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1.
Long-term dexamethasone (DEX) treatment is well known for its ability to increase insulin resistance in liver and adipose tissues leading to hyperinsulinemia. On the other hand, exercise enhances peripheral insulin sensitivity. However, it is not clear whether DEX and/or exercise affect beta-cell mass and function in diabetic rats, and whether their effects can be associated with the modulation of the insulin/IGF-I signaling cascade in pancreatic beta-cells. After an 8-week study, whole body glucose disposal rates in 90% pancreatectomized (Px) and sham-operated male rats decreased with a high dose treatment of DEX (0.1mg DEX/kg body weight/day)(HDEX) treatment, while disposal rates increased with exercise. First-phase insulin secretion was decreased and delayed by DEX via the impairment of the glucose-sensing mechanism in beta-cells, while exercise reversed the impairment of first-phase insulin secretion caused by DEX, suggesting ameliorated beta-cell functions. However, exercise and DEX did not alter second-phase insulin secretion except for the fact that HDEX decreased insulin secretion at 120 min during hyperglycemic clamp in Px rats. Unlike beta-cell functions, DEX and exercise exhibited increased pancreatic beta-cell mass in two different pathways. Only exercise, through increased proliferation and decreased apoptosis, increased beta-cell mass via hyperplasia, which resulted from an enhanced insulin/IGF-I signaling cascade by insulin receptor substrate 2 induction. By contrast, DEX expanded beta-cell mass via hypertrophy and neogenesis from precursor cells, rather than increasing proliferation and decreasing apoptosis. In conclusion, the improvement of beta-cell function and survival via the activation of an insulin/IGF-I signaling cascade due to exercise has a crucial role in preventing the development and progression of type 2 diabetes.  相似文献   

2.
Recent studies have revealed a surprising plasticity of pancreatic beta-cell mass. beta-cell mass is now recognized to increase and decrease in response to physiological demand, for example during pregnancy and in insulin-resistant states. Moreover, we and others have shown that mice recover spontaneously from diabetes induced by killing of 70-80% of beta-cells, by beta-cell regeneration. The major cellular source for new beta-cells following specific ablation, as well as during normal homeostatic maintenance of adult beta-cells, is proliferation of differentiated beta-cells. More recently, it was shown that one form of severe pancreatic injury, ligation of the main pancreatic duct, activates a population of embryonic-type endocrine progenitor cells, which can differentiate into new beta-cells. The molecular triggers for enhanced beta-cell proliferation during recovery from diabetes and for activation of embryonic-type endocrine progenitors remain unknown and represent key challenges for future research. Taken together, recent data suggest that regenerative therapy for diabetes may be a realistic goal.  相似文献   

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Diabetes is one of the fastest growing diseases worldwide, with an immense economic and health burden attached. It is now well accepted that a deficiency of functional insulin-producing pancreatic beta-cells is the main cause for all forms of diabetes. Several approaches are being taken to increase functional beta-cell mass. These include differentiation of new beta-cells from stem cells or progenitor cells, transdifferentiation of beta-cells from other mature cell types, as well as finding ways to enhance the function, proliferation, survival, and regeneration of preexisting beta-cells. This article enumerates on the role of parathyroid hormone-related protein (PTHrP) and its mode of action on pancreatic beta-cell function, proliferation, and survival in rodents as well as in human beta-cells. A further understanding of the mechanism of action of PTHrP and its role in the normal physiology and pathophysiology of the beta-cell will be important for its potential use in future as a therapeutic treatment for diabetes.  相似文献   

