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Introduction Treatment-related quality of life (QOL) is an important aspect of diabetes management. We evaluated the influence of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, on treatment-related QOL in Japanese patients with type 2 diabetes mellitus (T2DM). Methods This is the prespecified subanalysis study of the “Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)” trial. Treatment-related QOL was evaluated at baseline, week 26, week 52, and week 104 after the initiation of the study using the Diabetes Therapy-Related QOL questionnaire (DTR-QOL). Among the 340 patients in the original UTOPIA study, a total of 252 patients (127, tofogliflozin group; 125, conventional treatment group) who completed the DTR-QOL questionnaire at baseline were the study subjects of the current subanalysis. Results The tofogliflozin and conventional treatment groups exhibited almost comparable baseline clinical characteristics, while the use of antihypertensive drugs and lipid-lowering agents was significantly lower in the tofogliflozin treatment group than in the conventional treatment group. Tofogliflozin treatment increased the total score of DTR-QOL7 from baseline (P

Aims/Introduction The present study aimed to clarify the prevalence and clinical characteristics of sarcopenia and dynapenia, which are muscle weakness with and without low muscle mass, respectively, in Japanese patients with type 1 diabetes mellitus and type 2 diabetes mellitus. Materials and Methods This cross‐sectional study enrolled 1,328 participants with type 1 diabetes (n = 177), type 2 diabetes (n = 645) and without diabetes (n = 506). Sarcopenia was defined as a low grip strength and slow gait speed with low skeletal muscle mass index, whereas dynapenia was defined as low strengths of grip and knee extension with a normal skeletal muscle mass index. Participants without sarcopenia and dynapenia were defined as robust. Results Among participants aged ≥65 years, sarcopenia and dynapenia were observed in 12.2% and 0.5% of individuals without diabetes, 42.9% and 11.4% of type 1 diabetes patients, and 20.9% and 13.9% of type 2 diabetes patients. In both type 1 diabetes and type 2 diabetes patients, sarcopenic patients were significantly older and thinner, and showed a significantly higher rate of diabetic neuropathy than robust patients. In patients with type 1 diabetes and type 2 diabetes, dynapenic patients were older, and showed a higher rate of diabetic neuropathy and lower estimated glomerular filtration rate than robust patients. Patients complicated with sarcopenia and dynapenia showed a significantly lower physical quality of life and higher rate of incidental falls than robust patients. Conclusions Sarcopenia and dynapenia were more frequent in patients with type 1 diabetes and type 2 diabetes than in individuals without diabetes, which might contribute to their impaired quality of life and incidental falls., Sarcopenia was highly observed in type 1 diabetes patients compared with non‐diabetes and type 2 diabetes patients. In contrast, the prevalence of dynapenia was markedly higher in type 1 and type 2 diabetes patients compared with individuals without diabetes.

Background The association between glucose variability and the progression of atherosclerosis is not completely understood. We aimed to evaluate the associations of glucose variability with the progression of atherosclerosis in the early stages. Methods We conducted a cross-sectional analysis to investigate the associations of glucose variability, assessed by continuous glucose monitoring, with intima-media thickness (IMT) and gray-scale median (GSM) of the carotid arteries, which are different indicators for the progression of atherosclerosis. We used baseline data from a hospital-based multicenter prospective observational cohort study among Japanese patients with type 2 diabetes without a history of cardiovascular diseases aged between 30 and 80 years. Continuous glucose monitoring was performed by Freestyle Libre Pro, and glucose levels obtained every 15 min for a maximum of eight days were used to calculate the metrics of glucose variability. IMT and GSM were evaluated by ultrasonography, and the former indicates thickening of intima-media complex in the carotid artery wall, while the latter indicates tissue characteristics. Results Among 600 study participants (age: 64.9 ± 9.2 (mean ± SD) years; 63.2%: men; HbA1c: 7.0 ± 0.8%), participants with a larger intra- and inter-day glucose variability had a lower GSM and most of these associations were statistically significant. No trend based on glucose variability was shown regarding IMT. Standard deviation of glucose (regression coefficient, β = − 5.822; 95% CI − 8.875 to − 2.768, P P = 0.002), mean amplitude of glycemic excursion (β = − 1.689; − 2.567 to − 0.811, P P P = 0.002) had a statistically significant association with mean-GSM after adjustment for conventional cardiovascular risk factors, including HbA1c. No metrics of glucose variability had a statistically significant association with IMT. Conclusions Continuous glucose monitoring-assessed glucose variability was associated with the tissue characteristics of the carotid artery wall in type 2 diabetes patients without cardiovascular diseases.

Our previous study revealed that sarcopenia was frequently observed in subjects with type 1 diabetes mellitus (T1DM). However, the factors associated with sarcopenia that are related to T1DM have not yet been clarified. Insulin-like growth factor-1 (IGF-1) has been shown to play a role in skeletal muscle growth, differentiation, and regeneration. The present study, therefore, investigated the association between the serum IGF-1 level and sarcopenia and low skeletal muscle mass in subjects with T1DM.This cross-sectional study enrolled subjects with T1DM (n = 168) and without diabetes (n = 59) who had had their clinical data on serum IGF-1 collected in the iDIAMOND study.The z-score of serum IGF-1 was significantly lower in the subjects with T1DM than that in those without diabetes (p 0.001). Among subjects with T1DM, the z-score of serum IGF-1 was significantly lower in sarcopenic subjects than in non-sarcopenic subjects. The multivariable logistic regression analysis showed that the serum IGF-1 z-score was an independent determinant of sarcopenia and a low skeletal muscle mass index, but not low grip strength nor slow gait speed in subjects with T1DM.A low serum IGF-1 level is correlated with sarcopenia and low skeletal muscle mass in subjects with T1DM.

