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Hepatocyte growth factor (HGF) is a mitogen required for β-cell replication during pregnancy. To determine whether HGF/c-Met signaling is required for β-cell regeneration, we characterized mice with pancreatic deletion of the HGF receptor, c-Met (PancMet KO mice), in two models of reduced β-cell mass and regeneration: multiple low-dose streptozotocin (MLDS) and partial pancreatectomy (Ppx). We also analyzed whether HGF administration could accelerate β-cell regeneration in wild-type (WT) mice after Ppxo Mouse islets obtained 7 days post-Ppx displayed significantly increased c-Met, suggesting a potential role for HGF/c-Met in β-cell proliferation in situations of reduced β-cell mass. Indeed, adult PancMet KO mice displayed markedly reduced β-cell replication compared with WT mice 7 days post-Ppx. Similarly, β-cell proliferation was decreased in PancMet KO mice in the MLDS mouse model. The decrease in β-cell proliferation post-Ppx correlated with a striking decrease in D-cyclin levels. Importantly, PancMet KO mice showed significantly diminished β-cell mass, decreased glucose tolerance, and impaired insulin secretion compared with WT mice 28 days post-Ppx. Conversely, HGF administration in WT Ppx mice further accelerated β-cell regeneration. These results indicate that HGF/c-Met signaling is critical for β-cell proliferation in situations of diminished β-cell mass and suggest that activation of this pathway can enhance β-cell regeneration. Diabetes 2014;63:216-223 | DOI: 10.2337/db13-0333, Deficiency of functional β-cells ultimately leads to the development of diabetes. A potential future therapeutic approach to treat diabetes is to induce β-cell regeneration, but this requires deciphering the molecular [...]

OBJECTIVE--PKC-θ activation is a key signaling event for growth factor-induced B-cell replication in vitro. However, the effect of direct PKC-θ activation in the β-cell in vivo is unknown. In this study, we examined the effects of PKC-θ activation in β-cell expansion and function in vivo in mice and the mechanisms associated with these effects. RESEARCH DESIGN AND METHODS--We characterized glucose homeostasis and β-cell phenotype of transgenic (TG) mice with constitutive activation of PKC-θ in the β-cell. We also analyzed the expression and regulation of signaling pathways, G1/S cell cycle molecules, and β-cell functional markers in TG and wild-type mouse islets. RESULTS--TG mice displayed increased plasma insulin, improved glucose tolerance, and enhanced insulin secretion with concomitant upregulation of islet insulin and glucokinase expression. In addition, TG mice displayed increased β-cell proliferation, size, and mass compared with wild-type littermates. The increase in β-cell proliferation was associated with upregulation of cyclins D1, D2, D3, and A and downregulation of p21. Phosphorylation of D-cyclins, known to initiate their rapid degradation, was reduced in TG mouse islets. Phosphorylation/inactivation of GSK-3β and phosphorylation/activation of mTOR, critical regulators of D-cyclin expression and β-cell proliferation, were enhanced in TG mouse islets, without changes in Akt phosphorylation status. Rapamycin treatment in vivo eliminated the increases in β-cell proliferation, size, and mass; the upregulation of cyclins Ds and A in TG mice; and the improvement in glucose tolerance--identifying mTOR as a novel downstream mediator of PKC-θ-induced β-cell replication and expansion in vivo. CONCLUSIONS--PKC-θ, through mTOR activation, modifies the expression pattern of β-cell cycle molecules leading to increased β-cell replication and mass with a concomitant enhancement in β-cell function. Approaches to enhance PKC-θ activity may be of value as a therapeutic strategy for the treatment of diabetes. Diabetes 60:2546-2559, 2011, Diabetes appears when β-cell mass is insufficient to maintain normal glucose homeostasis. Therefore, deciphering the molecular mechanisms that induce β-cell expansion can be of great value for therapeutic approaches aimed [...]