6.
Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L-cells in response to nutrients. GLP-1 lowers blood glucose levels by stimulating insulin secretion from pancreatic beta-cells in a glucose-dependent manner. In addition, GLP-1 slows gastric emptying, suppresses appetite, reduces plasma glucagon, and stimulates glucose disposal, which are beneficial for glucose homeostasis. Therefore, incretin-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase IV, an enzyme which inactivates GLP-1, have been developed for treatment of diabetes. This review outlines our knowledge of the actions of GLP-1 on insulin secretion and biosynthesis, beta-cell proliferation and regeneration, and protection against beta-cell damage, as well as the involvement of recently discovered signaling pathways of GLP-1 action, mainly focusing on pancreatic beta-cells.  相似文献   

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Type 1 and type 2 diabetes both result from inadequate production of insulin by the beta-cells of the pancreatic islet. Accordingly, strategies that lead to increased pancreatic beta-cell mass, as well as retained or enhanced function of islets, would be desirable for the treatment of diabetes. Although pancreatic beta-cells have long been viewed as terminally differentiated and irreversibly arrested, evidence now indicates that beta-cells can and do replicate, that this replication can be enhanced by a variety of maneuvers, and that beta-cell replication plays a quantitatively significant role in maintaining pancreatic beta-cell mass and function. Because beta-cells have been viewed as being unable to proliferate, the science of beta-cell replication is undeveloped. In the past several years, however, this has begun to change at a rapid pace, and many laboratories are now focused on elucidating the molecular details of the control of cell cycle in the beta-cell. In this review, we review the molecular details of cell cycle control as they relate to the pancreatic beta-cell. Our hope is that this review can serve as a common basis and also a roadmap for those interested in developing novel strategies for enhancing beta-cell replication and improving insulin production in animal models as well as in human pancreatic beta-cells.  相似文献   

9.
胰岛β细胞凋亡的分子机制   总被引:2,自引:0,他引:2  
胰岛β细胞凋亡在糖尿病的发病中扮演重要角色,1、2型糖尿病β细胞凋亡的分子机制有所不同。在1型糖尿病中,胰岛β细胞主要通过死亡受体介导的信号转导途径及颗粒酶B途径发生凋亡,而在2型糖尿病中,线粒体途径是胰岛β细胞凋亡的主要信号转导途径。多种细胞因子通过激活核转录因子调节相应基因表达,进而调控胰岛β细胞的凋亡。  相似文献   

10.
自身免疫性糖尿病是由抗原特异性T淋巴细胞对胰岛β细胞的选择性破坏,凋亡是β细胞破坏的基本过程。凋亡的β细胞所产生的自身抗原通过树突状细胞递呈给幼稚的T淋巴细胞使之活化、进入循环、激发胰岛炎,并通过细胞毒性T细胞再次诱导β细胞凋亡,由此形成恶性循环,导致β细胞强烈而特异性的破坏。环孢菌素A通过对钙调磷酸酶的特异性抑制,下调T淋巴细胞某些早期基因的转录,抑制其活化与增殖,打断β细胞凋亡-T淋巴细胞激活-β细胞凋亡链;环孢菌素A还可能通过阻断钙调磷酸酶介导的线粒体膜通透性转运孔的开放,直接抑制胰岛β细胞凋亡。  相似文献   

