Dipeptidyl peptidase 4 inhibitors attenuates the decline of skeletal muscle mass in patients with type 2 diabetes

Bouchi, Ryotaro; Fukuda, Tatsuya; Takeuchi, Takato; Nakano, Yujiro; Murakami, Masanori; Minami, Isao; Izumiyama, Hajime; Hashimoto, Kazuhito; Yoshimoto, Takanobu; Ogawa, Yoshihiro

doi:10.1002/dmrr.2957

Cited by 39 publications

(35 citation statements)

References 40 publications

(49 reference statements)

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“…As a consequence, muscle mass and muscle function improved in Dex-induced muscle atrophy mice. In support of our results, recent studies reported that the inhibitors of DPP4, a GLP-1 degradation enzyme, are associated with improvement of reduced muscle mass in diabetic and elderly diabetic patients 15,71 and with improvement of mitochondrial biogenesis in a heart failure mouse model. 16 CKD is a model of cachexia that is mainly induced by inflammatory cytokines in the human pathological state.…”

Section: Discussionsupporting

confidence: 91%

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

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Background Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex‐4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP‐1R agonist for muscle wasting and the mechanisms involved. Methods Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex‐4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex‐4 in a Dex‐induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex‐4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)‐induced muscle atrophy model. Furthermore, we evaluated the effect of a long‐acting GLP‐1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J‐mdx mice, a Duchenne muscular dystrophy model. Results Ex‐4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F‐box only protein 32 (atrogin‐1) and muscle RING‐finger protein‐1 (MuRF‐1) in Dex‐treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP‐1R. In addition, Ex‐4 treatment inhibited glucocorticoid receptor (GR) translocation by up‐regulating the proteins of GR inhibitory complexes. In a Dex‐induced muscle atrophy model, Ex‐4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex‐4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long‐acting GLP‐1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J‐mdx mice. Conclusions GLP‐1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP‐1R‐mediated signalling pathways. These novel findings suggest that activating GLP‐1R signalling may be useful for the treatment of atrophy‐related muscular diseases.

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Section: Discussionsupporting

confidence: 91%

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

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“…Recently, it was reported that skeletal muscle indices were positively correlated with C-peptide, which showed endogenous insulin reserve [ 53 ], and dipeptidyl peptidase 4 inhibitors attenuated the decline of skeletal muscle in patients with T2DM [ 54 ]. Taken together, the present results demonstrated the importance of evaluating muscle quality in type 2 diabetic patients with visceral fat accumulation for potential risk assessment for atherosclerosis, suggesting that physicians might be better to consider selection of anti-diabetic agent from view point of the effect on skeletal muscle and support for patients in modifying their exercise habit.…”

Section: Discussionmentioning

confidence: 99%

Low muscle quality in Japanese type 2 diabetic patients with visceral fat accumulation

Murai

Nishizawa

Otsuka

et al. 2018

Cardiovasc Diabetol

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BackgroundAlthough obesity-related type 2 diabetes mellitus (T2DM) and sarcopenia in the elderly have been increasing worldwide, the associations among visceral fat accumulation, skeletal muscle indices (mass, strength, and quality) and cardiovascular diseases in T2DM remain poorly investigated.MethodsWe enrolled 183 Japanese T2DM inpatients (126 men, 57 women; mean age 64.7 ± 12.6 years, ± SD). The estimated-visceral fat area (eVFA) and skeletal muscle mass were measured by each device using bioelectrical impedance analysis method. We also measured grip strength by dynamometer and motor nerve conduction velocity (MCV). We analyzed the difference in skeletal muscle indices between T2DM patients with and without visceral fat accumulation, and examined the impact of skeletal muscle indices on cardiovascular diseases in patients with visceral fat accumulation.ResultsThe prevalence of sarcopenia defined by the Consensus of Asian Working Group for Sarcopenia and low skeletal muscle mass were both lower in the visceral fat accumulation (+) group than in (−) group. However, the prevalence of weak hand grip strength was similar in the visceral fat accumulation (−) and (+) groups, indicating that considerable patients with visceral fat accumulation had weak grip strength in spite of fair skeletal muscle mass. Muscle quality [grip strength (kg)/arm muscle mass (kg)] was significantly lower in patients with visceral fat accumulation. Multiple regression analysis identified eVFA, MCV and sex as significant and independent determinants of muscle quality. In visceral fat accumulation (+) group, the patients with low muscle quality had longer duration of diabetes, lower eGFR, higher serum adiponectin, lower MCV and higher prevalence of cardiovascular diseases, compared to the patients with high muscle quality. Finally, sex- and age-adjusted models showed significant association between low muscle quality and cardiovascular diseases in all subjects (odds ratio 2.28, p = 0.012), especially in patients with visceral fat accumulation (odds ratio 2.72, p = 0.018).ConclusionsT2DM patients with visceral fat accumulation had low muscle quality, and patients with low muscle quality were more affected with cardiovascular diseases.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0755-3) contains supplementary material, which is available to authorized users.

