**2.1.3 Discussion**

110 Steroids – Basic Science

HPLC/RIA method(Ueshiba et al.,1991) except DHEA-S which was measured using RIA kit(Mitsubisi Chemical Co., Tokyo, Japan), FPG by glucose oxidase method, HbA1c by HPLC, IRI by commercial kits (Daiichi, Tokyo, Japan). Data are showed as mean ± SD. Variables were compared by Bonferroni's analysis and p-values less than 0.05 were

Serum levels of DHEA and DHEA-S were low in both male and female patients with type 2 DM across the entire age range studied, compared to the age-matched normal subjects (Fig.1). IRI was high in all groups before the treatment (Table1). Following a 6-month treatment, FPG and HbA1c improved and IRI decreased in most patients (Table1). In parallel with the improvement of FPG and HbA1c, blood concentrations of DHEA and

> 183±16 111±14 93±7

> 172±18 106±14 94±5

> 176±19 108±14 90±7

> 172±16 108±12 94±7

> 166±16 112±15 92±7

> 175±19 107±9 93±5

Table 1. Clinical characteristics of type 2 diabetic patients before and after treatment and in

Number FPG(mg/dl) HbA1c(%) IRI(μU/ml)

11.6±1.2 7.2±0.6 5.2±0.3

11.7±1.2 6.8±0.6 5.1±0.3

11.4±1.1 6.7±0.6 5.2±0.2

12.0±1.1 7.0±0.6 5.1±0.2

11.6±0.8 7.1±0.4 5.1±0.3

11.9±1.2 6.8±0.5 5.3±0.3

11.8±3.9 8.7±2.1 5.9±2.3

12.4±3.7 8.4±1.5 6.1±2.1

13.3±4.1 8.9±3.4 5.8±1.8

11.9±3.2 9.3±2.8 5.4±1.5

12.3±3.8 8.1±2.4 4.8±1.6

11.6±2.8 7.9±2.7 4.7±1.8

DHEA-S levels increased to within the normal range in all the groups (Fig.1).

22 22 20

29 29 25

23 23 20

17 17 15

23 23 20

16 16 15

considered to indicate statistical significance.

**2.1.2 Results** 

Male 40 years Before treatment After treatment

Male 50 years Before treatment After treatment

Male 60 years Before treatment After treatment

Female 40 years Before treatment After treatment

Female 50 years Before treatment After treatment

Female 60 years Before treatment After treatment

age-matched normal subjects.

Normal

Normal

Normal

Normal

Normal

Normal

In this study we demonstrated that serum DHEA and DHEA-S levels decreased markedly with poor control of type 2 DM and increased to age-matched normal values with the improvement of FPG and HbA1c after 6 months' treatment with diet and/or sulfonylurea. Barrett-Connor showed that DHEA and DHEA-S levels were also low in patients with noninsulin-dependent diabetes mellitus (Barrett-Connor, 1992), but she did not measure the changes of these steroid hormones after treatment. Markedly reduced levels of DHEA and DHEA-S in type 2 DM with poor therapeutic control with slightly increased plasma IRI are consistent with an association between DHEA synthesis and/or metabolism and insulin. Nestler et al. showed that insulin reduces serum DHEA and DHEA-S by increasing the metabolic clearance rate of DHEA in men or inhibiting their productin (Nestler,1992). The metablic clearance rate of DHEA is reported to be increased two- to fivefold in obesity and insulin-resistant, hyperinsulinemic state (Nestler,1995). The infusion of a high dose of insulin reduces serum DHEA levels suggesting the involvement of the inhibition of adrenal 17,20lyase activity. The administration of metformin which inhibits hepatic glucose production and enhances peripheral tissue sensitivity to insulin, to healthy normal weight men and to obese men with hypertension but without diabetes mellitus decreased serum insulin levels and increased serum DHEA-S levels in obese men with hypertension and in healthy controls (Nestler,1995). However, Yamauchi et al. reported that serum DHEA and DHEA-S are low even in patients with impaired glucose tolerance and low insulin response (Yamauchi,1996), and therefore the decrease in serum DHEA levels may not exclusively arise from the hyperinsulinemic state. Hyperglycemia may reduce 17,20-lyase activity and consequently serum DHEA may decrease. The improvement of plasma glucose control parallels the recovery of 17,20-lyase activity.

DHEA and Impaired Glucose Tolerance Clinical and Basic Study 113

Blood samples were taken from intra-orbital vessels after 12 hrs starvation. Serum DHEA, DHEA-S, fasting plasma glucose (FPG) and serum c-peptide were measured in each group at four time points: before STZ administration; after 4 weeks; after 8 weeks; and after 12 weeks. Simultaneously glucose tolerance tests were performed. From 15 weeks of STZ administration DHEA-S(Mylis) (20mg/Kg) was administrated via the intra-abdominal route three times per week in three IGT group guinea pigs and three control group animals. After 4 weeks, 8 weeks and 12 weeks of DHEA-S administration, blood samples were taken by the

Data are expressed as mean±SD. Statistical analysis was performed using ANOVA with

Concentrations of serum DHEA showed no significant change during observation in the control group, however there was a tendency towards decrease in the IGT group (Fig. 2). Concentrations of serum DHEA-S also had no significant change in the control group. However, in the IGT group, concentrations of serum DHEA-S decreased significantly from 39.0±4.2 μg/dl (before STZ administration) to 27.5±5.0 μg/dl (after 8 weeks)(p<0.05)(Fig. 3).

**[Control]**

0 4 8 12

**[IGT]**

0 4 8 12

(W)

(W)

\* \*

\* : p<0.05 vs 0 W

Bonferroni's correction. A value of p<0.05 was considered statistically significant.

same method and glucose tolerance tests were also performed.

40

30

DHEA-S35

> 20 0

> 40

30

25

DHEA-S35

> 20 0

Fig. 3. Changes in Concentrations of Serum DHEA-S

50

45

(g/dL)

25

50

45

(g/dL)

**2.2.2 Results** 