Additional file 6: Table S5. Effects of tofogliflozin on brachial-ankle pulse wave velocity in individuals with all three measurements (baseline, week 52, and week 104).

Additional file 7: Table S6. Effects of tofogliflozin on brachial-ankle pulse wave velocity change in subgroups.

Additional file 4: Table S3. Changes in concomitantly used anti-diabetic agents.

Additional file 1: Table S1. Clinical characteristics of the participants of the multicenter prospective observational cohort study. Table S2. Comparisons of clinical parameters among thickened lesion-gray-scale median tertiles. Table S3. Comparisons of clinical parameters among plaque-gray-scale median tertiles. Table S4. Associations of the metrics of continuous glucose monitoring with thickened lesion-gray-scale median and plaque-gray-scale median. Table S5. Associations between the adjustment factors in the multivariable regression models. Table S6. Associations of the metrics of continuous glucose monitoring with intima-media thickness among the participants with hypertension. Table S7. Associations of the metrics of continuous glucose monitoring with gray-scale median among the participants with hypertension. Table S8. Associations of the metrics of continuous glucose monitoring with intima-media thickness among the participants without hypertension. Table S9. Associations of the metrics of continuous glucose monitoring with gray-scale median among the participants without hypertension. Table S10. Associations of the metrics of continuous glucose monitoring with intima-media thickness among the participants with dyslipidemia. Table S11. Associations of the metrics of continuous glucose monitoring with gray-scale median among the participants with dyslipidemia. Table S12. Associations of the metrics of continuous glucose monitoring with intima-media thickness among the participants without dyslipidemia. Table S13. Associations of the metrics of continuous glucose monitoring with gray-scale median among the participants without dyslipidemia. Table S14. Associations of the metrics of continuous glucose monitoring with intima-media thickness among participants using anti-diabetic medications. Table S15. Associations of the metrics of continuous glucose monitoring with gray-scale median among participants using anti-diabetic medications. Table S16. Associations of the metrics of continuous glucose monitoring with intima-media thickness among participants not using anti-diabetic medications. Table S17. Associations of the metrics of continuous glucose monitoring with gray-scale median among participants not using anti-diabetic medications. Table S18. Associations of the metrics of continuous glucose monitoring with intima-media thickness among participants using insulin therapy. Table S19. Associations of the metrics of continuous glucose monitoring with gray-scale median among participants using insulin therapy. Table S20. Associations of the metrics of continuous glucose monitoring with intima-media thickness among participants not using insulin therapy. Table S21. Associations of the metrics of continuous glucose monitoring with gray-scale median among participants not using insulin therapy. Table S22. Associations of the metrics of continuous glucose monitoring with intima-media thickness among participants using angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Table S23. Associations of the metrics of continuous glucose monitoring with gray-scale median among participants using angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Table S24. Associations of the metrics of continuous glucose monitoring with intima-media thickness among participants not using angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Table S25. Associations of the metrics of continuous glucose monitoring with gray-scale median among participants not using angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Table S26. Associations of the metrics of continuous glucose monitoring with intima-media thickness among participants using statins. Table S27. Associations of the metrics of continuous glucose monitoring with gray-scale median among participants using statins. Table S28. Associations of the metrics of continuous glucose monitoring with intima-media thickness among participants not using statins. Table S29. Associations of the metrics of continuous glucose monitoring with gray-scale median among participants not using statins. Table S30. List of sites and investigators.

Additional file 1: UTOPIA trial site investigators.

Additional file 3: Table S2. Between-group comparison of changes in clinical parameters during the treatment period.

