Exploring mechanisms underlying diabetes comorbidities and strategies to prevent vascular complications.

It is important to prevent not only diabetic complications but also diabetic comorbidities in diabetes care. We have elucidated multifaceted insulin action in various tissues mainly by means of model mice, and it was revealed that insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis, one of the major diabetic comorbidities. Insulin regulates gluconeogenesis not only in the liver but also in the proximal tubules of the kidney, which is also suppressed by reabsorbed glucose in the latter. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease, but also to bone loss and shorter longevity. Aging is regulated by adipokines as well, and it is deemed to be accelerated by 'imbalanced adipokines' in combination with genetic background of progeria. Moreover, we reported effects of intensive multifactorial intervention on diabetic complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, followed by reports of subsequent sub-analyses of renal events and fracture events. Various approaches to elucidate the mechanisms underlying the development of diabetes and how it should be treated are expected to help us improve diabetes management.