11.
In previous studies we demonstrated that insulin-like growth factor I (IGF-I) induces pituitary vasoactive intestinal peptide (VIP) gene expression and secretion, and that IGF-I-induced prolactin (PRL) release is mediated by VIP. In this study, we investigate the mitotropic action of IGF-I and VIP on pituitary lactotropes, and their possible interplay in this effect. Cultured male rat pituitary cells were treated with rhIGF-I (10(-7)M) and/or VIP (10(-7)M) for 48 h. 5-Bromo-2'-deoxyuridine (BrdU) (10 microM) was added for labeling proliferation of pituitary cells. BrdU-labeling indices indicative of the proliferation rate of lactotropes were determined by double-labeling immunofluorescence staining for PRL and BrdU. Treatment with either IGF-I or VIP increased BrdU-labeling indices of lactotropes, but there was no further increase upon combined incubation with both factors, suggesting an interaction between the signal transduction pathways of IGF-I and VIP. VIP antiserum partially suppressed IGF-I-induced BrdU-labeling indices of lactotropes. We also investigated the intracellular signal transduction pathways in the action of IGF-I and VIP on the proliferation of lactotropes. Treatment of pituitary cells with an inhibitor of the mitogen-activated protein kinase (MAPK) pathway completely abolished IGF-I-induced lactotrope proliferation, whereas it partially suppressed VIP-induced BrdU-labeling indices. The protein kinase A (PKA) inhibitor, which abolished the mitogenic action of VIP, markedly suppressed IGF-I-induced lactotrope proliferation. These results indicate that both IGF-I and VIP stimulate lactotrope proliferation, and that IGF-I-induced lactotrope proliferation is partially mediated by VIP produced locally. Also, this study suggests that interactions between MAPK and cyclic adenosine 3',5'-monophosphate-PKA signaling pathways are implicated in the lactotrope proliferation induced by IGF-I and VIP.  相似文献   

12.
In type 2 diabetes, there is a defect in the regulation of functional beta-cell mass to overcome high-fat (HF) diet-induced insulin resistance. Many signals and pathways have been implicated in beta-cell function, proliferation and apoptosis. The co-ordinated regulation of functional beta-cell mass by insulin signalling and glucose metabolism under HF diet-induced insulin-resistant conditions is discussed in this article. Insulin receptor substrate (IRS)-2 is one of the two major substrates for the insulin signalling. Interestingly, IRS-2 is involved in the regulation of beta-cell proliferation, as has been demonstrated using knockout mice models. On the other hand, in an animal model for human type 2 diabetes with impaired insulin secretion because of insufficiency of glucose metabolism, decreased beta-cell proliferation was observed in mice with beta-cell-specific glucokinase haploinsufficiency (Gck(+/) (-)) fed a HF diet without upregulation of IRS-2 in beta-cells, which was reversed by overexpression of IRS-2 in beta-cells. As to the mechanism underlying the upregulation of IRS-2 in beta-cells, glucose metabolism plays an important role independently of insulin, and phosphorylation of cAMP response element-binding protein triggered by calcium-dependent signalling is the critical pathway. Downstream from insulin signalling via IRS-2 in beta-cells, a reduction in FoxO1 nuclear exclusion contributes to the insufficient proliferative response of beta-cells to insulin resistance. These findings suggest that IRS-2 is critical for beta-cell hyperplasia in response to HF diet-induced insulin resistance.  相似文献   

13.
Type 1 diabetes (T1D) is a devastating disease precipitated by an autoimmune response directed at the insulin-producing beta-cells of the pancreas for which no cure exists. Stem cell-derived beta-cells show great promise for a cure as they have the potential to supply unlimited numbers of cells that could be derived from a patient''s own cells, thus eliminating the need for immunosuppression. Current in vitro protocols for the differentiation of stem cell-derived beta-cells can successfully generate pancreatic endoderm cells. In diabetic rodents, such cells can differentiate further along the beta-cell lineage until they are eventually capable of restoring normoglycemia. While these observations demonstrate that stem cell-derived pancreatic endoderm has the potential to differentiate into mature, glucose-responsive beta-cells, the signals that direct differentiation and maturation from pancreatic endoderm onwards remain poorly understood. In this review, we analyze the sequence of events that culminates in the formation of beta-cells during embryonic development. and summarize how current protocols to generate beta-cells have sought to capitalize on this ontogenic template. We place particular emphasis on the current challenges and opportunities which occur in the later stages of beta-cell differentiation and maturation of transplantable stem cell-derived beta-cells. Another focus is on the question how the use of recently identified maturation markers such as urocortin 3 can be instrumental in guiding these efforts.  相似文献   