Background: This study aimed to investigate the preventive effects of tofogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD) by monitoring carotid intima-media thickness (IMT). Methods: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study included 340 subjects with T2DM but no history of apparent CVD recruited at 24 clinical units. Subjects were randomly allocated to either the tofogliflozin treatment group (n=169) or conventional treatment group using drugs other than SGLT2 inhibitors (n=171). Primary outcomes were changes in mean and maximum common carotid IMT measured by echography during a 104-week treatment period. Findings: Although the mean IMT of the common carotid artery (mean-IMT-CCA), along with the right and left maximum IMT of the CCA (max-IMT-CCA), statistically significantly declined in both the tofogliflozin (-0.132 mm, SE 0.007; -0.163 mm, SE 0.013; -0.170 mm, SE 0.020; respectively) and the control group (-0·140 mm, SE 0·006; -0·190 mm, SE 0·012; -0·190 mm, SE 0·020; respectively), no significant difference was observed between the two groups. Relative to the control treatment effects, tofogliflozin statistically significantly reduced the HbA1c, blood glucose level, body weight/body mass index, abdominal circumference, and systolic blood pressure, and statistically significantly increased the HDL-C. Interpretation: A tofogliflozin treatment regimen of 104 weeks was not associated with improved inhibition of carotid wall thickening in T2DM patients without apparent CVD, as compared to the effect of the control treatment. Trial Registration: UMIN000017607. Funding Statement: Kowa Co., Ltd., Tokyo, Japan. Declaration of Interests: Naoto Katakami is a staff member of the endowed chair established by funds from Kowa Co., Ltd., and has received research funds from MSD, and lecture fees from Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim, Daiichi Sankyo Inc., Eli Lilly, Kowa Pharmaceutical Co., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Co., Novartis Pharmaceuticals, Novo Nordisk Pharma, Ono Pharmaceutical Co., Taisho Toyama Pharmaceutical Co., Takeda Pharmaceutical Co., and Sanofi-Aventis, and Shionogi & Co. Tomoya Mita has received lecture fees from Astellas Pharma Inc., Daiichi Sankyo Inc., Eli Lilly, Kowa Pharmaceutical Co., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Co., Novo Nordisk Pharma, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited and Sanofi-Aventis, scholarship donations from MSD K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co. Ltd., Sanofi-Aventis K.K., Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Terumo Corporation, Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Pfizer Japan Inc., Benefit One Health Care Inc., Mochida Pharmaceutical Co., Ltd., and Nitto Boseki Co., Ltd. as well as funds of endowed chair from MSD K.K., Takeda Pharmaceutical Company Limited. Toshihiko Shiraiwa has received lecture fees from Sanofi-Aventis K.K. and Takeda Pharmaceutical Company Limited and research funding from Novo Nordisk Pharma Ltd., Sanofi-Aventis K.K., Takeda Pharmaceutical Company Limited, AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. Tetsuyuki Yasuda has received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. and Sanofi-Aventis K.K. Yosuke Okada has received lecture fees from Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bayer Holding Ltd., Novartis Pharmaceuticals Corp., Novo Nordisk Pharma Ltd., Eli Lilly Japan K.K., and Kissei Pharmaceutical Co., Ltd. as well as research funding from Kowa Pharmaceutical Co. Ltd. and Mitsubishi Tanabe Pharma Corporation. Hideaki Kaneto has received lecture fees from Nippon Boehringer Ingelheim Co., Ltd., Sanofi-Aventis K.K., Novo Nordisk Pharma Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K., Astellas Pharma Inc., Novartis Pharmaceuticals Corp., and Sumitomo Dainippon Pharma Co.; scholarship donations from Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis K.K., Eli Lilly Japan K.K., Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, MSD K.K., Takeda Pharmaceutical Company Limited, AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Kissei Pharmaceutical Co., Ltd., and Kyowa Hakko Kirin Co. Ltd; and research funding from Taisho Pharmaceutical Co., Sumitomo Dainippon Pharma Co. Takeshi Osonoi has received lecture fees from Takeda Pharmaceutical Company Limited, Astellas Pharma Inc., Novo Nordisk Pharma Ltd., and Sanwa Kagaku Kenkyusho Co., Ltd.; manuscript fees from Sanwa Kagaku Kenkyusho Co., Ltd.; and research funding from Takeda Pharmaceutical Company Limited, Novo Nordisk Pharma Ltd., Astellas Pharma Inc., Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., Taisho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Company, Limited, Bayer Holding Ltd., Kowa Pharmaceutical Co. Ltd., and AbbVie Inc. Nobuichi Kuribayashi has received lecture fees from Takeda Pharmaceutical Company Limited, Sanofi-Aventis K.K., Novo Nordisk Pharma Ltd., MSD K.K., and Mitsubishi Tanabe Pharma Corporation. Satoru Sumitani has received lecture fees from Sumitomo Dainippon Pharma Co., Ltd. Yasunori Sato has received lecture fees from Mochida Pharmaceutical Co., Ltd. Hirotaka Watada has received lecture fees from Sumitomo Dainippon Pharma CO., Ltd., Bayer Yakuhin, Ltd. Sanofi-Aventis K.K., MSD K.K., Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd, Mitsubishi Tanabe Pharma Co., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Kowa Co., Ltd., Novartis Pharmaceuticals Corp., Daiichi Sankyo Company, Ltd, Kyowa Hakko Kirin Co. Ltd., Ono Pharmaceutical Co., Ltd., and Kissei Pharmaceutical Co., Ltd. and research support from Novartis Pharmaceuticals Corp., Otsuka Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., MSD K.K., Astellas Pharma Inc., Bayer Yakuhin, Ltd. Teijin Pharma Ltd., Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co. Ltd., Kowa Pharmaceutical Co. Ltd., Sanofi-Aventis K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Daiichi Sankyo Company, Ltd, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Ltd, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Pfizer Japan Inc., Shionogi & Co., Ltd. Yakult, and Kissei Pharmaceutical Co., Ltd. Iichiro Shimomura has received lecture fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co., Kyowa Kirin Co., Ltd., Kowa Company, Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Daiichi Sankyo Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Novartis Pharma K.K., Novo Nordisk Pharma, Mochida Pharmaceutical Co., Taisho Pharmaceutical Co. Ltd., Nippon Chemiphar Co., Ltd., Covidien Japan Inc., Amgen Astellas Biopharma K.K., KOBAYASHI Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Rohto Pharmaceutical Co., Ltd.; and research funds from Astellas Pharma Inc., MSD K.K, Ono Pharmaceutical Co., Kaken Pharmaceutical Co., Kyowa Kirin Co., Ltd., Sanofi K.K., Shionogi & Co., Daiichi Sankyo Co., Dainippon Sumitomo Pharma Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Novartis Pharma K.K., Novo Nordisk Pharma, Eli Lilly Japan K.K, Kowa Company, Ltd.; and consulting fees from AstraZeneca K.K., MSD K.K., Taisho Pharmaceutical Co. Ltd., Novo Nordisk Pharma, Lotte Co., Ltd. Hidenori Yoshii, Yutaka Umayahara, Tsunehiko Yamamoto, Kazuhisa Maeda, Hiroki Yokoyama, Keisuke Kosugi, Kentaro Ohtoshi, Isao Hayashi, Mamiko Tsugawa, Kayoko Ryomoto, Hideki Taki, Tadashi Nakamura, and Satoshi Kawashima declare that they have no conflict of interest. Ethics Approval Statement: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study.

Additional file 1: Materials S1: Safety evaluation. List of UTOPIA trial site investigators. Table S1. Effects of tofogliflozin on intima-media thickness were analyzed using covariance models. Table S2. Changes in concomitantly used anti-diabetic agents. Table S3. Changes in concomitantly used cardiovascular medications.

