Insulin resistance and sarcopenia: mechanistic links between common co-morbidities

Abstract

Insulin resistance (IR) in skeletal muscle is a key defect mediating the link between obesity and type 2 diabetes, a disease that typically affects people in later life. Sarcopenia (age-related loss of muscle mass and quality) is a risk factor for a number of frailty-related conditions that occur in the elderly. In addition, a syndrome of 'sarcopenic obesity' (SO) is now increasingly recognised, which is common in older people and is applied to individuals that simultaneously show obesity, IR and sarcopenia. Such individuals are at an increased risk of adverse health events compared with those who are obese or sarcopenic alone. However, there are no licenced treatments for sarcopenia or SO, the syndrome is poorly defined clinically and the mechanisms that might explain a common aetiology are not yet well characterised. In this review, we detail the nature and extent of the clinical syndrome, highlight some of the key physiological processes that are dysregulated and discuss some candidate molecular pathways that could be implicated in both metabolic and anabolic defects in skeletal muscle, with an eye towards future therapeutic options. In particular, the potential roles of Akt/mammalian target of rapamycin signalling, AMP-activated protein kinase, myostatin, urocortins and vitamin D are discussed. R67-R81 229:2 Muscle insulin resistance and sarcopenia Associations between obesity, diabetes and skeletal muscle ageingThe International Diabetes Federation has estimated that there were 382 million people living with diabetes in 2013, with this number predicted to rise to 592 million by 2035, of which the significant majority would be of >40 years old (IDF 2013). Of these, 90% suffer from type 2 diabetes (T2D), which is characterised by both β-cell failure and resistance to the actions of insulin at the tissue level (insulin resistance, IR). As skeletal muscle is responsible for the majority of the body's postprandial glucose disposal, IR in this tissue results in substantial whole-body metabolic disturbances. However, it is likely that the metabolic disturbances associated with T2D are further exacerbated by the marked loss of skeletal muscle mass that can also be associated with these conditions (Park et al. 2009, Kim et al. 2010. Specifically, loss of muscle mass induces a 2-3% decline in basal metabolic rate per decade after the age of 20 years and 4% per decade after the age of 50 years, resulting from concomitant loss of mitochondrial volume density and oxidative capacity (Conley et al. 2000). Journal of EndocrinologyThis loss of muscle mass in the elderly is also the principal factor responsible for 'frailty', a syndrome that has been clinically defined as the possession of three of: unintentional weight loss (10 pounds (~4.5 kg) in the past year), self-reported exhaustion, weakness (poor grip strength), slow walking speed and low physical activity (Fried et al. 2001). Loss of muscle mass (atrophy) is an inevitable, although somewhat modifiable, process that occurs with ageing (Sayer et al. 2008), w...

From Sarcopenia to Frailty: The Pathophysiological Basis and Potential Target Molecules of Intervention

“…However, muscle of older individuals with type 2 diabetes [29] metabolic syndrome [30] demonstrated a significant low proportion of type I fibers that is positively associated with the severity of insulin resistance. Thus, the loss of muscle mass and the alterations of myofiber type proportion due to insulin resistance could potentially affect whole body glucose homeostasis [31]. Age-related hormone changes, for example, the decline of anabolic hormone testosterone leads to the loss of both muscle mass and strength [32].…”

“…Muscle growth promoters through their receptors phosphorylate SMAD 1/5/8 decrease the inhibition of Alt/mTOR signal and maintain muscle mass and strength. Insulin resistance due to aging, obesity, and diabetes results in the suppression of insulin/insulin-like growth factor-1/phosphatidyl Inositol 3-kinase/protein kinase B (IGF 1/PI3K/AKT)/mTOR, and muscle hypotrophy and dysfunction of metabolism; the less activated Alk fails to block the nuclear translocation of Foxo 3 to enhance the expression of autophagy-related genes and the consequent protein degradation [31,52].…”

“…A number of aging-associated molecular signals might be the potential target in the prevention and treatment of sarcopenia, frailty, and cognitive impairment. Genetic or pharmacological regulation of NAD+/Sirt1, sestrins/AMPK/PGC1α, IGF-1/Akt/mTOR, TGF-β, myostatin, activins, GDFs /SMAD2/3, BMPs/SMAD1/5/8 signal molecules, myokine irisin and FGF21, the antagonist of myokine myostatin propeptide follistatin or follistatin-like 3, and urocortins can not only improve muscle mass and/or function but also delay frailty and agerelated diseases [31,54,68]. Besides dietary restriction and exercise, geroscience interventions with translational potential include mTOR inhibitors, metformin and acarbose, NAD precursors and sirtuin activators, modifiers of senescence and telomere dysfunction, hormonal and circulating factors, and mitochondrial-targeted therapeutics [78].…”

Dysregulated homeostatic pathways in sarcopenia among frail older adults

“…

Insulin signaling and energy metabolism (ISEM: denoted by insulin, C‐peptide, leptin). Based on present evidence, it remains unclear whether increased insulin resistance or reduced endogenous insulin secretion (or both) is underlying mechanisms in sarcopenia and frailty (Cleasby et al, 2016; Tanaka, Kanazawa, & Sugimoto, 2015). Our result shows that low fasting plasma insulin and C‐peptide (a better measure of portal insulin secretion) levels are associated with low muscle mass and function and suggests that in this Asian group, endogenous reduction of insulin level and dysregulated insulin signaling activity in older individuals (with and without diabetes) diminish the anabolic capacity of insulin to alleviate muscle protein breakdown in skeletal muscles.

…”

“…Circulating insulin (Barzilay et al, 2007; Cleasby, Jamieson, & Atherton, 2016), testosterone (Auyeung et al, 2011), insulin‐like growth factor‐1 (IGF‐1; Gielen et al, 2015), and dehydroepiandrosterone sulfate (DHEAS; Tajar et al (2011)) have been interrogated in a majority of studies mostly in isolation and with conflicting results. In contrast, several studies, such as the InCHIANTI Study, the WHAS I and II, and the MSSA (Fried et al, 2009; Gruenewald, Seeman, Karlamangla, & Sarkisian, 2009; Maggio et al, 2010), have found that an increased number of multiple hormonal biomarker abnormalities strongly predict physical frailty when individual biomarker abnormalities did not.…”