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Aims/Introduction:  Type 2 diabetes is progressive in that therapy must be altered over time, which is partly as a result of the progressive loss of pancreatic β‐cell function. To elucidate the relationship between residual endogenous insulin secretion and the necessity of insulin therapy to achieve good glycemic control, indices using serum C‐peptide immunoreactivity (CPR) were analyzed in patients with type 2 diabetes.Materials and Methods:  The data of 201 Japanese patients with type 2 diabetes who achieved the target of glycemic control during admission were analyzed retrospectively. Indices using CPR including fasting CPR (FCPR), CPR 6 min after intravenous injection of glucagon (CPR‐6 min), increment of CPR (ΔCPR), secretory unit of islet in transplantation index (SUIT) and C‐peptide index (CPI) were compared between the group requiring insulin (insulin group) and the group not requiring insulin (non‐insulin group). A receiver–operator characteristic (ROC) curve was made, and optimal cut‐off point and likelihood ratio were determined for each index.Results:  All indices of CPR were lower in the insulin group compared with those in the non‐insulin group. Likelihood ratios at the optimal point of FCPR, CPR‐6 min, ΔCPR, SUIT, and CPI were 2.0, 2.1, 1.6, 2.3 and 2.8, respectively. Optimal cut‐off point of CPI was 1.1 ng/mg. Sensitivity and specificity at optimal point of CPI were 61 and 78%, respectively.Conclusions:  The advantage of CPI of the indices of CPR to select insulin therapy to achieve good glycemic control was shown, but limitations of the predictive abilities of the indices using CPR should be taken into account. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00096.x, 2011)

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. Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity. Am J Physiol Endocrinol Metab 288: E365-E371, 2005. First published October 12, 2004; doi:10.1152/ ajpendo.00390.2004.-Tacrolimus is widely used for immunosuppressant therapy, including various organ transplantations. One of its main side effects is hyperglycemia due to reduced insulin secretion, but the mechanism remains unknown. We have investigated the metabolic effects of tacrolimus on insulin secretion at a concentration that does not influence insulin content. Twenty-four-hour exposure to 3 nM tacrolimus reduced high glucose (16.7 mM)-induced insulin secretion (control 2.14 Ϯ 0.08 vs. tacrolimus 1.75 Ϯ 0.02 ng ⅐ islet Ϫ1 ⅐ 30 min Ϫ1 , P Ͻ 0.01) without affecting insulin content. In dynamic experiments, insulin secretion and NAD(P)H fluorescence during a 20-min period after 10 min of high-glucose exposure were reduced in tacrolimus-treated islets. ATP content and glucose utilization of tacrolimus-treated islets in the presence of 16.7 mM glucose were less than in control (ATP content: control 9.69 Ϯ 0.99 vs. tacrolimus 6.52 Ϯ 0.40 pmol/islet, P Ͻ 0.01; glucose utilization: control 103.8 Ϯ 6.9 vs. tacrolimus 74.4 Ϯ 5.1 pmol ⅐ islet Ϫ1 ⅐ 90 min Ϫ1 , P Ͻ 0.01). However, insulin release from tacrolimus-treated islets was similar to that from control islets in the presence of 16.7 mM ␣-ketoisocaproate, a mitochondrial fuel. Glucokinase activity, which determines glycolytic velocity, was reduced by tacrolimus treatment (control 65.3 Ϯ 3.4 vs. tacrolimus 49.9 Ϯ 2.8 pmol ⅐ islet Ϫ1 ⅐ 60 min Ϫ1 , P Ͻ 0.01), whereas hexokinase activity was not affected. These results indicate that glucose-stimulated insulin release is decreased by chronic exposure to tacrolimus due to reduced ATP production and glycolysis derived from reduced glucokinase activity.islet; adenosine 5Ј-triphosphate TACROLIMUS (FK-506) IS AN IMMUNOSUPPRESSANT widely used in human organ transplantation. Immunosuppression by the agent is due to blocking of antigen-stimulated expression of genes, including interleukin-2 in T lymphocytes, which is required for T-cell proliferation (34). Interleukin-2 gene transcription is activated by dephosphorylation and nuclear translocation of a transcriptional cofactor, the nuclear factor of activated T cells (NFAT). Tacrolimus binds specific intracellular proteins, FK-506-binding proteins (FKBPs), and inhibits calcineurin (protein phosphatase-2B), a Ca 2ϩ

Aims/hypothesis Na + /K + -ATPase inhibition by ouabain suppresses ATP production by generating reactive oxygen species (ROS) and impairs glucose-induced insulin secretion from pancreatic islets. To clarify the signal-transducing function of Na + /K + -ATPase in decreasing ATP production by the generation of ROS in pancreatic islets, the involvement of Src was examined. In addition, the significance of Src activation in diabetic islets was examined. Methods Isolated islets from Wistar rats and diabetic GotoKakizaki (GK) rats (a model for diabetes) were used. ROS was measured by 5-(and 6)-chloromethyl-2′,7′-dichlorofluorescein fluorescence using dispersed islet cells. After lysates were immunoprecipitated by anti-Src antibody, immunoblotting was performed. Results Ouabain caused a rapid Tyr 418 phosphorylation, indicating activation of Src in the presence of high glucose. The specific Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) restored the ouabain-induced decrease in ATP content and the increase in ROS production. Both PP2 and ROS scavenger restored the impaired insulin release and impaired ATP elevation in GK islets, but had no such effect in control islets. PP2 reduced the high glucose-induced increase in ROS generation in GK islet cells but had no effect on that in control islet cells. Moreover, ouabain had no effect on ATP content and ROS production in the presence of high glucose in GK islets. Conclusions/interpretation These results indicate that Src plays a role in the signal-transducing function of Na + /K + -ATPase, in which ROS generation decreases ATP production in control islets. Moreover, ROS generated by Src activation plays an important role in impaired glucoseinduced insulin secretion in GK islets, in which Src is endogenously activated independently of ouabain.