Introduction Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-diabetic agents that improve glycemic control with a low risk of hypoglycemia and ameliorate a variety of cardiovascular risk factors. The aim of the ongoing study described herein is to investigate the preventive effects of tofogliflozin, a potent and selective SGLT2 inhibitor, on the progression of atherosclerosis in subjects with type 2 diabetes (T2DM) using carotid intima-media thickness (IMT), an established marker of cardiovascular disease (CVD), as a marker. Methods The Study of Using Tofogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, blinded-endpoint, multicenter, and parallel-group comparative study. The aim was to recruit a total of 340 subjects with T2DM but no history of apparent CVD at 24 clinical sites and randomly allocate these to a tofogliflozin treatment group or a conventional treatment group using drugs other than SGLT2 inhibitors. As primary outcomes, changes in mean and maximum IMT of the common carotid artery during a 104-week treatment period will be measured by carotid echography. Secondary outcomes include changes in glycemic control, parameters related to β-cell function and diabetic nephropathy, the occurrence of CVD and adverse events, and biochemical measurements reflecting vascular function. Conclusion This is the first study to address the effects of SGLT2 inhibitors on the progression of carotid IMT in subjects with T2DM without a history of CVD. The results will be available in the very near future, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent CVD. Funding Kowa Co., Ltd. Clinical Trial Registration UMIN000017607. Electronic supplementary material The online version of this article (doi:10.1007/s13300-017-0292-1) contains supplementary material, which is available to authorized users.

BACKGROUND Previous studies showed higher risk of cardiovascular and cerebrovascular (CCV) events in primary aldosteronism compared with essential hypertension, but the patients of these studies were limited to primary aldosteronism patients with high plasma aldosterone concentration (PAC). The introduction of the aldosterone-renin ratio as the screening test for primary aldosteronism led to the recognition of primary aldosteronism patients with normal PAC (nPA). However, there is no information on the risk of primary aldosteronism including nPA. METHOD In this retrospectively and cross-sectional study, the clinical features and CCV event risk of primary aldosteronism at diagnosis including nPA were investigated and compared with essential hypertension. The study included 292 consecutive primary aldosteronism patients and 498 essential hypertension outpatients. All primary aldosteronism patients were diagnosed by autonomous aldosterone secretion using confirmatory tests, and then divided into nPA (n = 130) and primary aldosteronism patients with high PAC (hPA: n = 162) using a PAC cutoff level of less than 443 pmol/l (16 ng/dl), representing the normal upper limit of PAC. RESULTS nPA patients were significantly older at diagnosis of primary aldosteronism and at onset of hypertension compared with hPA patients. They had milder hypokalemia and easier-to-control blood pressure. The results suggested that nPA could be considered a mild type of primary aldosteronism but not an early-stage hPA. Moreover, the risk of all CCV events in nPA was significantly lower than that in hPA (odds ratio 0.42, 95% confidence interval 0.18-0.90, P

OBJECTIVE The effect of additional treatment with oral hypoglycemic agents on the progression of atherosclerosis remains unknown in insulin-treated patients with type 2 diabetes mellitus (T2DM). We assessed the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on carotid intima-media thickness (IMT) in T2DM. RESEARCH DESIGN AND METHODS This prospective, randomized, open-label, blinded end point, multicenter, parallel-group, comparative study included 282 insulin-treated patients with T2DM free of a history of apparent cardiovascular diseases who were recruited at 12 clinical units and randomly allocated to either the sitagliptin group (n = 142) or the control group (n = 140). The primary outcomes were changes in mean and maximum IMT of the common carotid artery measured by echography at the end of a 104-week treatment period. RESULTS Sitagliptin had a more potent glucose-lowering effect compared with the conventional treatment (−0.5 ± 1.0% vs. −0.2 ± 0.9%; P = 0.004), without increasing hypoglycemic episodes or body weight. Changes in the mean and left maximum IMT, but not right maximum IMT, of the common carotid arteries were significantly greater after sitagliptin treatment compared with conventional treatment (−0.029 [SE 0.013] vs. 0.024 [0.013] mm [P = 0.005]; −0.065 [0.027] vs. 0.022 [0.026] mm [P = 0.021]; −0.007 [0.031] vs. 0.027 [0.031] mm [P = 0.45], respectively). Over 104 weeks, sitagliptin, but not conventional treatment, significantly reduced the mean IMT and left maximum IMT of common carotid arteries relative to the baseline. CONCLUSIONS Sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment.

The aim of this study was to investigate the clinical and endocrinological characteristics of adrenal incidentalomas in Osaka region, Japan. The study was a multicenter retrospective analysis of 150 patients with adrenal incidentalomas who underwent radiographic and endocrine evaluations between 2005 and 2013. Most adrenal incidentalomas were discovered by computed tomography (77.0%) and the rest were identified by abdominal ultrasonography (14.6%), magnetic resonance imaging (4.2%), or positron emission tomography (4.2%). Adrenal incidentalomas were more frequently localized on the left side than on the right. The average diameter of tumors was 21 ± 11 mm. On endocrinological evaluation, 14 patients were diagnosed with primary aldosteronism (9.3%), 10 with subclinical Cushing's syndrome (6.7%), 7 with pheochromocytoma (4.7%), 7 with Cushing's syndrome (4.7%), 2 with both subclinical Cushing's syndrome and primary aldosteronism (1.3%), and 110 with non-functioning tumors (73.3%). Patients with functioning tumors were significantly younger and had larger tumor diameters than those with non-functioning tumors. Except for hypertension, complications were comparable between patients with functioning and non-functioning tumors, including the presence of glucose intolerance, cardiovascular disease, and dyslipidemia. In conclusion, a higher prevalence of primary aldosteronism was observed compared with a previous report. Complications were comparable between patients with functioning and non-functioning tumors, including the frequencies of glucose intolerance, cardiovascular disease, and dyslipidemia. Long-term follow-up is required in patients with non-functioning tumors because the frequency of complications, such as glucose intolerance, cardiovascular disease, and dyslipidemia, was equal to that in patients with functioning tumors.

