our results support the hypothesis that HNPs can suppress hepatic glucose production through an intracellular mechanism distinct from the classical insulin signaling pathway.     

1型糖尿病葡萄糖代谢与胰岛素信号传导途径异常导致大鼠海马Alzheimer样tau蛋白过度磷酸化修饰

Tau蛋白过度磷酸化是Alzheimer病(Alzheimer disease, AD)的一个重要病理特征.采用 I 型糖尿病大鼠模型,研究胰岛素信号传导途径及葡萄糖代谢失调对tau蛋白过度磷酸化的形成机制进行探讨.以同龄Wistar大鼠做对照（CTL）,胰腺大部分切除造低胰岛素组（PX）,STZ较大剂量一次性注射造1型糖尿病模型即低胰岛素高血糖组（T1DM）.葡萄糖氧化酶法检测血浆血糖,放免法检测血浆胰岛素,蛋白质印迹分析海马内总tau蛋白及tau蛋白上部分位点（Ser199、Thr212、Ser214、Ser396及Ser422）的磷酸化及神经细胞膜上葡萄糖转运子3（Glucose transport 3,GLUT3）水平.γ-32P-ATP和特异性底物肽检测海马内胰岛素信号传导系统中的关键酶糖原合成酶激酶-3β（Glycogen synthase kinase-3β, GSK-3β）活性.发现3组大鼠海马回总tau蛋白水平无显著差异,但以高血糖、低胰岛素血症为特征的T1DM组在tau蛋白Ser199、Thr212、Ser214、Ser396及Ser422位点上,呈现过度磷酸化状态,以低胰岛素血症为特征而血糖正常的PX组在位点Ser199、Thr212及Ser396上磷酸化程度比CTL组显著上升, 在位点Ser214及 Ser422上的磷酸化程度的改变不显著;T1DM及PX组大鼠海马 GSK-3β活性显著高于CTL组, 而GLUT3水平在T1DM和PX组均降低, 尤以T1DM组降低更显著.研究结果显示,胰岛素水平低下可能通过激活GSK-3β和下调细胞内葡萄糖代谢的双重作用引起脑内tau蛋白过度磷酸化.     

Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism

Glycogen synthase kinase 3 comprises two isoforms (GSK-3alpha and GSK-3beta) that are implicated in type II diabetes, neurodegeneration, and cancer. GSK-3 activity is elevated in human and rodent models of diabetes, and various GSK-3 inhibitors improve glucose tolerance and insulin sensitivity in rodent models of obesity and diabetes. Here, we report the generation of mice lacking GSK-3alpha. Unlike GSK-3beta mutants, which die before birth, GSK-3alpha knockout (GSK-3alpha KO) animals are viable but display enhanced glucose and insulin sensitivity accompanied by reduced fat mass. Fasted and glucose-stimulated hepatic glycogen content was enhanced in GSK-3alpha KO mice, whereas muscle glycogen was unaltered. Insulin-stimulated protein kinase B (PKB/Akt) and GSK-3beta phosphorylation was higher in GSK-3alpha KO livers compared to wild-type littermates, and IRS-1 expression was markedly increased. We conclude that GSK-3 isoforms exhibit tissue-specific physiological functions and that GSK-3alpha KO mice are insulin sensitive, reinforcing the potential of GSK-3 as a therapeutic target for type II diabetes.     

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P < 0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signaling pathway involved in glycogen synthesis were examined by Western blot analysis, with the only significant change observed being the level of phosphorylated (at Ser 9) glycogen synthase kinase-3β (GSK-3β) (P < 0.001). No differences in the protein levels for the insulin receptor β (IRβ), insulin receptor substrates (IRS1 and IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) or their phosphorylated forms were observed between control and resistin treated primary rat hepatocytes. In a mouse model with high liver-specific expression of resistin, fasting blood glucose levels and liver glycogen content changed. Fasting blood glucose levels were significantly higher (P < 0.001) in the model mice, compared to the control mice, while the glycogen content of the liver tissue was about 60% of that of the control mice (P < 0.05). The gluconeogenic response was not altered between the experimental and control mice. The level of phosphorylated GSK-3β in the liver tissue was also decreased (P < 0.05) in the model mice, consistent with the results from the primary rat hepatocytes. Our results suggest that resistin reduces the levels of GSK-3β phosphorylated at Ser 9 leading to impaired hepatic insulin action in primary rat hepatocytes and in a mouse model with high liver-specific expression of resistin.     