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“…Indeed, DPP4 was shown to impair insulin signalling in smooth muscle cells, and its levels were increased in obese subjects causing insulin resistance 45,46 . Moreover, DPP4 inhibitors used in diabetes 2 treatment of elderly patients were demonstrated to prevent sarcopenia 47,48 . In this case, insulin insensitivity causes muscle loss.…”

Section: Discussionmentioning

confidence: 99%

Chromatin and transcriptome changes in human myoblasts show spatio-temporal correlations and demonstrate DPP4 inhibition in differentiated myotubes

Kolanowski

Rozwadowska

Zimna

et al. 2020

Sci Rep

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Although less attention was paid to understanding physical localization changes in cell nuclei recently, depicting chromatin interaction maps is a topic of high interest. Here, we focused on defining extensive physical changes in chromatin organization in the process of skeletal myoblast differentiation. Based on RNA profiling data and 3D imaging of myogenic (NCAM1, DES, MYOG, ACTN3, MYF5, MYF6, ACTN2, and MYH2) and other selected genes (HPRT1, CDH15, DPP4 and VCAM1), we observed correlations between the following: (1) expression change and localization, (2) a gene and its genomic neighbourhood expression and (3) intra-chromosome and microscopical locus-centromere distances. In particular, we demonstrated the negative regulation of DPP4 mRnA (p < 0.001) and protein (p < 0.05) in differentiated myotubes, which coincided with a localization change of the DPP4 locus towards the nuclear lamina (p < 0.001) and chromosome 2 centromere (p < 0.001). Furthermore, we discuss the possible role of DPP4 in myoblasts (supported by an inhibition assay). We also provide positive regulation examples (VCAM1 and MYH2). Overall, we describe for the first time existing mechanisms of spatial gene expression regulation in myoblasts that might explain the issue of heterogenic responses observed during muscle regenerative therapies. The changes in the localization of chromosomes and their genes in the three-dimensional nuclear space are tightly regulated but highly variable phenomena. These nuclear interactions have an impact on transcriptional regulation, cell fate and inheritance mechanisms 1-3. Recent years have led to the development of many high-throughput techniques that have vastly increased our knowledge and understanding of chromatin interaction mechanisms 4-7. However, these high-throughput techniques (called '3C techniques') rely on sequence proximity in order to map ongoing interactions. However, creating a physical map of chromatin positioning in relation to the other components of nuclei remains a challenge. To define specific position changes of chromatin in nuclei, microscopic observations of labelled material are necessary, and these techniques have been developed simultaneously with 3C techniques, ultimately combining both approaches 8-12. Human muscle-derived stem cells have been used in regenerative therapies for nearly two decades. Since pluripotent stem cell (iPSC)-based technology is still lacking clinical feasibility, myoblast-based therapies can be considered generally safe and effective for regaining muscle contraction after sphincter rupture or when used in experimental therapies of muscle dystrophies 13. One of the difficulties of cellular therapies is patient variability

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Dipeptidyl peptidase 4 inhibitors attenuates the decline of skeletal muscle mass in patients with type 2 diabetes

Abstract: Our data suggest the potential of DPP4i to prevent the progressive loss of muscle mass with ageing in patients with type 2 diabetes.

Cited by 39 publications

References 40 publications

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Low muscle quality in Japanese type 2 diabetic patients with visceral fat accumulation

Chromatin and transcriptome changes in human myoblasts show spatio-temporal correlations and demonstrate DPP4 inhibition in differentiated myotubes

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