OBJECTIVE Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1–dependent and –independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period. RESULTS Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (−0.3 ± 0.7% vs. −0.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (−0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; −0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and −0.079 mm [SE 0.018] vs. −0.015 mm [SE 0.018], P = 0.013, respectively). CONCLUSIONS Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

Ectopic ACTH syndrome (EAS) is a potentially fatal endocrine disease that results from a variety of neuroendocrine tumors (NETs), such as small cell lung cancer (SCLC) and bronchial typical carcinoid. Typical carcinoid is usually slow growing, not associated with plasma progastrin releasing peptide (ProGRP) elevation. Here, we report a 47-year-old female smoker with progressive typical carcinoid and plasma ProGRP elevation. Several types of Cushingoid features were found on physical examination. In addition, laboratory examination showed elevated plasma ACTH and serum cortisol levels. These findings indicated ACTH-dependent Cushing's syndrome. Moreover, the serum cortisol level was not suppressed by overnight high-dose dexamethasone treatment, suggesting the presence of an extra-pituitary tumor. Contrast-enhanced brain MRI revealed no pituitary adenoma, which also supported the idea that EAS occurred in the present case. Strikingly, chest computed tomographic (CT) scan showed a single 18-mm peripheral nodule in the right middle lobe of the lung. Tumor marker analysis revealed an elevation in plasma ProGRP. These data suggested a possibility that SCLC secreted ACTH and caused EAS in this patient. Of note, the plasma ACTH level was increased (1.7 fold) in l-desamino-8-D-arginine vasopressin (DDAVP) test, also suggesting the specific clinical feature in this case. After additional imaging examinations, we performed surgical resection with the suspicion of limited SCLC. As a result, pathological examination revealed a vasopressin receptor Ib (V1b) receptor-negative bronchial typical carcinoid with ACTH production and mediastinal lymphatic metastasis. In summary, we present a case of EAS caused by progressive bronchial typical carcinoid with plasma ProGRP elevation. We propose a novel subtype of lung typical carcinoid.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapies have demonstrated efficacy and safety in the treatment of type 2 diabetes (T2D). Recent studies suggested the potential roles of SGLT2i in the restoration of pancreatic β-cell function. SGLT2i is a new class of antidiabetic agent, independent from insulin action, however, its mechanism are not enough elucidated. We investigated the effects of SGLT2i on pancreatic β-cell function in T2D patients. This open-label, single-arm trial was conducted in our single medical hospital. A total of 30 patients (mean age 57.9±9.0 years, hemoglobin A1c 8.35±1.09%, BMI 29.2±4.5 kg/m2, diabetes duration 9.6±7.0 years) received some kinds of SGLT2i, canagliflozin, dapagliflozin or empagliflozin. Any change in the medication of oral hypoglycemic agents was not prohibited during the period of this trial. After 3 months of treatment, changes in hemoglobin A1c,body weight, fat mass, proinsulin-to-C-peptide ratio (ProINS/CPR, as an indicator of distressed pancreatic β-cell) and secretory units of islets in transplantation index (SUIT, as a marker of pancreatic β-cell function) were evaluated. Mean hemoglobin A1c decreased from 8.35 to 7.39% (p Disclosure T. Yamamoto: None.

The large Maf transcription factors, MafA and MafB, are expressed with distinct spatial–temporal patterns in rodent islet cells. Analysis of Mafa−/− and pancreas-specific Mafa∆panc deletion mutant mice demonstrated a primary role for MafA in adult β-cell activity, different from the embryonic importance of MafB. Our interests here were to precisely define when MafA became functionally significant to β-cells, to determine how this was affected by the brief period of postnatal MafB production, and to identify genes regulated by MafA during this period. We found that islet cell organization, β-cell mass, and β-cell function were influenced by 3 weeks of age in MafaΔpanc mice and compromised earlier in MafaΔpanc;Mafb+/− mice. A combination of genome-wide microarray profiling, electron microscopy, and metabolic assays were used to reveal mechanisms of MafA control. For example, β-cell replication was produced by actions on cyclin D2 regulation, while effects on granule docking affected first-phase insulin secretion. Moreover, notable differences in the genes regulated by embryonic MafB and postnatal MafA gene expression were found. These results not only clearly define why MafA is an essential transcriptional regulator of islet β-cells, but also why cell maturation involves coordinated actions with MafB.

Aim Alogliptin, an efficacious inhibitor of DPP-4 that improves glycemic control, as well as the pancreatic beta-cell function, is now increasingly used to accomplish glycemic targets in type 2 diabetic patients. Interestingly, recent experimental studies have shown that alogliptin exerts anti-atherosclerotic effects in GLP-1-dependent and -independent manners. The aim of the present ongoing study is to investigate the preventive effects of alogliptin on the progression of atherosclerosis in type 2 diabetic subjects using the carotid intima-media thickness (IMT), an established marker of cardiovascular disease. Methods and results The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between March 2011 and March 2012, 341 participants were recruited at 11 clinical sites, and were randomly allocated either to an alogliptin treatment group (172 patients) or a conventional treatment group (169 patients). The primary outcomes are the changes in the maximum and mean IMT of the common carotid artery during a 24-month treatment period, as measured by carotid arterial echography. The secondary outcomes include the changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, the occurrence of cardiovascular events and adverse events and biochemical measurements reflecting vascular function. Conclusions This is the first study to address the effects of DPP-4 inhibitors on the progression of changes in the carotid IMT, with the patients without DPP-4 inhibitor treatment serving as a control group. The results will be available soon, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent cardiovascular disease.

