Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.

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Aims/Introduction Advanced glycation end‐products (AGEs), which are a major cause of diabetic vascular complications, accumulate in various tissues under chronic hyperglycemic conditions, as well as with aging in patients with diabetes. The loss of muscle mass and strength, so‐called sarcopenia and dynapenia, has recently been recognized as a diabetic complication. However, the influence of accumulated AGEs on muscle mass and strength remains unclear. The present study aimed to evaluate the association of sarcopenia and dynapenia with accumulated AGEs in patients with type 2 diabetes. Materials and Methods We recruited 166 patients with type 2 diabetes aged ≥30 years (mean age 63.2 ± 12.3 years; body mass index 26.3 ± 4.9 kg/m2; glycated hemoglobin 7.1 ± 1.1%). Skin autofluorescence as a marker of AGEs, limb skeletal muscle mass index, grip strength, knee extension strength and gait speed were assessed. Results Sarcopenia and dynapenia were observed in 7.2 and 13.9% of participants, respectively. Skin autofluorescence was significantly higher in patients with sarcopenia and dynapenia. Skin autofluorescence was the independent determinant for skeletal muscle mass index, grip strength, knee extension strength, sarcopenia and dynapenia. Conclusions Accumulated AGEs could contribute to reduced muscle mass and strength, leading to sarcopenia and dynapenia in patients with type 2 diabetes.

Accumulation of advanced glycation end‐products (AGEs) is thought to contribute to muscle weakness in a diabetic animal model. Skin autofluorescence is a proposed marker for accumulation of AGEs in the skin. We aimed to investigate the relationship between AGEs accumulation, sarcopenia and muscle function of Japanese patients with type 1 diabetes. A total of 36 patients with type 1 diabetes participated in the present cross‐sectional study. Sarcopenia parameters (skeletal muscle mass index and knee extension strength) were compared with subcutaneous AGEs accumulation using skin autofluorescence. The prevalence of sarcopenia and impaired knee extension strength was 16.6% (men 0.0%, women 22.2%) and 47.2% (men 22.2%, women 55.6%), respectively. Knee extension strength was negatively correlated with skin autofluorescence (r² = 0.14, P < 0.05), but not with skeletal muscle mass index. In conclusion, the AGEs accumulation might be one of the reasons of impaired lower limb muscle function in Japanese patients with type 1 diabetes.

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