14.
We have previously shown that fetuses from protein-caloric undernourished pregnant rats (35% of control diet during the last week of pregnancy) at 21.5 d post coitum exhibit increased beta-cell mass. This alteration is correlated with increased insulinemia and total pancreatic insulin content, a pattern similar to that reported in infants of mild diabetic mothers. In this work, we investigated in undernourished fetuses: 1) whether availability of growth factors such as insulin, GH, and IGFs and their binding proteins (IGFBPs) could be implicated in this alteration, and 2) the beta-cell mitogenic response to IGFs in vitro. The results show that maternal undernutrition increases pancreatic IGF-I expression and islet IGF-I receptor content in undernourished fetuses, whereas hepatic IGF-I expression and serum IGF-I levels were decreased. No changes were observed in serum IGF-II, and its expression was diminished in undernourished pancreases and unchanged in the liver, compared with control fetuses. Serum levels and liver and pancreatic mRNA expression of IGFBP-1 were found to be normal in undernourished fetuses, whereas the serum concentration and abundance of IGFBP-2 mRNA in pancreas were increased. Finally, the beta-cell mitogenic response to IGFs in vitro was significantly increased in undernourished fetal islets, compared with controls. In conclusion, in undernourished fetuses the increased beta-cell mass can be related to the stimulation of replicative beta-cell response due to locally increased pancreatic IGF-I mRNA; this effect is perhaps potentiated or favored by the enhanced islet IGF-I receptor content and pancreatic IGFBP-2 gene expression.  相似文献   

15.
IGF-I regulates islet beta-cell growth, survival, and metabolism and protects against type 1 diabetes (T1D). However, the therapeutic efficacy of free IGF-I may be limited by its biological half-life in vivo. We investigated whether prolongation of its half-life as an IGF-I/IGF binding protein (IGFBP)-3 complex affords increased protection against T1D and whether this occurs by influencing T cell function and/or islet beta-cell growth and survival. Administration of IGF-I either alone or as an IGF-I/IGFBP-3 complex reduced the severity of insulitis and delayed the onset of T1D in nonobese diabetic mice, but IGF-I/IGFBP-3 was significantly more effective. Protection from T1D elicited by IGF-I/IGFBP-3 was mediated by up-regulated CCL4 and down-regulated CCL3 gene expression in pancreatic draining lymph nodes, activation of the phosphatidylinositol 3-kinase and Akt/protein kinase B signaling pathway of beta-cells, reduced beta-cell apoptosis, and stimulation of beta-cell replication. Reduced beta-cell apoptosis resulted from elevated Bcl-2 and Bcl-X(L) activity and diminished caspase-9 activity, indicating a novel role for a mitochondrial-dependent pathway of beta-cell death. Thus, IGF-I/IGFBP-3 affords more efficient protection from insulitis, beta-cell destruction, and T1D than IGF-I, and this complex may represent an efficacious therapeutic treatment for the prevention of T1D.  相似文献   

16.
Preservation of pancreatic beta-cells in patients with type 2 diabetes would be a substantial therapeutic improvement as the disease is associated with a progressive loss of insulin-producing beta-cells. In various preclinical studies glucagon-like peptide 1 (GLP-1) led to preservation of beta-cell mass by inducing beta-cell proliferation and neogenesis as well as inhibiting apoptosis. These results cannot readily be translated to the situation in humans and further clinical evidence is needed.  相似文献   

