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Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3′- phosphoinositide-dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammatory markers in adipose tissue differed between A-PDK1KO and A-PDK1/FoxO1KO mice. Lipidomics and microarray analyses revealed that leukotriene B4 (LTB4) levels in plasma and in adipose tissue as well as the expression of 5- lipoxygenase (5-LO) in adipose tissue were increased and restored in A-PDK1KO mice and A-PDK1/FoxO1KO mice, respectively. Genetic deletion of the LTB4 receptor BLT1 as well as pharmacological intervention to 5-LO or BLT1 ameliorated insulin resistance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4 production through downregulation of 5-LO expression via the PDK1−FoxO1 pathway in isolated adipocytes. Our results indicate that insulin signaling in adipocytes negatively regulates the production of LTB4 via the PDK1−FoxO1 pathway and thereby maintains systemic insulin sensitivity. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Insulin is synthesized in the β-cells from preproinsulin. Preproinsulin becomes proinsulin after leaving the signal peptide. Proinsulin is separated into C-peptide and insulin by 2 enzymes. Hyperproinsulinemia is suspected to be a pancreatic β-cell defect that is augmented by the increased demand placed on the β-cell by hyperglycemia. CASE PRESENTATION: A 39-year-old Japanese man visited to Shin-suma hospital in May 2013. Liver dysfunction, dyslipidemia, and hyperuricemia had been found in medical checkups in his workplace. Therefore, he visited Shin-suma hospital in order to receive intensive examination. Diet and exercise therapy were initiated. In November 2013, intact proinsulin and proinsulin per insulin (PI/I) ratio were evaluated as part of an ongoing study. His intact proinsulin level and PI/I ratio were markedly elevated. A 75 g oral OGTT revealed that his glucose tolerance was impaired. His glycosylated hemoglobin was 6.9%. He was diagnosed as having type 2 diabetes mellitus. Although, diet and exercise therapy continued, his hyperproinslinemia and diabetes mellitus remained. Therefore, aloguliptin was started in order to recover insulin secretion in November 2014. Thereafter, pioglitazone was added to improve insulin resistance. Finally, luseogliflozin was commenced to expect glucose-lowering effects. His HbA1c was stabilized. To the best of our knowledge, there have been few reports of patients with hyperproinsulinemia. CONCLUSION: When the physicians face treatment resistance in diabetes mellitus, we emphasize that evaluation of proinsulin should be considered as one of the methods. [ABSTRACT FROM AUTHOR]