Objective: Progressive β-cell dysfunction and loss of β-cell mass are fundamental pathogenic features of type 2 diabetes. To examine if anti-diabetic reagents, such as insulin, pioglitazone (pio), and alogliptin (alo), have protective effects on β-cell mass and function in vivo, we treated obese diabetic db/db mice with these reagents. Methods: Male db/db mice were treated with a chow including pio, alo, or both of them from 8 to 16 weeks of age. Insulin glargine (gla) was daily injected subcutaneously during the same period. Results: At 16 weeks of age, untreated db/db mice revealed marked increase of HbA1c level, whereas those treated with pio, pio + alo, or insulin revealed the almost same HbA1c levels as non-diabetic db/m mice. Islet mass evaluated by direct counting in the whole pancreas and insulin content in isolated islets were preserved in pio, pio + alo and gla groups compared with untreated or alo groups, and there was no difference among pio, pio + alo and gla groups. To precisely evaluate islet β-cell functions, islet perifusion analysis was performed. In pio, pio + alo and gla groups, biphasic insulin secretion was preserved compared with untreated or alo groups. In particular, pio + alo as well as gla therapy preserved almost normal insulin secretion, although pio therapy improved partially. To examine the mechanism how these reagents exerted beneficial effects on β-cells, we evaluated expression levels of various factors which are potentially important for β-cell functions by real-time RT-PCR and immunohistochemistry. The results showed that expression levels of MafA and GLP-1 receptor were markedly decreased in untreated and alo groups, but not in pio, pio + alo and gla groups. Conclusion: Combination therapy with pio and alo almost completely normalized β-cell functions in vivo, which was comparable with gla treatment.

A 38-year-old woman was admitted with severe thirst and polyuria at 31 weeks' gestation. The plasma concentration of vasopressin (AVP) was very low (0.73 pg/ml) under conditions of high plasma osmolality (316 mOsm/ kg). T1-weighted magnetic resonance (MR) images revealed enlargement of the pituitary posterior lobe with absence of the hyperintense signal. After delivery, restoration of the hyperintense signal was demonstrated. This depletion-repletion process, which reflects the decrease and increase in amount of neurosecretory granules, is recognized in the case of transient central diabetes insipidus during pregnancy. We consider that an increase in cystine-aminopeptidase (CAP) activity is implicated in the pathogenesis.

OBJECTIVE—Ischemic heart disease is a pivotal complication for diabetic patients. Electron-beam computed tomography (EBCT) represents the only noninvasive method that allows for accurate quantification of coronary artery calcification that reflects underlying atherosclerotic disease. Although coronary calcium score (CCS) cut points that predict the presence of angiographic stenosis have been established in nondiabetic individuals, it is not known whether coronary calcifications in diabetic patients are associated with the presence of significant coronary stenoses. In this study, we evaluated the relationship between coronary calcifications and angiographic stenosis in symptomatic patients with or without type 2 diabetes. RESEARCH DESIGN AND METHODS—In this study, 282 patients (204 men and 78 women) with chest pain, including 101 diabetic patients and 181 nondiabetic patients (mean age 63 ± 9.6 years), underwent coronary angiography and EBCT with determination of CCS using Agatston’s method. Luminal stenosis ≥ 50% was defined as significant coronary stenosis. RESULTS—Angiography identified 205 patients with significant stenoses (89 of 101 diabetic patients, 114 of 181 nondiabetic patients). The sensitivity and specificity of EBCT to detect significant coronary stenosis were not significantly different between diabetic and nondiabetic patients. In diabetic patients, a CCS ≥90 was associated with 75% sensitivity and 75% specificity, whereas a CCS ≥200 was associated with 64% sensitivity and 83% specificity. CONCLUSIONS—We demonstrated that calcification of the coronary arteries in symptomatic diabetic patients is well associated with severity of coronary stenosis, as in nondiabetic patients.

The effect of additional treatment with oral hypoglycemic agents on the progression of atherosclerosis remains unknown in insulin-treated patients with type 2 diabetes mellitus (T2DM). We assessed the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on carotid intima-media thickness (IMT) in T2DM.This prospective, randomized, open-label, blinded end point, multicenter, parallel-group, comparative study included 282 insulin-treated patients with T2DM free of a history of apparent cardiovascular diseases who were recruited at 12 clinical units and randomly allocated to either the sitagliptin group (n = 142) or the control group (n = 140). The primary outcomes were changes in mean and maximum IMT of the common carotid artery measured by echography at the end of a 104-week treatment period.Sitagliptin had a more potent glucose-lowering effect compared with the conventional treatment (-0.5 ± 1.0% vs. -0.2 ± 0.9%; P = 0.004), without increasing hypoglycemic episodes or body weight. Changes in the mean and left maximum IMT, but not right maximum IMT, of the common carotid arteries were significantly greater after sitagliptin treatment compared with conventional treatment (-0.029 [SE 0.013] vs. 0.024 [0.013] mm [P = 0.005]; -0.065 [0.027] vs. 0.022 [0.026] mm [P = 0.021]; -0.007 [0.031] vs. 0.027 [0.031] mm [P = 0.45], respectively). Over 104 weeks, sitagliptin, but not conventional treatment, significantly reduced the mean IMT and left maximum IMT of common carotid arteries relative to the baseline.Sitagliptin attenuated the progression of carotid IMT in insulin-treated patients with T2DM free of apparent cardiovascular disease compared with conventional treatment.

Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period.Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (-0.3 ± 0.7% vs. -0.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (-0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; -0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and -0.079 mm [SE 0.018] vs. -0.015 mm [SE 0.018], P = 0.013, respectively).Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

We examined a possible association between subclinical hypothyroidism and albuminuria in 159 people with type 2 diabetes. Patients with subclinical hypothyroidism had significantly higher levels of urinary albumin-to-creatinine ratio (UACR) than those with euthyroidism. Multivariate logistic regression analyses demonstrated that serum TSH level was an independent risk factor of albuminuria.

Background Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to achieve glycemic targets in patients with type 2 diabetes mellitus (T2DM). The addition of DPP-4 inhibitors to ongoing insulin therapy is expected to reduce insulin dosage, leading to a reduction in the frequency of hypoglycaemia and/or weight gain. Recent studies have demonstrated potential anti-atherosclerotic effects for DPP-4 inhibitors. The aim of the present ongoing study is to assess the effects of sitagliptin on the progression of atherosclerosis in patients with insulin-treated T2DM using carotid intima-media thickness (IMT), an established marker of cardiovascular disease. Methods and Design The Sitagliptin Preventive study of Intima media thickness Evaluation (SPIKE) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between February 2012 and September 2012, 282 participants who failed to achieve glycemic control despite insulin therapy were recruited at 12 clinics and randomly allocated to the sitagliptin group (n = 142) or the control group (n = 140). Primary outcomes are changes in maximum and mean IMT of the common carotid artery after 24-month treatment period measured by carotid arterial echography. Secondary outcomes include changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, occurrence of cardiovascular events and adverse events such as hypoglycaemia, and biochemical markers of vascular function. Discussion The present study is designed to assess the effects of sitagliptin on the progression of carotid IMT. Results will be available in the near future, and the findings are expected to provide new strategy to prevent atherosclerosis in patients with insulin-treated T2DM. Clinical Trial Registration UMIN000007396

We report an 18-year-old male with a history of polyuria, polydipsia, and thirst since childhood. In a hypertonic saline infusion test, the patient's plasma vasopressin rose only to 0.28 pg/ml. In a water deprivation test, his urinary osmolality rose only to 189 mosmol/kg and then rose to 538 mosmol/kg by vasopressin administration. A T1-weighted magnetic resonance imaging (MRI) scan revealed a loss of the posterior pituitary bright spot. Sequencing of the vasopressin gene showed a heterozygous point mutation that replaced Ala at the carboxyterminus of the signal peptide with Thr. His father also had similar history, and we therefore diagnosed his illness as familial central diabetes insipidus.

Rab3A small GTP-binding protein and its associated proteins, such as Rabphilin-3A, a putative target protein for Rab3A, MSS4, a stimulatory GDP/GTP exchange protein for Rab3A, and Rab GDI, a translocator for the Rab family members including Rab3A, are implicated in neurotransmitter release. We have investigated here the phosphorylation of these proteins by cyclic AMP-dependent protein kinase (protein kinase A). Neither Rab3A, MSS4, nor Rab GDI was phosphorylated, but Rabphilin-3A was phosphorylated Rab GDI was phosphorylated, but Rabphilin-3A was phosphorylated at its N-terminal region. About 0.8 mol of phosphate was maximally incorporated into one mol of Rabphilin-3A. These results suggest that Rabphilin-3A is one of the targets for protein kinase A which modulates neurotransmitter release.

OBJECTIVE Several transcription factors are essential to pancreatic islet β-cell development, proliferation, and activity, including MafA and MafB. However, MafA and MafB are distinct from others in regard to temporal and islet cell expression pattern, with β-cells affected by MafB only during development and exclusively by MafA in the adult. Our aim was to define the functional relationship between these closely related activators to the β-cell. RESEARCH DESIGN AND METHODS The distribution of MafA and MafB in the β-cell population was determined immunohistochemically at various developmental and perinatal stages in mice. To identify genes regulated by MafB, microarray profiling was performed on wild-type and MafB−/− pancreata at embryonic day 18.5, with candidates evaluated by quantitative RT-PCR and in situ hybridization. The potential role of MafA in the expression of verified targets was next analyzed in adult islets of a pancreas-wide MafA mutant (termed MafAΔPanc). RESULTS MafB was produced in a larger fraction of β-cells than MafA during development and found to regulate potential effectors of glucose sensing, hormone processing, vesicle formation, and insulin secretion. Notably, expression from many of these genes was compromised in MafAΔPanc islets, suggesting that MafA is required to sustain expression in adults. CONCLUSIONS Our results provide insight into the sequential manner by which MafA and MafB regulate islet β-cell formation and maturation.

OBJECTIVE Islet β-cells loose their ability to synthesize insulin under diabetic conditions, which is at least partially due to the decreased activity of insulin transcription factors such as MafA. Although an in vitro study showed that reactive oxygen species (ROS) decrease MafA expression, the underlying mechanism still remains unclear. In this study, we examined the effects of c-Jun, which is known to be upregulated by ROS, on the expression of MafA under diabetic conditions. RESEARCH DESIGN AND METHODS To examine the protein levels of MafA and c-Jun, we performed histological analysis and Western blotting using diabetic db/db mice. In addition, to evaluate the possible effects of c-Jun on MafA expression, we performed adenoviral overexpression of c-Jun in the MIN6 β-cell line and freshly isolated islets. RESULTS MafA expression was markedly decreased in the islets of db/db mice, while in contrast c-Jun expression was increased. Costaining of these factors in the islets of db/db mice clearly showed that MafA and insulin levels are decreased in c-Jun–positive cells. Consistent with these results, overexpression of c-Jun significantly decreased MafA expression, accompanied by suppression of insulin expression. Importantly, MafA overexpression restored the insulin promoter activity and protein levels that were suppressed by c-Jun. These results indicate that the decreased insulin biosynthesis induced by c-Jun is principally mediated by the suppression of MafA activity. CONCLUSIONS It is likely that the augmented expression of c-Jun in diabetic islets decreases MafA expression and thereby reduces insulin biosynthesis, which is often observed in type 2 diabetes.

