Systemic Klotho therapy protects against insulitis and enhances beta-cell mass in NOD mice

• Published in: Biochemical and biophysical research communications 2020-05, Vol.525 (3), p.693-698
• Main Authors: Prud’homme, Gérald J., Glinka, Yelena, Kurt, Merve, Liu, Wenjuan, Wang, Qinghua
• Format: Article
• Language: English
• Subjects: Beta cells; Diabetes; GABA; Insulitis; Islet; Klotho; NOD mice
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.02.123

The levels of the anti-aging protein α-Klotho, in its soluble form (s-Klotho), are depressed in the circulation of patients with type 1 diabetes (T1D) or type 2 diabetes (T2D). Gene transfer experiments have suggested a protective role for β-cell specific expression of α-Klotho in murine models of T1D and T1D, but these approaches are not easily translatable to clinical therapy. It is unknown whether systemic s-Klotho protein treatment ameliorates disease in T1D, which is characterized by autoimmune destruction of β cells. We previously reported from in vitro experiments with β cells that s-Klotho increases insulin secretion, reduces cells death and promotes β-cell replication. Here, we investigated s-Klotho protein therapy in NOD mice, which have autoimmune T1D. We observed that diabetic NOD mice have significantly lower plasma levels of s-Klotho, compared to their non-diabetic counterparts. To examine in vivo effects of Klotho, we treated NOD mice with s-Klotho protein, or with a Klotho blocking antibody. Systemic treatment with s-Klotho ameliorated diabetes; notably increasing β-cell replication and total β-cell mass. Klotho expression was increased locally in the islets. s-Klotho also markedly reduced immune-cell infiltration of islets (insulitis). In contrast, administration of the Klotho antibody was detrimental, and aggravated the loss of β-cell mass. Thus, s-Klotho has protective effects in this model of T1D, and this appears to depend on a combination of increased β-cell replication and reduced insulitis. These findings suggest that s-Klotho might be effective as a new therapeutic agent for T1D. •Systemic treatment of NOD mice with s-Klotho ameliorated diabetes.•Pancreatic β-cell replication and total β-cell mass were increased.•s-Klotho markedly reduced immune-cell infiltration of islets (insulitis) in this autoimmune disease.•Administration of a Klotho blocking antibody was detrimental, and aggravated the loss of β-cell mass.•These findings suggest that Klotho plays an important role in this disease and might be effective as a new therapeutic agent.