Identification of Akt-independent Regulation of Hepatic Lipogenesis by Mammalian Target of Rapamycin (mTOR) Complex 2

Mammalian target of rapamycin complex 2 (mTORC2) is a key activator of protein kinases that act downstream of insulin and growth factor signaling. Here we report that mice lacking the essential mTORC2 component rictor in liver (Lrictor(KO)) are unable to respond normally to insulin. In response to insulin, Lrictor(KO) mice failed to inhibit hepatic glucose output. Lrictor(KO) mice also fail to develop hepatic steatosis on a high fat diet and manifest half-normal serum cholesterol levels. This is accompanied by lower levels of expression of SREBP-1c and SREBP-2 and genes of fatty acid and cholesterol biosynthesis. Lrictor(KO) mice had defects in insulin-stimulated Akt Ser-473 and Thr-308 phosphorylation, leading to decreased phosphorylation of Akt substrates FoxO, GSK-3β, PRAS40, AS160, and Tsc2. Lrictor(KO) mice also manifest defects in insulin-activated mTORC1 activity, evidenced by decreased S6 kinase and Lipin1 phosphorylation. Glucose intolerance and insulin resistance of Lrictor(KO) mice could be fully rescued by hepatic expression of activated Akt2 or dominant negative FoxO1. However, in the absence of mTORC2, forced Akt2 activation was unable to drive hepatic lipogenesis. Thus, we have identified an Akt-independent relay from mTORC2 to hepatic lipogenesis that separates the effects of insulin on glucose and lipid metabolism.     

Zinc deficiency exacerbates diabetic down-regulation of Akt expression and function in the testis: essential roles of PTEN, PTP1B and TRB3

Since zinc (Zn) plays an important role in the spermatogenesis and Zn deficiency exacerbated diabetes-induced testicular apoptosis, the present study investigated the effect of Zn deficiency on diabetes-induced testicular Akt-mediated glucose metabolism changes and inflammation. Zn deficiency was induced by chronic treatment of normal and diabetic mice with the Zn chelator N,N,N',N', tetrakis (2-pyridylmethyl) ethylenediaminepentaethylene (TPEN). After diabetes onset induced by streptozotocin, both diabetic and age-matched control mice were given TPEN intraperitoneally for 4 months. Western blotting assay revealed that Akt-mediated glucose metabolism signaling was down-regulated in the diabetic testis and was further decreased in diabetic mice with Zn deficiency, reflected by reduced phosphorylation of both Akt and GSK-3β and increased phosphorylation of glycogen synthase along with a disarrangement of fatty acid metabolism (increased expression of PPAR-α and decreased adenosine-monophosphate-activated protein kinase phosphorylation). Testicular expressions of plasminogen activator inhibitor-1 and intracellular adhesion molecule-1 as inflammatory factors were increased in the TPEN or diabetes-alone group, but not additive in the group of diabetes with Zn deficiency. A mechanistic study showed that Akt negative regulators phosphatase and tensin homology deleted on chromosome 10 (PTEN), protein tyrosine phosphatases 1B and Tribbles 3 all increased in diabetic testis and further increased in the testis of diabetic mice with Zn deficiency. These studies suggest that Zn deficiency significantly exacerbated diabetic down-regulation of Akt expression and function, most likely by up-regulation of Akt negative regulators. Therefore, prevention of Zn deficiency for diabetic patients is important in order to avoid the exacerbation of diabetic inhibition of glucose metabolism in the testis.     

