慶應義塾研究者情報データベース

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• Worksite-based intensive lifestyle therapy has profound cardiometabolic benefits in people with obesity and type 2 diabetes

  Yoshino, M., Yoshino, J., Smith, G. I., Stein, R. I., Bittel, A. J., Bittel, D. C., Reeds, D. N., Sinacore, D. R., Cade, W. T., Patterson, B. W., Cho, K., Patti, G. J., Mittendorfer, B. and Klein, S.

  Cell Metab 34 （ 10 ） 1431 - 1441 e5 2022年10月

  査読有り,  ISSN  1932-7420

  　概要を見る

  Lifestyle therapy (energy restriction and exercise) is the cornerstone of therapy for people with type 2 diabetes (T2D) but is difficult to implement. We conducted an 8-month randomized controlled trial in persons with obesity and T2D (17 women and 1 man) to determine the therapeutic effects and potential mechanisms of intensive lifestyle therapy on cardiometabolic function. Intensive lifestyle therapy was conducted at the worksite to enhance compliance and resulted in marked (17%) weight loss and beneficial changes in body fat mass, intrahepatic triglyceride content, cardiorespiratory fitness, muscle strength, glycemic control, beta cell function, and multi-organ insulin sensitivity, which were associated with changes in muscle NAD(+) biosynthesis, sirtuin signaling, and mitochondrial function and in adipose tissue remodeling. These findings demonstrate that intensive lifestyle therapy provided at the worksite has profound therapeutic clinical and physiological effects in people with T2D, which are likely mediated by specific alterations in skeletal muscle and adipose tissue biology.

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• Response to Comment on "Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women"

  Klein, S. and Yoshino, M.

  Science 373 （ 6554 ）  2021年07月

  査読有り,  ISSN  1095-9203

  　概要を見る

  In evaluating any randomized clinical trial, it is important to determine whether baseline differences between groups could have affected the primary outcome. In our study, muscle insulin sensitivity, which was identical in both groups at baseline, improved after nicotinamide mononucleotide (NMN), not placebo, therapy. Differences in baseline intrahepatic triglyceride content between groups do not negate the effects of NMN observed in muscle.

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• Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

  Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., Sindelar, M., Pietka, T., Patterson, B. W., Imai, S. I. and Klein, S.

  Science 372 （ 6547 ） 1224 - 1229 2021年06月

  査読有り,  ISSN  1095-9203

  　概要を見る

  In rodents, obesity and aging impair nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, which contributes to metabolic dysfunction. Nicotinamide mononucleotide (NMN) availability is a rate-limiting factor in mammalian NAD(+) biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese. Insulin-stimulated glucose disposal, assessed by using the hyperinsulinemic-euglycemic clamp, and skeletal muscle insulin signaling [phosphorylation of protein kinase AKT and mechanistic target of rapamycin (mTOR)] increased after NMN supplementation but did not change after placebo treatment. NMN supplementation up-regulated the expression of platelet-derived growth factor receptor beta and other genes related to muscle remodeling. These results demonstrate that NMN increases muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese (clinicaltrial.gov NCT03151239).

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• Effect of Diet versus Gastric Bypass on Metabolic Function in Diabetes. Reply

  Yoshino, M., Kayser, B. D. and Klein, S.

  N Engl J Med 383 （ 24 ） 2393 - 2394 2020年12月

  査読有り,  ISSN  1533-4406

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• Obesity Is Associated With Increased Basal and Postprandial β-Cell Insulin Secretion Even in the Absence of Insulin Resistance

  van Vliet S., Koh H.C.E., Patterson B.W., Yoshino M., LaForest R., Gropler R.J., Klein S., Mittendorfer B.

  Diabetes （Diabetes)  69 （ 10 ） 2112 - 2119 2020年10月

  査読有り

  　概要を見る

  We tested the hypothesis that obesity, independent of insulin resistance, is associated with increased insulin secretion. We compared insulin kinetics before and after glucose ingestion in lean healthy people and people with obesity who were matched on multiorgan insulin sensitivity (inhibition of adipose tissue lipolysis and glucose production and stimulation of muscle glucose uptake) as assessed by using a two-stage hyperinsulinemic-euglycemic pancreatic clamp procedure in conjunction with glucose and palmitate tracer infusions and positron emission tomography. We also evaluated the effect of diet-induced weight loss on insulin secretion in people with obesity who did not improve insulin sensitivity despite marked (∼20%) weight loss. Basal and postprandial insulin secretion rates were >50% greater in people with obesity than lean people even though insulin sensitivity was not different between groups. Weight loss in people with obesity decreased insulin secretion by 35% even though insulin sensitivity did not change. These results demonstrate that increased insulin secretion in people with obesity is associated with excess adiposity itself and is not simply a compensatory response to insulin resistance. These findings have important implications regarding the pathogenesis of diabetes because hyperinsulinemia causes insulin resistance and insulin hypersecretion is an independent risk factor for developing diabetes.

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