Kiyokazu Matoba

Pleiotropic Effects of Sitagliptin in the Treatment of Type 2 Diabetes Mellitus Patients

Background Sitagliptin is a DPP-4 inhibitor that became available for use in Japan three years ago. This study was conducted to identify the pleiotropic effects of sitagliptin other than blood glucose lowering in Japanese type 2 diabetes mellitus patients. Methods A retrospective, observational study of 940 type 2 diabetes mellitus patients was conducted. The primary outcome measures were HbA1c, blood pressure, and lipid profiles measured at 0, 4, and 12 weeks of sitagliptin therapy. Results After 12 weeks of sitagliptin treatment, compared with baseline, HbA1c decreased 0.64% ± 0.86%; systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased significantly; and serum creatinine (Cr) and uric acid (UA) levels were mildly but significantly elevated. A correlation analysis of the changes in systolic blood pressure, diastolic blood pressure, creatinine, and uric acid (ΔSBP, ΔDBP, ΔCr, ΔUA) from baseline to 12 weeks showed significant negative correlations between ΔSBP and ΔCr, ΔSBP and ΔUA, and ΔDBP and ΔCr. Total cholesterol and postprandial triglycerides were significantly decreased at both 4 and 12 weeks. Alkaline phosphatase (ALP) decreased significantly, and there was a significant positive correlation between changes in ALP and HbA1c. Conclusions Sitagliptin seems to be effective not only in lowering blood glucose but also in lowering blood pressure, lipid, and ALP levels. Sitagliptin appears to contribute to a Na-diuretic action due to GLP-1.

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00221.x, 2012)

The status of glycemic control by general practitioners and specialists for diabetes in Japan: a cross-sectional survey of 15,652 patients with diabetes mellitus.

To determine the status of diabetes care by general practitioners and diabetes specialists in Japan, we conducted a nation-wide cross-sectional survey. We asked 8112 clinics and hospitals randomly, from throughout Japan, to participate in this study and 721 facilities agreed. A total of 15,652 patients aged from 15 to 97 with type 1 and type 2 diabetes were enrolled. Of these, 14,560 (93.0%) and 1092 (7.0%) patients were cared for by general practitioners and diabetes specialists, respectively. HbA1c levels were measured by a latex agglutination method, and age, height, body weight, type of diabetes and treatment modality were obtained from each patient. Mean HbA1c level for all patients treated by general practitioners was significantly lower than for those treated by the diabetes specialists (6.8+/-1.2% vs. 7.0+/-1.2%, p=0.0002). Mean HbA1c level for patients without insulin therapy was lower than for those treated with insulin, irrespective of caring physician. The proportion of patients treated with insulin therapy by diabetes specialists was higher (17.7%) than that by general practitioners (6.5%). This study showed that average HbA1c levels in Japanese patients treated by either general practitioners or specialists was acceptable, regardless of study limitations or bias.

Relationship between age-adjusted heart rate and anaerobic threshold in estimating exercise intensity in diabetics

We compared heart rates at the anaerobic threshold (AT) with age-adjusted heart rates in two groups of diabetics (DMY, mean age 31; and DMO, mean age 48) to ascertain whether the AT is useful for evaluating the intensity of exercise therapy for diabetics. In both the DMY and DMO groups the AT was reached at lower heart rates than in control groups of healthy subjects, indicating that the metabolism of diabetics may become anaerobic if their age-adjusted heart rate is higher than their heart rate at the AT. In this study, 86% of the DMY and 50% of the DMO group had age-adjusted heart rates, at 70% of maximum, that were higher than the heart rates at the AT. Thus, exercise intensity with an age-adjusted heart rate at 70% of maximum may induce anaerobic metabolism in some diabetics. We also studied the relationship between exercise intensity and the glycosylated hemoglobin (HbA1c) level at the AT in order to understand why the heart rate at the AT in diabetics was less than in healthy subjects. Exercise intensity at the AT in both diabetic groups was less than in healthy groups, and so did not increase the heart rates. Both exercise intensity and the heart rate at the AT were inversely related to the HbA1c level, suggesting that HbA1c may be important for keeping low the exercise intensity and the heart rate at the AT. As far as possible, we excluded cardiovascular autonomic neuropathy, so that it could not explain the mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin Resistance in Mitochondrial Gene Mutation

From the Saiseikai Central Hospital (Y.S., K.H., Y.A., K.M.); Institute for Diabetes Care and Research, Asahi Life Foundation (H. Kadowaki); Third Department of Internal Medicine (H. Katagiri, T.K., Y.O., Y.Y.), Faculty of Medicine, University of Tokyo; and the Department of Biochemistry (M.S.), School of Medicine, Keio University, Tokyo, Japan. Address correspondence to Yoshihiko Suzuki, MD, at Saiseikai Central Hospital, 1-417, Mita, Minato-ku, Tokyo 108, Japan.