Pancreatic and duodenal homeobox factor 1 (Pdx1) has been demonstrated to play a crucial role in pancreas development and in maintenance of mature beta-cell function. However, it remains to be elucidated how Pdx1 gene expression is regulated in non-beta cells during pancreas development. Pdx1 and Ptf1a are expressed in pancreatic progenitor cells, which give rise to all three types of pancreatic tissue. In addition, Ptf1a has been shown to bind the mammalian Suppressor of Hairless (RBP-J) within the PTF1 complex. Furthermore, loss-of-function approaches have revealed that all three factors are essential for early pancreas development. We therefore hypothesized that Ptf1a and RBP-J regulate expression of the Pdx1 gene in pancreatic precursors. Reporter gene analyses showed that Ptf1a transactivated Pdx1 promoter in pancreatic Panc-1 cells, which was enhanced by RBP-J. Deletion/mutation analyses of the Pdx1 promoter and electrophoretic gel-mobility shift assays identified the Ptf1a binding site in the well-conserved regulatory sequence domain, termed Area III, which was also confirmed by the chromatin immunoprecipitation assay. Furthermore, adenovirus-mediated overexpression of Ptf1a, together with RBP-J, markedly increased Pdx1 protein levels in pancreatic AR42J-B13 cells. Our data suggest a novel transcriptional network, where Ptf1a and RBP-J cooperatively regulate Pdx1 gene expression through binding to Area III.

A 76-year-old woman suffered from somnolence while fasting for almost 2 years. Fasting plasma glucose (FPG) (40 mg/dl) and the immunoreactive insulin (IRI) level (8.8 μU/ml) were not compatible with Fajan's ratio or Turner's ratio observed in typical insulinoma. The secretin test showed no response to insulin secretion, suggesting the presence of insulinoma. Abdominal dynamic computed tomography (CT) revealed a 12-mm hypervascular lesion in the head of the pancreas. A selective arterial calcium infusion test (SACI) was performed, during which IRI in the hepatic venous blood was measured following selective intraarterial calcium infusion. An increase in IRI levels in the gastroduodenal and superior mesenteric arteries suggested the presence of a functional insulinoma in the head of the pancreas. Enucleation of the tumor improved FPG and IRI levels to 138 mg/dl and 3.8 μU/ml, respectively. After surgery, a secretin test showed a 5-fold increase in IRI levels, suggesting normal β cell function. This case illustrates the value of the secretin test for the diagnosis of insulinoma and for the postoperative assessment of β cell function. It further illustrates the value of the SACI for localizing an insulinoma.(Internal Medicine 41: 839-841, 2002)

To examine the glycemic response during exercise after administration of short-acting insulin lispro, we compared changes in plasma glucose concentrations during exercise performed by patients with diabetes after the administration of either insulin lispro or regular human insulin. Seven patients with diabetes (two with type 1 and five with type 2) participated in this study. Each of the insulin-depleted subjects received the same number of units of either insulin lispro or regular human insulin, delivered subcutaneously to the abdomen. The next day, each subject received a similar injection of the solution not previously administered. After each injection, the subjects were fed a standard meal of approximately 9 kcal/kg body weight. One hour after eating the test meal, the subjects performed 30 min of cycle ergometer exercise at 50% maximal oxygen uptake. Plasma glucose, insulin, glucagon, growth hormone (GH), and catecholamine concentrations were then measured at specific intervals. Insulin concentrations were higher and peaked earlier after administration of insulin lispro than after administration of regular human insulin. The length of time, needed to reach minimum plasma glucose concentration after exercise was begun, was significantly shorter after administration of insulin lispro, and the percentage of plasma glucose decrease induced by exercise relative to the peak concentration was significantly greater. No differences were found in the concentration changes of counterregulatory hormones between the insulin lispro data and the regular human insulin data. Compared with regular human insulin, insulin lispro induces a more rapid and greater decrease in plasma glucose concentration during exercise because of its faster absorption.

OBJECTIVE To investigate the basal insulin requirement in total daily insulin dose in Japanese type 1 diabetic patients who use the insulin pump. RESEARCH DESIGN AND METHODS The basal insulin requirement in 35 type 1 diabetic patients without detectable C-peptide using the insulin pump (Paradigm 712) was investigated during 2–3 weeks of hospitalization. The patients were served diabetic diets of 25–30 kcal/kg ideal body weight. Each meal omission was done to confirm stable blood glucose levels within 30 mg/dL variance until the next meal. Target blood glucose level was set at 100 mg/dL before each meal and 150 mg/dL at 2 h after each meal. RESULTS Total daily insulin dose was 31.6 ± 8.5 units, and total basal insulin requirement was 8.7 ± 2.9 units, which was 27.7 ± 6.9% of the total daily dose. CONCLUSIONS Basal insulin requirement is ∼30% of the total daily dose in Japanese type 1 diabetic patients who use the insulin pump.

To evaluate the effect of exercise training on serum leptin levels 50 sedentary subjects with type 2 diabetes were enrolled in either 6 weeks of aerobic exercise training with diet therapy (n = 23) or diet therapy alone (n = 27). The training program consisted of walking and cycle ergometer exercise for 1 hour at least 5 times per week, with the intensity of exercise maintained at 50% of maximum oxygen uptake. Serum leptin levels decreased significantly in the exercise training (TR) group (7.2 +/- 3.6 to 4.6 +/- 2.5 ng/mL, P