Insulin Resistance and Inflammation as Precursors of Frailty

Abstract

Background: Our research group has previously shown that the geriatric syndrome of frailty is associated with features of the metabolic syndrome (MetS) on crosssectional analysis.Methods: To test whether MetS and its physiologic determinants-insulin resistance as measured by homeostasismodelassessmentscore(IR-HOMA),increasedinflammation and coagulation factor levels, and elevated blood pressure-are associated with incident frailty, we studied a subcohort of participants from the Cardiovascular Health Study observed from 1989/1990 through 1998/1999: 3141 community-dwelling adults, aged 69 to 74 years, without frailty and illnesses that increase inflammation markers or mimic frailty. The association of baseline MetS, IR-HOMA, levels of inflammation and coagulation factors, and systolic blood pressure (SBP) with time to onset of frailty was adjusted for demographic and psychosocial factors and incident events. Our main outcome measure was incident frailty.Results: Metabolic syndrome was not significantly associated with incident frailty (hazard ratio, 1.16 (95% confidence interval [CI], 0.85-1.57). On the other hand, IR-HOMA and C-reactive protein levels were associated with incident frailty: for every standard deviation increment the hazard ratio for frailty was 1.15 (95% CI, 1.02-1.31) and 1.16 (95% CI, 1.02-1.32), respectively. The white blood cell count and factor VIIIc levels had a borderline association. Elevated systolic blood pressure had no association. Similar trends were found for incident prefrailty, a condition that precedes frailty. Conclusions:Two physiologic components of MetS-IR-HOMA and inflammation-are associated with incident frailty. Based on these results, IR-HOMA can be considered part of a larger process that leads to generalized decline.

The association between frailty, the metabolic syndrome, and mortality over the lifespan

“…The relationship between metabolic syndrome and the FI was very weak in those aged over 65 years, although those with metabolic syndrome did have higher mean FI scores than those without the syndrome. Other studies have found an association between these syndromes in populations aged 50 plus (Viscogliosi 2016) but not in those aged over 70 (Barzilay et al 2007) or over 90 (Hao et al 2016). Overall, the current study indicates that there is a relationship between FI and metabolic syndrome, but this relationship declines in old age.…”

“…Common pathophysiological pathways such as inflammation (Cesari et al 2006;Barzilay et al 2007;Hubbard and Woodhouse 2010;Collerton et al 2012) and changes in body composition could help explain the link between frailty and metabolic syndrome in younger adults. The FI quantifies health deficit accumulation across a range of systems, so it seems likely if someone has the metabolic syndrome then they will have more health-related deficits.…”

“…In adults aged 50+ years, people who are frail are more likely to have metabolic syndrome (Viscogliosi 2016), and likewise, the metabolic syndrome is linked to an increased risk of frailty (Tang et al 2013;Lin et al 2015). Other studies, however, report no association between metabolic syndrome and frailty in older populations (70+ years) (Barzilay et al 2007;Hao et al 2016). A recent study in very old people (90+ years) showed that while a higher FI score was associated with a greater risk of mortality, metabolic syndrome status was not (Hao et al 2016).…”

Dysregulated homeostatic pathways in sarcopenia among frail older adults

“…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.…”

Hyperbolic relation between beta-cell function and insulin sensitivity for type 2 diabetes mellitus, malaria, influenza, Helicobacter pylori, Chlamydia pneumoniae,and hepatitis C virus infection-induced inflammation/oxidative stress and temporary insulin resistance in Central Africans*

“…Clinical and epidemiological data show that inflammatory factors and insulin resistance may be associated with obesity, important risk factors of insulin resistance (7,19,20), type 2 diabetes mellitus (21), and acute phase reactants (22). In this sense, the burden of infection (enteroviruses and Chlamydia pneumoniae) and their treatment are associated with chronic low-grade inflammation and oxidative stress, resulting in insulin resistance and atherosclerosis (23,24).…”