There have been increasing evidences that thiazolidinediones, peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, may have some antiatherogenic actions. We have previously reported that troglitazone has a potent inhibitory effect on common carotid arterial intima-media thickness (IMT) in subjects with type 2 diabetes. However, some studies suggested a possibility that PPARgamma activators may have protoatherogenic actions, raising concern about their detrimental effects in diabetic subjects. In the present study, we investigated the effect of treatment with pioglitazone, another PPARgamma agonist, on IMT in a total of 106 Japanese subjects with type 2 diabetes. Pioglitazone (30 mg daily) was administered for 6 months in 53 patients. Compared to control group (n = 53), the group given pioglitazone showed a significant decrease in IMT as early as 3 months after the administration. The decrease in IMT was also found after 6 months (IMT change: -0.084[SE 0.023] mm vs. control 0.022[SE 0.006] mm, P < 0.001), although the difference between those after 3 and 6 months did not reach any statistical significance. These findings indicate that thiazolidinediones cause an inhibition of early atherosclerotic process PPARgamma activation.

. 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

Abstract. Sodium-glucose co-transporter-2 inhibitors are newly established anti-diabetic agents with a unique glucoselowering mechanism. In the present study, we investigated the efficacy and safety of the sodium-glucose co-transporter-2 inhibitor ipragliflozin (Ipra) for metabolic markers and cardiovascular parameters in Japanese patients with type 2 diabetes mellitus (T2DM). This study was an investigator-initiated, open-label, single-arm, multicenter prospective study. Patients with T2DM were treated with 50 mg Ipra for 24 and 52 weeks. The primary outcome investigated was the reduction of glycated hemoglobin (HbA1c) level. The secondary outcome was the change in other metabolic and cardiovascular parameters by 24 weeks. Before and after 52 weeks of treatment, carotid intima-media thickening (IMT) was measured by echography. A total of 134 patients were recruited in the study. A 24-week treatment with 50 mg Ipra daily significantly reduced HbA1c level (-0.6%, p < 0.01). Body mass index (BMI), blood pressure and serum C-peptide were reduced significantly (p < 0.05), while serum glucagon level was unchanged. Interestingly, the serum adiponectin and high-density lipoprotein (HDL) cholesterol levels were significantly increased by Ipra. However, 52 weeks of Ipra treatment did not change carotid IMT. Multiple regression analysis revealed that the only significant contributing factor for HbA1c reduction by Ipra was baseline HbA1c level. These data suggest that Ipra decreased not only glucose level but also BMI, blood pressure and serum C-peptide, and the contributing factor for HbA1c reduction by Ipra was baseline HbA1c level. Further, Ipra improved serum adiponectin and HDL cholesterol levels.

These results indicate that normal pancreatic beta-cells have the ability to secrete sufficient insulin to compensate for the insulin resistance induced by a high-fat diet. In contrast, glucose metabolism in diabetic rats after high-fat diet deteriorated partly because of insufficient insulin secretion caused by genetic defects and lipotoxicity due to chronically high FFA levels.

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