Hepatic morphological alterations,glycogen content and cytochrome P450 activities in rats treated chronically with N<Superscript>ω</Superscript>-nitro-L-arginine methyl ester (L-NAME)

Chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension mediated partly by enhanced angiotensin-I-converting enzyme (ACE) activity. We examined the influence of L-NAME on rat liver morphology, on hepatic glycogen, cholesterol, and triglyceride content, and on the activities of the cytochrome P450 isoforms CYP1A1/2, CYP2B1/2, CYP2C11, and CYP2E1. Male Wistar rats were treated with L-NAME (20 mg/rat per day via drinking water) for 2, 4, and 8 weeks, and their livers were then removed for analysis. Enzymatic induction was produced by treating rats with phenobarbital (to induce CYP2B1/2), beta-naphthoflavone (to induce CYP1A1/2), or pyrazole (to induce CYP2E1). L-NAME significantly elevated blood pressure; this was reversed by concomitant treatment with enalapril (ACE inhibitor) or losartan (angiotensin II AT(1) receptor antagonist). L-NAME caused vascular hypertrophy in hepatic arteries, with perivascular and interstitial fibrosis involving collagen deposition. Hepatic glycogen content also significantly increased. L-NAME did not affect fasting glucose levels but significantly reduced insulin levels and increased the insulin sensitivity of rats, based on an intraperitoneal glucose tolerance test. Immunoblotting experiments indicated enhanced phosphorylation of protein kinase B and of glycogen synthase kinase 3. All these changes were reversed by concomitant treatment with enalapril or losartan. L-NAME had no effect on hepatic cholesterol or triglyceride content or on the basal or drug-induced activities and protein expression of the cytochrome P450 isoforms. Thus, the chronic inhibition of NO biosynthesis produced hepatic morphological alterations and changes in glycogen metabolism mediated by the renin-angiotensin system. The increase in hepatic glycogen content probably resulted from enhanced glycogen synthase activity following the inhibition of glycogen synthase kinase 3 by phosphorylation.     

Ⅱ型糖尿病大鼠海马Alzheimer病样Tau蛋白过度磷酸化修饰及机制探讨

Tau蛋白过度磷酸化是Alzheimer病 (Alzheimer′s disease, AD) 的一个重要特征.本研究检测了Ⅱ型糖尿病大鼠海马tau蛋白磷酸化水平,对其形成机制进行探讨. 以同龄正常Wistar大鼠作为对照,高脂高蛋白高糖饮食加小剂量链脲佐菌素（streptozotocin,STZ）注射诱导造Ⅱ型糖尿病模型（T2DM组）.放免法检测血浆胰岛素;葡萄糖氧化酶法检测血浆葡萄糖;蛋白质印迹技术检测各组大鼠海马内总tau蛋白、tau蛋白上部分位点磷酸化、神经细胞膜上胰岛素受体及葡萄糖转运子3（glucose transport 3,GLUT3）水平;表面等离子共振技术（surface plasmon resonance, SPR）检测细胞膜上胰岛素受体与血浆胰岛素结合力;γ32-P标记的ATP和特异性底物肽检测海马内胰岛素信号传导系统中的关键酶糖原合酶激酶-3β（glycogen synthase kinase-3β, GSK-3β）活性.结果显示,T2DM组血浆血糖、血浆胰岛素及运用HOMA-IR公式计算的胰岛素抵抗指数显著高于对照组.蛋白质印迹结果显示两组大鼠海马回总tau蛋白水平无差异;T2DM组中tau蛋白在Ser199、Thr212、Ser214、Thr217、Ser396及Ser422位点上的磷酸化水平均显著高于对照组;T2DM组海马神经细胞膜上胰岛素受体水平及与胰岛素结合的功能均显著低于对照组;GSK-3β活性检测结果显示,T2DM组大鼠模型海马回中GSK-3β活性明显增高.研究结果表明,Ⅱ型糖尿病中由于胰岛素抵抗导致GSK-3β激活从而出现AD样tau蛋白的过度磷酸化,葡萄糖代谢紊乱也可能在tau蛋白的过度磷酸化起一定作用.     