17.
Pancreatic beta-cell mitogenesis is increased by insulin-like growth factor I (IGF-I) in a glucose-dependent manner. In this study it was found that alternative beta-cell nutrient fuels to glucose, pyruvate, and glutamine/leucine independently induced and provided a platform for IGF-I to induce INS-1 cell DNA synthesis in the absence of serum. In contrast, long chain FFA (>/=C(12)) inhibited 15 mM glucose-induced [(3)H]thymidine incorporation (+/-10 nM IGF-I) by 95% or more within 24 h above 0.2 mM FFA complexed to 1% BSA (K(0.5) for palmitate/1% BSA = 65-85 microM for 24 h; t(0.5) for 0.2 mM palmitate/1% BSA = approximately 6 h). FFA-mediated inhibition of glucose/IGF-I-induced ss-cell DNA synthesis was reversible, and FFA oxidation did not appear to be required, nor did FFA interfere with glucose metabolism in INS-1 cells. An examination of mitogenic signal transduction pathways in INS-1 cells revealed that glucose/IGF-I induction of early signaling elements in SH2-containing protein (Shc)- and insulin receptor substrate-1/2-mediated pathways leading to downstream mitogen-activated protein kinase and phosphoinositol 3'-kinase activation, were unaffected by FFA. However, glucose-/IGF-I-induced activation of protein kinase B (PKB) was significantly inhibited, and protein kinase Czeta was chronically activated by FFA. It is possible that FFA-mediated inhibition of ss-cell mitogenesis contributes to the reduction of beta-cell mass and the subsequent failure to compensate for peripheral insulin resistance in vivo that is key to the pathogenesis of obesity-linked diabetes.  相似文献   

18.
We investigated the role of hepatocyte growth factor (HGF) in beta-cell growth and its complex intracellular signal transduction pathways. Cell proliferation was measured in the beta-cell line INS-1 using [3H]thymidine incorporation. Activation of mitogenic signaling proteins was assessed using co-immunoprecipitation, immunoblot analysis and specific protein activity inhibitors in proliferation assays. HGF (1 x 375 nM) increased INS-1 cell proliferation in the presence of 3-24 mM glucose up to 45-fold vs unstimulated controls. HGF exceeded the effect of glucose alone (2 x 2-fold at 3 mM glucose and 1 x 7-fold in the presence of 15 mM glucose). The HGF-induced INS-1 cell proliferation was further increased by addition of IGF-I or GH. Stimulation with HGF activated the JAK-2/STAT-5 pathway with a subsequent activation of phosphatidylinositol-3'-kinase (PI3'K). PI3'K activation was necessary for HGF- and glucose-stimulated INS-1 cell proliferation. The effect of PI3'K was mediated via 70 kDa S6 kinase and protein kinase B, which showed maximum activation in the presence of 3-6 mM glucose. Protein kinase C was essential for HGF-induced INS-1 cell proliferation. The HGF effect was also mediated at low glucose concentrations via insulin receptor substrate 4 (IRS-4) whereas other IRS proteins did not show any activation. High glucose concentrations also showed an increased IRS-4/PI3'K binding and therefore activation. In conclusion, beta-cell proliferation is mediated via complex interacting signal transduction pathways. HGF, in contrast to other growth factors, seems to be of importance particularly in the presence of low glucose concentrations and therefore takes a special role in this complex concert.  相似文献   

19.
Islet amyloid polypeptide and type 2 diabetes   总被引:9,自引:0,他引:9  
Type 2 diabetes is associated with progressive beta-cell failure manifest as a decline in insulin secretion and increasing hyperglycemia. A growing body of evidence suggests that beta-cell failure in type 2 diabetes correlates with the formation of pancreatic islet amyloid deposits, indicating that islet amyloid may have an important role in beta-cell loss in this disease. Islet amyloid polypeptide (IAPP; amylin), the major component of islet amyloid, is co-secreted with insulin from beta-cells. In type 2 diabetes, this peptide aggregates to form amyloid fibrils that are toxic to beta-cells. The mechanism(s) responsible for islet amyloid formation in type 2 diabetes is still unclear but it appears that an increase in the secretion of IAPP, per se, is not sufficient. Other factors, such as impairment in the processing of proIAPP, the IAPP precursor, have been proposed to contribute to the development of islet amyloid deposits. Inhibitors of islet amyloid fibril formation might prevent the progression to beta-cell failure in type 2 diabetes and should therefore be considered as a therapeutic approach to treat this disease.  相似文献   

20.
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