Growth hormone receptor regulates β cell hyperplasia and glucose-stimulated insulin secretion in obese mice

Wu, Yingjie; Liu, Chengyu; Sun, Hui; Vijayakumar, Archana; Giglou, Pejman Raeisi; Qiao, Ruifang; Oppenheimer, J.; Yakar, Shoshana; LeRoith, Derek

doi:10.1172/jci45027

Cited by 91 publications

(85 citation statements)

References 22 publications

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“…3B). These data concur with the reported GHR-dependent islet hyperplasia (24) and the compensatory hyperinsulinemia mechanism associated with GHdependent insulin resistance (25).…”

Section: Nod-tg Bgh Mice Have Normal Delayed Type Hypersensitivitysupporting

confidence: 92%

Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Evidence supports a relationship between the neuroendocrine and the immune systems. Data from mice that overexpress or are deficient in growth hormone (GH) indicate that GH stimulates T and B-cell proliferation and Ig synthesis, and enhances maturation of myeloid progenitor cells. The effect of GH on autoimmune pathologies has nonetheless been little studied. Using a murine model of type 1 diabetes, a T-cell-mediated autoimmune disease characterized by immune cell infiltration of pancreatic islets and destruction of insulin-producing β-cells, we observed that sustained GH expression reduced prodromal disease symptoms and eliminated progression to overt diabetes. The effect involves several GH-mediated mechanisms; GH altered the cytokine environment, triggered anti-inflammatory macrophage (M2) polarization, maintained activity of the suppressor T-cell population, and limited Th17 cell plasticity. In addition, GH reduced apoptosis and/or increased the proliferative rate of β-cells. These results support a role for GH in immune response regulation and identify a unique target for therapeutic intervention in type 1 diabetes.beta cells | Tregs G rowth hormone (GH) is a pleiotropic hormone that affects a broad spectrum of physiological functions, from carbohydrate and lipid metabolism to the immune response (1). Several studies have linked GH with autoimmune diseases, although its effects on the immune system are still debated. Whereas some reports using GH-deficient mice indicate that it does not affect immune competence (2), others suggest that GH is necessary for correct immune system development (1, 3). The GH receptor (GHR) is expressed by several lymphocyte subpopulations (4). GH stimulates in vitro T and B-cell proliferation (5) and Ig synthesis (6); enhances human myeloid progenitor cell maturation (7); and modulates in vivo Th1/Th2 (8) and humoral immune responses (1). In addition, therapeutic activation of the GH/STAT5B axis is postulated as a target for restoring mucosal tolerance in Crohn disease (9, 10). A single point mutation in STAT5B limits its DNA binding activity as well as maintenance of FOXP3 expression by Treg cells in nonobese diabetic (NOD) mice (11). These mice develop type 1 diabetes, which is characterized by autoimmune destruction of pancreatic β-cells due to the effect of environmental factors on genetically predisposed individuals (12,13). Although this murine model does not completely mimic the human disease, most steps in the pathogenesis, including prodromal and clinical symptoms, are closely comparable (14).Despite the interdependence of GH and insulin regulation and the known effects of GH and insulin-like growth factor 1 (IGF1) on pancreatic β-cell survival, proliferation and neogenesis (15, 16), hormone influences have not been described in type 1 diabetes; no specific studies have addressed the consequences of long-term GH replacement therapy in this disease. Here we show the effects of long-term GH supplementation as a tool to modulate autoimmune attack on pancreatic β-cells. NOD...

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“…3B). These data concur with the reported GHR-dependent islet hyperplasia (24) and the compensatory hyperinsulinemia mechanism associated with GHdependent insulin resistance (25).…”

Section: Nod-tg Bgh Mice Have Normal Delayed Type Hypersensitivitysupporting

confidence: 92%

Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…22 Genomic PCR of fluorescence-activated cell sorter isolated BM cells confirmed efficient hematopoietic deletion of Ghr in the experimental mice (supplemental Figure 3A). To assess how loss of Ghr in HSCs impacted steady-state hematopoiesis, we analyzed complete blood cell counts and peripheral blood (PB) composition of age-matched experimental and control mice.…”

Section: Genetic Ablation Reveals That Ghr Is Dispensable For Hsc Funmentioning

confidence: 71%

Growth hormone receptor signaling is dispensable for HSC function and aging

Stewart

Gutierrez-Martinez

Beerman

et al. 2014

Blood

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“…Additionally, the restoration of insulin secretion and glucose homeostasis obtained with chronic S107 treatment provides further support for the RyR2-mediated leak as the culprit in both of these abnormalities. We did not perform an arginine test to assess the maximal insulin response (60)(61)(62). Such a test could have helped distinguish between the role of RyR2 in acute function versus the maintenance of β cell mass (63).…”

Section: 7mentioning

confidence: 99%

“…The ob/ob mouse used in this study to test in vivo the effects of S107 on insulin secretion and glucose homeostasis is a well-established model of T2DM (33,34,62,64). However, β cell failure is not considered the main trigger of diabetes in this murine model, in which a major pathophysiological role is played by insulin resistance; therefore, modifications in RyR2 observed in pancreatic islets from these mice could represent an epiphenomenon of a prolonged hyperglycemic status.…”

Section: 7mentioning

confidence: 99%