Hepatocyte Growth Factor Preserves Beta Cell Mass and Mitigates Hyperglycemia in Streptozotocin-induced Diabetic Mice

Abstract

Type I diabetes is an autoimmune disease that results in destructive depletion of the insulin-producing beta cells in the islets of Langerhans in pancreas. With the knowledge that hepatocyte growth factor (HGF) is a potent survival factor for a wide variety of cells, we hypothesized that supplementation of HGF may provide a novel strategy for protecting pancreatic beta cells from destructive death and for preserving insulin production. In this study, we demonstrate that expression of the exogenous HGF gene preserved insulin excretion and mitigated hyperglycemia of diabetic mice induced by streptozotocin. Blood glucose levels were significantly reduced in mice receiving a single intravenous injection of naked HGF gene at various time points after streptozotocin administration. Consistently, HGF concomitantly increased serum insulin levels in diabetic mice. Immunohistochemical staining revealed a marked preservation of insulin-producing beta cells by HGF in the pancreatic islets of the diabetic mice. This beneficial effect of HGF was apparently mediated by both protection of beta cells from death and promotion of their proliferation. Delivery of HGF gene in vivo induced prosurvival Akt kinase activation and Bcl-xL expression in the pancreatic islets of diabetic mice. These findings suggest that supplementation of HGF to prevent beta cells from destructive depletion and to promote their proliferation might be an effective strategy for ameliorating type I diabetes.Diabetes is a devastating illness with significant morbidity and mortality, and its incidence has increased steadily worldwide (1). Type I diabetes is an autoimmune disease that results in extensive destruction of the insulin-producing beta cells in the islets of Langerhans in pancreas. Current clinical therapy for type I diabetes is to replace insulin through multiple injections, or replace the destroyed beta cell mass via islet or whole pancreas transplantation (2-4). Strategies in development include the establishment of human cell lines that can produce, process, store, and release insulin (5); direct intra-pancreatic injection of adenoviral vector containing human insulin gene (6, 7); and the induction of endocrine differentiation of stem cells or/and beta cell precursors (8 -11). However, these approaches have their inherent limitations. For instance, injections at best only produce fluctuated, dysregulated levels of circulating insulin. Likewise, the shortage of human islets precludes the clinical use of islet transplantation on a large patient population. In addition, it remains a question whether the transplanted beta cells can survive for a long duration, in light of the continuous presence of the autoimmune triggers responsible for initial destruction of beta cells. In this context, we hypothesized that protecting pancreatic beta cells from destructive death may represent a new, novel strategy for preserving insulin production and for prevention and treatment of type I diabetes.Hepatocyte growth factor (HGF) 1 is a mesenchyme-derived, multifunct...

Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes

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Downregulation of protein kinase B/Akt-1 mediates INS-1 insulinoma cell apoptosis induced by dominant-negative suppression of hepatocyte nuclear factor-1alpha function

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Intravenous Administration of Hepatocyte Growth Factor Gene Ameliorates Diabetic Nephropathy in Mice

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