In our previous study, 6 mo of DHEA replacement resulted in an improvement in insulin action evidenced by a smaller increase in insulin during an OGTT without a change in glucose response [10
]. In the present study, a longer period of DHEA replacement resulted not only in a reduction in insulin resistance, but also in improved glucose tolerance, in elderly, overweight or obese women and men with abnormal glucose tolerance. The magnitude of this improvement was impressive, as DHEA replacement for 1 yr resulted in an 18 mg/dl decrease in the 2h glucose value of the OGTT (p,0.02 vs. placebo) and 2 yr of DHEA resulted in a 21 mg/dl in the 2h glucose value. These findings have relevance to the current epidemic of impaired glucose tolerance and type 2 diabetes [13
] because they raise the possibility that DHEA could be an effective treatment for impaired glucose tolerance and for prevention of type 2 diabetes.
Visceral fat, measured by MRI, decreased ~10% in both men and women [10
]. This finding, together with the observation that DHEA protects laboratory rodents against visceral fat accumulation and insulin resistance with aging [7
] and in response to high fat diets [5
], led us to conclude that DHEA improves insulin action largely by reducing intra-abdominal fat [10
While the present results confirm that DHEA replacement decreases insulin resistance in individuals with abnormal glucose tolerance, they do not support our previous conclusion that this improvement is largely mediated by a decrease in visceral fat. In the present study, the women had a small increase in fat free mass without a decrease in abdominal fat, while the men had only a small decrease in visceral fat in response to DHEA, suggesting that the reduction in visceral fat observed in our previous, 6 mo study is a transient effect.
In addition to our earlier study [10
], other studies have found an improvement in insulin action in response to DHEA replacement, including in hypoadrenal women [13
], middle-aged hypercholesterolemic men [14
], and postmenopausal women [15
]. However, in contrast to the present results, it was recently reported by Nair et al. [16
] and Basu et al. [17
] that two years of DHEA treatment had no effect on insulin action or postprandial glucose turnover in elderly men and women. The difference between the results of their study and ours, despite a similar study design, would be puzzling were it not for our finding that DHEA replacement improved glucose tolerance/insulin resistance only in those participants who had abnormal glucose tolerance, with no improvement in those with normal glucose tolerance. Although Nair et al. [16
] and Basu, et al. [17
] did not perform a standard OGTT, it appears that their subjects were unusually insulin sensitive for their age. This is evidenced by a fasting insulin level of ~3.6 μU/ml, a value similar to that of their young controls and about 50% lower than that of our participants with abnormal glucose tolerance, a fasting glucose value ~5 mgdl lower than that of our participants, and a calculated HOMA index [18
] of insulin resistance of 0.88 compared to 1.88 for our participants with abnormal glucose tolerance. Thus, the lack of effect of DHEA on insulin action in the study by Nair et al. [16
] and Basu et al. [17
] is in keeping with our finding that DHEA improves insulin action only in individuals with abnormal glucose tolerance.
Regarding mechanisms by which DHEA may reverse insulin resistance, one possibility is by activation of PPARα for which DHEA is a ligand [19
]. Activated PPARα stimulates expression of the mitochondrial enzymes involved in fat oxidation and represses activation of enzymes involved in fat synthesis[20
]. As a result, PPARα activation lowers triglycerides [21
], and could result in less fat deposition in liver and muscle. PPARα activation also suppresses inflamemation [21
], and DHEA has been shown to inhibit nuclear factor Kappa B and production of IL-6 and TNFα by various cell types, and to lower circulating levels of these inflammatory cytokines [22
]. Chronic inflammation in adipose tissue and macrophages is thought to be one of the factors that mediates insulin resistance [27
]. In the present study, DHEA replacement resulted in significant reductions in plasma IL-6 and TNFα, suggesting a decrease in inflammation. It is of interest relative to a role of PPARα activation in the improvement in insulin action induced by DHEA, that fibrates, which mediate their effects on lipid metabolism by activating PPARα [21
], have also been reported to improve insulin action and glucose tolerance [29
Another mechanism by which DHEA or some of its metabolites might enhance insulin action is by improving impaired activation of phosphatidyl inositol 3-kinase and Akt/PkB by insulin in insulin resistant muscle [37
]. It is interesting in this regard that 17α-ethynyl-5-androstene-3β, 7β, 17β triol, an analog of a DHEA metabolite, enhances insulin-stimulated Akt/PkB phosphorylation in muscle, and improves muscle and liver insulin sensitivity and glucose tolerance in Zucker diabetic rats and improves insulin sensitivity in insulin resistant humans [37
In conclusion, the results of this study confirm our previous finding that DHEA replacement in elderly men and women improves insulin action [10
]. They further show that a longer period of DHEA treatment than was evaluated in our previous study, 12 mo vs. 6 mo, also significantly improves glucose tolerance, and that this improvement occurs only in those individuals who have abnormal glucose tolerance. These findings raise the possibility that DHEA could become a first line treatment for glucose intolerance/insulin resistance and diabetes prevention in older individuals and ameliorate the increase in chronic inflammation that occurs with aging.