Anaerobic threshold can provoke microalbuminuria in non-insulin-dependent diabetics

We examined two groups of non-insulin-dependent diabetic men (group A, 13 patients without microalbuminuria; group B, 9 patients with intermittent microalbuminuria) to ascertain whether the anaerobic threshold (AT) can provoke microalbuminuria, comparing them with 12 healthy subjects matched for age and sex (group C). All subjects exercised on a bicycle ergometer until the AT was reached. In intermittent microalbuminuria, the albumin:creatinine ratio (ACR) was over 0.25 mg/mmol.Cr 1-3-fold in 5 measurements. The ACR after exercise was increased to over 0.25 mg/mmol.Cr in 4/9 cases in group B (P < 0.05), in 2/13 cases in group A, but not at all in group C. We also studied the mechanism of exercise-induced microalbuminuria. In group B, ACR before exercise correlated positively with the baseline plasma glucose. Furthermore, positive correlation was found between ACR after exercise and HbA1c in group B. The AT did not affect the urinary beta 2-microglobulin in any groups. The plasma atrial natriuretic factor (ANF) after exercise was elevated most prominently in group B (P < 0.05). Positive correlation was found between increments of ACR and increments of plasma ANF after exercise in group B. We conclude that the AT can provoke microalbuminuria in some non-insulin-dependent diabetics. The plasma ANF and metabolic control may play an important role in the pathophysiology of exercise-induced microalbuminuria.

Safety and efficacy of adding sitagliptin to insulin in patients with type 2 diabetes: The ASSIST-K study

We retrospectively studied more than 1000 patients with type 2 diabetes attending 36 Japanese clinics to investigate the efficacy and safety of adding sitagliptin to various insulin regimens. We found that the treatment with add-on sitagliptin for 6-months was effective, irrespective of the type or dose of concomitant insulin.

Effects of sarpogrelate on serotonin-induced increases in cytosolic Ca2+ in cultured rat mesangial cells

The effects of the new 5-HT2A receptor antagonist sarpogrelate on the cellular action of serotonin were examined in cultured rat mesangial cells by measuring cytosolic free calcium concentration ([Ca2+]i). Sarpogrelate inhibited serotonin-induced increases in [Ca2+]i in a concentration-dependent manner. M1, a major metabolite of sarpogrelate, also exhibited an inhibitory effect exceeding that of sarpogrelate. The inhibitory effects of sarpogrelate and M1 were abolished by washing out these compounds. In contrast, the increase in [Ca2+]i induced by angiotensin II or arginine vasopressin was not affected by pretreatment of the cells with sarpogrelate or M1. These results suggest that sarpogrelate and its major metabolite (M1) act as reversible and specific 5-HT2A receptor antagonists against the contractile action of platelet-derived serotonin in mesangial cells.

Present status of insulin therapy for type 2 diabetes treated by general practitioners and diabetes specialists in Japan: Third report of a cross-sectional survey of 15,652 patients.

Aims/Introduction:  Insulin therapy is often required to achieve good glycemic control in patients with type 2 diabetes mellitus. However, some providers, particularly general practitioners (GPs), are reluctant to prescribe insulin to their patients. The aim of the present study was to clarify any differences in, as well as any problems associated with, insulin therapy in patients with type 2 diabetes being treated by either a GP or a diabetes specialist in Japan.

Factors Predicting Therapeutic Efficacy of Combination Treatment With Sitagliptin and Insulin in Type 2 Diabetic Patients: The ASSIST-K Study.

Background It is unclear whether dipeptidyl peptidase-4 inhibitors decrease hemoglobin A1c (HbA1c) in a glucose-dependent manner in patients on insulin therapy who have impaired insulin secretion. This study investigated factors influencing the efficacy of sitagliptin when used concomitantly with insulin to treat type 2 diabetes mellitus (T2DM) in the real-world setting. Methods A retrospective study was conducted of 1,004 T2DM patients at 36 Japanese clinics associated with the Diabetes Task Force of the Kanagawa Physicians Association. Eligible patients had been on insulin for at least 6 months, with a baseline HbA1c of 7.0% (53 mmol/mol) or higher. Baseline characteristics and laboratory data from 495 patients were subjected to multiple regression analysis to identify factors influencing the change of HbA1c. Results Most patients (n = 809) received sitagliptin at a dose of 50 mg. In the 1,004 patients, HbA1c decreased by 0.74% (6 mmol/mol) and body weight increased by 0.1 kg after 6 months of combination therapy. Multiple regression analysis showed that a higher baseline HbA1c, older age, and lower body mass index influenced the change of HbA1c after 6 months. Hypoglycemic symptoms occurred in 7.4%, but none were severe. Conclusions These results emphasize the importance of a higher HbA1c at the commencement of sitagliptin therapy in patients on insulin. Glucose-dependent suppression of glucagon secretion by sitagliptin may be useful in patients with impaired insulin secretion. Sitagliptin can be used concomitantly with insulin irrespective of the insulin regimen, duration of insulin treatment, and concomitant medications.