Role of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscle

The serine/threonine kinase Akt/PKB plays diverse roles in cells, and genetic studies have indicated distinct roles for the three Akt isoforms expressed in mammalian cells and tissues. Akt2 is a key signaling intermediate for insulin-stimulated glucose uptake and glycogen synthesis in skeletal muscle. Akt2 has also been shown to be activated by exercise and muscle contraction in both rodents and humans. In this study, we used Akt2 knockout mice to explore the role of Akt2 in exercise-stimulated glucose uptake and glycogen synthesis as well as intracellular signaling pathways that regulate glycogen metabolism in skeletal muscle. We found that Akt2 deficiency does not affect basal or exercise-stimulated glucose uptake or intracellular glycogen content in the soleus muscle. In addition, lack of Akt2 did not result in alterations in basal Akt Thr(308) or basal and contraction-stimulated glycogen synthase kinase-3beta (GSK-3beta) Ser(9) phosphorylation, glycogen synthase phosphorylation, or glycogen synthase activity. In contrast, in situ contraction failed to elicit normal increases in Akt T-loop Thr(308) phosphorylation and GSK-3alpha Ser(21) phosphorylation in tibialis anterior muscles from Akt2-deficient animals. Our data establish a key role for Akt2 in the regulation of GSK-3alpha Ser(21) phosphorylation with contraction and add genetic evidence to support the separation of the intracellular pathways regulated by insulin and exercise that converge on glucose uptake and glycogen synthesis in skeletal muscle.     

大脑胰岛素信号途径受损导致2型糖尿病时阿尔茨海默病发病风险增高

大脑胰岛素不仅可调节血糖,而且可改善记忆和认知,而大脑胰岛素缺乏常导致Alzheimer病（Alzheimer’s disease, AD）的发生. 本研究检测了正常及2型糖尿病（type 2 diabetes, T2D）大鼠外周及大脑胰岛素信号传导途径,以探讨T2D时由于大脑胰岛素异常导致AD发病的可能性.以同龄正常SD大鼠为对照（CTL组）,高糖、高脂、高蛋白饮食加链脲佐菌素（streptozotocin, STZ）腹腔注射建造T2D大鼠模型（T2D组）.葡萄糖氧化酶法检测血浆血糖,放免法检测脑脊液及血浆胰岛素,免疫印迹技术检测大脑海马tau蛋白上部分位点磷酸化水平,大脑及肝脏、肌肉组织胰岛素信号传导途径中磷脂酰肌醇3 激酶（phosphatidylinositol 3 kinase, PI3K）/ 蛋白激酶B（protein kinase B,Akt)、糖原合成激酶3β（glycogen synthase kinase 3β, GSK 3β）活性. 结果显示：和对照组相比,T2D大鼠血浆葡萄糖水平及胰岛素水平显著升高,脑脊液胰岛素水平显著降低,大脑海马组织tau蛋白上所检测位点均呈过度磷酸化改变,海马及外周组织（肝脏、肌肉）胰岛素信号传导途径PI3K/Akt活性均显著下降,GSK 3β活性升高. 研究结果表明：2型糖尿病大鼠大脑胰岛素缺乏及其信号传导途径下调可能是导致阿尔茨海默病发病的重要原因.     

Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity

Rictor is an essential component of mTOR (mammalian target of rapamycin) complex 2 (mTORC2), a kinase complex that phosphorylates Akt at Ser473 upon activation of phosphatidylinositol 3-kinase (PI-3 kinase). Since little is known about the role of either rictor or mTORC2 in PI-3 kinase-mediated physiological processes in adult animals, we generated muscle-specific rictor knockout mice. Muscle from male rictor knockout mice exhibited decreased insulin-stimulated glucose uptake, and the mice showed glucose intolerance. In muscle lacking rictor, the phosphorylation of Akt at Ser473 was reduced dramatically in response to insulin. Furthermore, insulin-stimulated phosphorylation of the Akt substrate AS160 at Thr642 was reduced in rictor knockout muscle, indicating a defect in insulin signaling to stimulate glucose transport. However, the phosphorylation of Akt at Thr308 was normal and sufficient to mediate the phosphorylation of glycogen synthase kinase 3 (GSK-3). Basal glycogen synthase activity in muscle lacking rictor was increased to that of insulin-stimulated controls. Consistent with this, we observed a decrease in basal levels of phosphorylated glycogen synthase at a GSK-3/protein phosphatase 1 (PP1)-regulated site in rictor knockout muscle. This change in glycogen synthase phosphorylation was associated with an increase in the catalytic activity of glycogen-associated PP1 but not increased GSK-3 inactivation. Thus, rictor in muscle tissue contributes to glucose homeostasis by positively regulating insulin-stimulated glucose uptake and negatively regulating basal glycogen synthase activity.     

Essential role of p38 MAPK for activation of skeletal muscle glucose transport by lithium

Lithium increases glucose transport and glycogen synthesis in insulin-sensitive cell lines and rat skeletal muscle, and has been used as a non-selective inhibitor of glycogen synthase kinase-3 (GSK-3). However, the molecular mechanisms underlying lithium action on glucose transport in mammalian skeletal muscle are unknown. Therefore, we examined the effects of lithium on glucose transport activity, glycogen synthesis, insulin signaling elements (insulin receptor (IR), Akt, and GSK-3beta), and the stress-activated p38 mitogen-activated protein kinase (p38 MAPK) in the absence or presence of insulin in isolated soleus muscle from lean Zucker rats. Lithium (10 mM LiCl) enhanced basal glucose transport by 62% (p < 0.05) and augmented net glycogen synthesis by 112% (p < 0.05). Whereas lithium did not affect basal IR tyrosine phosphorylation or Akt ser(473) phosphorylation, it did enhance (41%, p < 0.05) basal GSK-3beta ser(9) phosphorylation. Lithium further enhanced (p < 0.05) the stimulatory effects of insulin on glucose transport (43%), glycogen synthesis (44%), and GSK-3beta ser(9) phosphorylation (13%). Lithium increased (p < 0.05) p38 MAPK phosphorylation both in the absence (37%) and presence (41%) of insulin. Importantly, selective inhibition of p38 MAPK (using 10 microM A304000) completely prevented the basal activation of glucose transport by lithium, and also significantly reduced (52%, p < 0.05) the lithium-induced enhancement of insulin-stimulated glucose transport. Theses results demonstrate that lithium enhances basal and insulin-stimulated glucose transport activity and glycogen synthesis in insulin-sensitive rat skeletal muscle, and that these effects are associated with a significant enhancement of GSK-3beta phosphorylation. Importantly, we have documented an essential role of p38 MAPK phosphorylation in the action lithium on the glucose transport system in isolated mammalian skeletal muscle.     

Insulin and exercise decrease glycogen synthase kinase-3 activity by different mechanisms in rat skeletal muscle.

Glycogen synthase activity is increased in response to insulin and exercise in skeletal muscle. Part of the mechanism by which insulin stimulates glycogen synthesis may involve phosphorylation and activation of Akt, serine phosphorylation and deactivation of glycogen synthase kinase-3 (GSK-3), leading to dephosphorylation and activation of glycogen synthase. To study Akt and GSK-3 regulation in muscle, time course experiments on the effects of insulin injection and treadmill running exercise were performed in hindlimb skeletal muscle from male rats. Both insulin and exercise increased glycogen synthase activity (%I-form) by 2-3-fold over basal. Insulin stimulation significantly increased Akt phosphorylation and activity, whereas exercise had no effect. The time course of the insulin-stimulated increase in Akt was closely matched by GSK-3alpha Ser(21) phosphorylation and a 40-60% decrease in GSK-3alpha and GSK-3beta activity. Exercise also deactivated GSK-3alpha and beta activity by 40-60%. However, in contrast to the effects of insulin, there was no change in Ser(21) phosphorylation in response to exercise. Tyrosine dephosphorylation of GSK-3, another putative mechanism for GSK-3 deactivation, did not occur with insulin or exercise. These data suggest the following: 1) GSK-3 is constitutively active and tyrosine phosphorylated under basal conditions in skeletal muscle, 2) both exercise and insulin are effective regulators of GSK-3 activity in vivo, 3) the insulin-induced deactivation of GSK-3 occurs in response to increased Akt activity and GSK-3 serine phosphorylation, and 4) there is an Akt-independent mechanism for deactivation of GSK-3 in skeletal muscle.     

