Reversion of aging-related DHEAS decline in mouse plasma alleviates aging-related glucose tolerance impairment by potentiation of glucose-stimulated insulin secretion of acute phase

https://doi.org/10.1016/j.bbrc.2018.04.134Get rights and content

Highlights

  • Aging-related DHEAS decline in mouse plasma contribute to aging-related impairment of glucose tolerance.

  • Reversion of aging-related DHEAS deficiency in aging mice could alleviate aging-related glucose tolerance impairment.

  • In vitro, physical concentration of DHEAS potentiated GSIS of acute phase in aging mice pancreatic islets and MIN6 cells.

Abstract

Aims/hypothesis

The latest research proposes mild age-related diabetes (MARD) as a subgroup of type 2 diabetes. While in human circulating dehydroepiandrosterone sulfate (DHEAS) decline with age is related to MARD, the role of circulating DHEAS in insulin secretion remains little known.

Methods

After intraperitoneal administration of glucose (2 g/kg) together with DHEAS (50 μg/kg) or equivalent DMSO to young (6–8 week old) or aging (12 month old) male C57BL/6 mice, plasma DHEAS and blood glucose were measured at indicated time point. Then in vitro, we investigated DHEAS effects on GSIS of acute phase in aging mice pancreatic islets as well as in MIN6 cells. Finally we conducted pharmacological studies in MIN6 cells to examine whether exert its effects on insulin secretion by itself.

Results

We found in vivo that aging mice had lower plasma DHEAS levels and impaired glucose tolerence compared to young mice and that the aged mice but not the young mice receiving DHEAS supplement had improved glucose tolerance as soon as 15 min after glucose injection compared to the ones with DMSO administration. These results indicate that in male mice, aging-related DHEAS decline in plasma contribute to aging-related impairment of glucose tolerence and that reversion of aging-related DHEAS deficiency in aging mice plasma could alleviate aging-related glucose tolerance impairment. Consistently, in vitro DHEAS glucose-and dose-dependently potentiated glucose-stimulated insulin secretion (GSIS) of acute phase in both aging male mice pancreatic islets and MIN6 cells. Moreover, none of steroid sulfatase (STS) inhibitor STX64 (10 nM), androgen receptor (AR) blocker flutamide (1 mM) or estrogen receptor (ER) antagonist ICI182780 (1 mM), affected DHEAS-potentiated high GSIS of acute phase indicating this potentiation exercised by DHEAS per se

Conclusions

/interpretation These results lead us to tentatively conclude that aging-related DHEAS decline may imply MARD development and that adequate DHEAS supplement may be a precise medicine and preventive measure for MARD.

Introduction

Diabetes is a big health problems worldwide with increasing prevalence. Large-scale clinical studies have shown that in recent three decades, diabetes prevalence among chinese adults surprisingly went up to 11.6% from 3.5% [1]. Although a growing number of young people suffered diabetes, aged adults have been the main population for diabetes or prediabetic state [2]. In line, a latest research indicates instead of traditional classification of adult-onset diabetes into type 1 and type 2 diabetes, the later should be reclassed into five subgroups, one of which is termed mild age-related diabetes (MARD) accounting for about 40% patients [3]. The new classification means precise treatment for MARD. However at present we are far from the precise medicine for want of specific medicine to MARD pathogenesis.

In humans, dehydroepiandrosterone sulfate (DHEAS) de are the most abundant adrenal steroid hormones in peripheral circulation [4]. In male, DHEAS plasma concentration peaks in the third decade and falls gradually thereafter diminishing about 95% by the age of 85 years [5,6]. The specific falling pattern of DHEAS with age, along with its reciprocal relationship to atherosclerotic disease [7], obesity [8], osteoporosis [9,10], Alzheimer's disease [7,11], hypertension [12], earns its acknowledged status as aging biomarker [13] and correlation to the development of some age-related diseases [14].Furthermore it was reported that male diabetes patients have lower serum DHEAS levels and in healthy males, lowed serum DHEAS with age are associated with elevated plasma glucose [15,16], which leads to hypothesis that aging-related DHEAS decline in male may play a role for MARD development.

MARD is characterized with onset of old age, almost normal insulin sensitivity and moderate insulin deficiency [3]. Thus it is reasonable to attribute MARD development to the factors contributing to impaired pancreatic β cell function. But sparse are the studies about the direct effects of DHEAS on pancreatic β cell function. Only two available studies have reported that either 30 μM or 100 μM DHEAS potentiates high glucose-stimulated insulin secretion (GSIS) in rodent insulin-secreting β cell lines after long term of DHEAS treatment [17,18]. However the DHEAS dose used in these two studies are extremely beyond rodent circulating concentrations of DHEAS. In fact, as low as nanomole-scale (nM) DHEAS circulates in young for devoid of cytochrome p450c17 (CYP17) enzyme which is key to DHEAS synthesis in rodent adrenals and only lowly expressed in liver or gonadal glands [19]. In addition, up to date, short-term effect of circulating DHEAS on insulin secretion is scarcely investigated, although DHEAS is recently reported to exert the rapid, plasma membrane-dependent, non-genomic effects in various tissues [24,27,28], rather than functions conventionally as a gene transcription factor which activates the classical pathway by binding to specific intracellular receptor [26].

In this study we demonstrate whether circulating concentrations of DHEAS in young and aging mice exert an acute-phase effect on insulin secretion in vivo and vitro.

Section snippets

Materials

DHEAS was purchased from International Laboratory (IL, USA). Dulbecco's modified Eagle's medium and other culture reagents were obtained from Gibco Life Technologies (Grand Island, NY, USA). General DHEAS ELISA kits were bought from Signalway Antibody LLC (USA). Mouse insulin detection ELISA kits were obtained from Crystal Chem (USA). The BCA Protein Assay Kit was from Pierce Chemical (USA). All other chemical reagents not described specifically were from Sigma-Aldrich (USA).

Experimental animals

Young (6- to

DHEAS supplement improves impaired glucose tolerance in aging male mice

To precisely analyze the effects of DHEAS supplement on physiological circulating concentrations in mice, we firstly determine plasma DHEAS levels15-min after intraperitoneal injection of glucose together with DHEAS (50 μg/kg) or equivalent DMSO in young and aging male mice. After DMSO administration, plasma DHEAS levels in aging mice were dramatically lower than in young mice (0.52 ± 0.11 nM vs. 8.13 ± 1.22, p < 0.01) suggesting a marked decline with age in mouse blood DHEAS (Fig. 1A). Of

Discussion

We demonstrated here that in vivo age-related large decline in male mouse plasma DHEAS was accompanied by aging-related glucose tolerance impairment and reversion of the former to young state could alleviate the later, because rodent physical concentration of DHEAS per se potentiated high GSIS of acute phase.

In men, DHEAS plasma concentrations peak in the third decade and fall gradually thereafter from near 10 to 1 μM [5,6]. In contrast, we demonstrated in the present study that in vivo there

Acknowledgement

This study was supported by the National Natural Science Foundation of China (NO. 81471029 to Shengxian Li, NO. 81270875 and NO. 81471424 to Wei Liu). We thank Xuanchun Wang for MIN6 cell line.

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