In the present study, we have identified independent risk factors for frailty, defined using the CFS, in 148 elderly T2DM patients, using multiple logistic regression analysis. These were serum Alb <4.0 g/dl (p <0.001), AST activity <25 IU/L (p =0.009), and BM <53 kg (p =0.012). In our previous study of 132 elderly T2DM patients, multiple regression analysis revealed that advanced age, and low albumin, HDL-C, SBP, HbA1c, and BM were risk factors for frailty, quantified using CFS, of which albumin was the most potent 4.
Low albumin was also identified to be the most potent risk factor for frailty in the present study. Therefore, we recommended that the serum albumin concentration of elderly people is maintained at ≥4.0 g/dL to prevent frailty. In Japan, protein intake is low in the elderly, which is likely to cause frailty. Furthermore, mortality in hospitalized patients is associated with hypoalbuminemia, and hypoalbuminemia has been shown to increase mortality 22.
In the present study, low Alb concentration and BM were shown to be independent risk factors for frailty, as shown previously, but HDL-C, SBP, and HbA1c were not. This is probably because the participants and sample size differed from those in the previous study, even though there was an overlap in the participants in each study (the number were 74 of 148 cases). However, although the list of risk factors differed between the studies, the common factors suggest that malnutrition or a related condition may be the most important cause of frailty in elderly T2DM patients. Malnutrition may be a constitutional syndrome or may be the result of strict dietary control imposed by the individual or their doctor. However, a number of endocrine factors may also be involved in malnutrition 5, as discussed below.
Interestingly, in the present study, the ALT and AST activities were significantly lower in the frail group than in the non-frail group, and AST <25 IU/L was shown to be an independent risk factor for frailty. Recently, low serum ALT activity has been shown to be associated with aging23, higher prevalence of frailty23, 24 and sarcopenia24 and to be a predictor of their subsequent higher mortality23, 24, 25 in the elderly. Thus, ALT has been suggested to be a useful biomarker for aging and frailty.
However, there is no explanation for these associations. Low serum ALT and AST activities occur secondary to low serum concentrations of vitamin B6, because AST, and especially ALT, require vitamin B6 as a cofactor 26. Furthermore, vitamin B6 deficiency has been shown to be associated with low activity and low serum albumin in elderly nursing home residents 27. Thus, one plausible explanation for the low transaminase activities in frail T2DM patients may be relative vitamin B6 deficiency, resulting from malnutrition.
Although serum cortisol, DHEA-S and cortisol/DHEA-S ratio were not found to be independent risk factors in the multiple regression analysis, there is evidence that they contribute to frailty in elderly T2DM patients. In the present study, while log serum DHEA-S decreased significantly with age, even in the range of 65-95 years old, serum cortisol increased significantly. Serum DHEAS <70 µg/dL was found to be a risk factor for frailty in simple regression analysis, but no significant relationship was identified between serum cortisol and frailty. Serum cortisol significantly increased, while serum DHEA-S significantly decreased with increasing CFS, between grades 1 and 7. As a result, a cortisol/DHEAS ratio ³0.2 was a significant risk factor for frailty in simple regression analysis. As for elderly T2DM patients with sarcopenia 9, frail T2DM patients are thought to be under stress. Whereas cortisol is as catabolic hormone, DHEA-S is anabolic and antagonizes cortisol. Therefore, the relative cortisol overactivity may disrupt homeostasis, resulting in frailty and sarcopenia.
Interestingly, serum albumin concentration positively correlated with serum DHEA-S concentration (r =0.240), suggesting that DHEA-S may have an anabolic effect in the liver. DHEA has also been suggested to reduce urinary albumin excretion in the kidney 28, which may also contribute to the maintenance of the serum albumin concentration. A protective action of DHEA-S in the liver has been also suggested by other studies: the serum DHEA-S concentration is low in non-alcoholic fatty liver disease (NAFLD) 29, 30 and DHEA reduces liver fat deposition in obese (fa/fa) Zucker rats 31. The underlying molecular mechanism for the protective effect of DHEA-S in liver may involve the induction of CYP4A, which removes harmful substances. Alternatively, the dihydrotestosterone, ΔAdiol, and 3b-Adiol generated from DHEA-S may promote miR-21 production, leading to the proliferation of hepatocytes 32. Therefore, it may be that the low serum DHEA-S in frail T2DM patients identified in the present study may lead to an impairment in liver function, illustrated by the altered serum Alb concentration and transaminase activities.
As discussed above, BM <53 kg (p =0.012) was also identified to be an independent risk factor for frailty in the present study, and as the severity of frailty worsened (for CFS grades 1 to 7), BM decreased. Usually, adipose tissue and fat deposition are necessary for growth in adolescence 33, 34. However, in middle age, metabolic syndrome is characterized by visceral fat deposition and an inverse relationship between DHEA-S concentration and BMI 35. An anti-obesity effect of DHEA has been shown in both humans and animals 31, 36, 37, which involves the inhibition of 11β-hydroxysteroid dehydrogenase type 1 38 and the activation of dual-specificity protein phosphatase 39, a target gene of DHEA 40. Although the apparently paradoxical effect of DHEA in middle-aged and elderly people remain to be explained, DHEA-S is thought to play a role in maintaining homeostasis by controlling fat deposition, but in a manner that is dependent on life stage.
One limitation of the present study was that we could not evaluate sarcopenia in all of the participants. However, in the 108 participants (32 frail and 76 non-frail) in whom this was possible, those who were frail showed a significantly higher prevalence of sarcopenia than those who were not. This finding is consistent with the concept that sarcopenia is an essential factor determining frailty8.