Activation of glycogen synthase in myocardium induced by intermittent hypoxia is much lower in fasted than in fed rats

Obstructive sleep apnea is characterized by intermittent obstruction of the upper airway, which leads to intermittent hypoxia. Myocardial glycogen is a major energy resource for heart during hypoxia. Previous studies have demonstrated that intermittent hypoxia rapidly degrades myocardial glycogen and activates glycogen synthase (GS). However, the underlying mechanisms remain undefined. Because sleep apnea/intermittent hypoxia usually happens at night, whether intermittent hypoxia leads to GS activation in the postabsorptive state is not known. In the present study, male adult rats were studied after either an overnight fast or ad libitum feeding with or without intermittent ventilatory arrest (3 90-s periods at 10-min intervals). Hearts were quickly excised and freeze-clamped. Intermittent hypoxia induced a significant decrease in myocardial glycogen content in fed rats and stimulated GS in both fasted and fed rats. However, the portion of GS in the active form increased by approximately 38% in fasted rats compared with a larger, approximately 130% increase in fed rats. The basal G-6-P content was comparable in fasted and fed animals and increased approximately threefold after hypoxia. The basal phosphorylation states of Akt and GSK-3beta and the activity of protein phosphatase 1 (PP1) were comparable between fasted and fed control rats. Hypoxia significantly increased Akt phosphorylation and PP1 activity only in fed rats. In contrast, hypoxia did not induce significant change in GSK-3beta phosphorylation in either fasted or fed rats. We conclude that hypoxia activates GS in fed rat myocardium through a combination of rapid glycogenolysis, elevated local G-6-P content, and increased PP1 activity, and fasting attenuates this action independent of local G-6-P content.     

In vivo and in vitro application of black soybean peptides in the amelioration of endoplasmic reticulum stress and improvement of insulin resistance

AimsHepatic endoplasmic reticulum (ER) stress plays a key role in the development of obesity-induced insulin resistance. This study evaluated the effects of peptides from black soybean (BSP) on ER stress and insulin signaling in vitro and in vivo.Main methodsUsing C2C12 myotubes or HepG2 cells, we evaluated the effects of BSP on the expression of proteins involved in insulin signaling and in the ER stress response in insulin-sensitive or insulin-resistant cells. BSP was given orally to db/db mice for 5 weeks to investigate its antidiabetic effects in vivo and the underlying mechanisms.Key findingsBSP increased GLUT4 translocation and glucose transport in myotubes and stimulated Akt-mediated glycogen synthase kinase-3β (GSK-3β) and Foxo1 phosphorylation in HepG2 cells. BSP significantly restored the suppression of insulin-mediated Akt phosphorylation in insulin-resistant cells. BSP significantly inhibited the activation of ER stress-responsive proteins by thapsigargin. BSP also significantly reduced blood glucose and improved glucose tolerance in db/db mice. The serum lipid profile (triglyceride and high-density lipoprotein concentrations) improved concomitantly with the BSP-induced downregulation of hepatic fatty acid synthase expression in db/db mice. Consistent with the results observed in HepG2 cells, BSP downregulated the elevated hepatic ER stress response in diabetic mice concomitantly with an increased expression of phospho-Foxo1.SignificanceA peptide mixture, BSP, showed beneficial effects through multiple mechanisms involving the suppression of hepatic ER stress and restoration of insulin resistance, suggesting that it has potential as an antidiabetic agent.