DPP-4 inhibition with linagliptin ameliorates the progression of premature aging in klotho−/− mice

Hasegawa, Yu; Hayashi, Kenyu; Takemoto, Yushin; Cao, Cheng; Takane, Koki; Lin, Bo; Komohara, Yoshihiro; Kim‐Mitsuyama, Shokei

doi:10.1186/s12933-017-0639-y

Cited by 22 publications

(21 citation statements)

References 41 publications

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“…506 In another study, the effects of linagliptin on an animal model of premature aging supported a positive role in preventing muscle loss, based on the larger size of the gastrocnemius muscle in linagliptintreated mice compared with control. 514 Teneligliptin, when compared with a GLP-1R agonist, did not appear to have negative effects on skeletal muscle mass of patients with T2D on dialysis. 511 However, with the recent increase in DPP-4 inhibitor use, there have been reports of this class of medications causing myalgia, extremity pain, muscle weakness, and other musculoskeletal adverse events, such as arthralgia.…”

Section: Incretinsmentioning

confidence: 88%

“…MK‐0626, a DPP‐4 inhibitor, was associated with improvements in mitochondrial biogenesis in skeletal muscle and improvement in exercise capacity of mice who had suffered recent myocardial infarction . In another study, the effects of linagliptin on an animal model of premature aging supported a positive role in preventing muscle loss, based on the larger size of the gastrocnemius muscle in linagliptin‐treated mice compared with control . Teneligliptin, when compared with a GLP‐1R agonist, did not appear to have negative effects on skeletal muscle mass of patients with T2D on dialysis .…”

Section: Drugs and Musclementioning

confidence: 96%

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Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Section: Incretinsmentioning

confidence: 88%

Section: Drugs and Musclementioning

confidence: 96%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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“…The lifespan of klotho −/− mice was prolonged, and their body weight was significantly related to greater kidney weight in the intervention of linagliptin [194]. Although no conclusive evidence has demonstrated that DPP4 inhibition improves diabetic kidney lesions, it may control blood glucose and albuminuria as well as be tolerated in patients with DM and CKD, indicating potential renal benefits [195].…”

Section: Potential Therapeutic Strategy Targeting Accelerated Kidney mentioning

confidence: 99%

Accelerated Kidney Aging in Diabetes Mellitus

Guo

Zheng

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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With aging, the kidney undergoes inexorable and progressive changes in structural and functional performance. These aging-related alterations are more obvious and serious in diabetes mellitus (DM). Renal accelerated aging under DM conditions is associated with multiple stresses such as accumulation of advanced glycation end products (AGEs), hypertension, oxidative stress, and inflammation. The main hallmarks of cellular senescence in diabetic kidneys include cyclin-dependent kinase inhibitors, telomere shortening, and diabetic nephropathy-associated secretory phenotype. Lysosome-dependent autophagy and antiaging proteins Klotho and Sirt1 play a fundamental role in the accelerated aging of kidneys in DM, among which the autophagy-lysosome system is the convergent mechanism of the multiple antiaging pathways involved in renal aging under DM conditions. Metformin and the inhibitor of sodium–glucose cotransporter 2 are recommended due to their antiaging effects independent of antihyperglycemia, besides angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Additionally, diet intervention including low protein and low AGEs with antioxidants are suggested for patients with diabetic nephropathy (DN). However, their long-term benefits still need further study. Exploring the interactive relationships among antiaging protein Klotho, Sirt1, and autophagy-lysosome system may provide insight into better satisfying the urgent medical needs of elderly patients with aging-related DN.

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“…Moreover, klotho levels are decreased by Ang-2 [ 187 ] and one of the downstream effects of klotho is regulation of NO signaling (Fig. 2 c, f) [ 188 ].…”

Section: Introductionmentioning

confidence: 99%

“…To our knowledge, this was the first study suggesting that the vasculo-protective effects of linagliptin involve modulation of klotho signaling. In addition, a more recent study showed that amelioration of progression of premature aging in klotho knock out mice by linagliptin and these salutary effects were associated with increased bioavailable NO in the cerebral vasculature [ 188 ]. Angiotensin II decreases klotho levels and linagliptin improves Ang II signaling, including downregulation of AT1R [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

The role of dipeptidylpeptidase-4 inhibitors in management of cardiovascular disease in diabetes; focus on linagliptin

Aroor

Manrique‐Acevedo

DeMarco

2018

Cardiovasc Diabetol

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Multiple population based analyses have demonstrated a high incidence of cardiovascular disease (CVD) and cardiovascular (CV) mortality in subjects with T2DM that reduces life expectancy by as much as 15 years. Importantly, the CV system is particularly sensitive to the metabolic and immune derangements present in obese pre-diabetic and diabetic individuals; consequently, CV dysfunction is often the initial CV derangement to occur and promotes the progression to end organ/tissue damage in T2DM. Specifically, diabetic CVD can manifest as microvascular complications, such as nephropathy, retinopathy, and neuropathy, as well as, macrovascular impairments, including ischemic heart disease, peripheral vascular disease, and cerebrovascular disease. Despite some progress in prevention and treatment of CVD, mainly via blood pressure and dyslipidemia control strategies, the impact of metabolic disease on CV outcomes is still a major challenge and persists in proportion to the epidemics of obesity and diabetes. There is abundant pre-clinical and clinical evidence implicating the DPP-4-incretin axis in CVD. In this regard, linagliptin is a unique DPP-4 inhibitor with both CV and renal safety profiles. Moreover, it exerts beneficial CV effects beyond glycemic control and beyond class effects. Linagliptin is protective for both macrovascular and microvascular complications of diabetes in preclinical models, as well as clinical models. Given the role of endothelial-immune cell interactions as one of the key events in the initiation and progression of CVD, linagliptin modulates these cell–cell interactions by affecting two important pathways involving stimulation of NO signaling and potent inhibition of a key immunoregulatory molecule.

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DPP-4 inhibition with linagliptin ameliorates the progression of premature aging in klotho−/− mice

Cited by 22 publications

References 41 publications

Diabetes pharmacotherapy and effects on the musculoskeletal system

Diabetes pharmacotherapy and effects on the musculoskeletal system

Accelerated Kidney Aging in Diabetes Mellitus

The role of dipeptidylpeptidase-4 inhibitors in management of cardiovascular disease in diabetes; focus on linagliptin

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