Epidemiology: testosterone and the metabolic syndrome

Low levels of testosterone, hypogonadism, have several common features with the metabolic syndrome. In the Troms? Study, a population-based health survey, testosterone levels were inversely associated with anthropometrical measurements, and the lowest levels of total and free testosterone were found in men with the most pronounced central obesity. Total testosterone was inversely associated with systolic blood pressure, and men with hypertension had lower levels of both total and free testosterone. Furthermore, men with diabetes had lower testosterone levels compared to men without a history of diabetes, and an inverse association between testosterone levels and glycosylated hemoglobin was found. Thus, there are strong associations between low levels of testosterone and the different components of the metabolic syndrome. In addition, an independent association between low testosterone levels and the metabolic syndrome itself has recently been presented in both cross-sectional and prospective population-based studies. Thus, testosterone may have a protective role in the development of metabolic syndrome and subsequent diabetes mellitus and cardiovascular disease in aging men. However, clinical trials are needed to confirm this assumption.     

Testosterone,the metabolic syndrome and diabetes mellitus

Both cross-sectional and longitudinal epidemiological studies have convincingly established that low plasma levels of testosterone and sex hormone binding globulin (SHBG) are correlated with / predict the metabolic syndrome and diabetes mellitus. Visceral obesity with its associated hyperinsulinism suppresses SHBG synthesis and, concomitantly, circulating testosterone levels. It also may impair the strength of LH signaling to the testis. Further, insulin and leptin have a suppressive effect on testicular steroidogenesis. Thus, there are reasons to consider adiposity a significant factor capable of lowering circulating levels of testosterone. Conversely, low levels of testosterone predict the development of the metabolic syndrome and diabetes mellitus type2. This notion is supported by the appearance of a metabolic syndrome-like condition in men with prostate cancer whose plasma testosterone levels are rendered low. Furthermore, the observation that differentiation of pluripotent stem cells is androgen dependent (adipogenic in a low testosterone milieu and myogenic with normal levels of testosterone) provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men.Administration of testosterone has been found to improve insulin sensitivity in non-diabetic and diabetic men, although this has not been universally the case. Our own study in men with diabetes mellitus and low androgen status found an improvement of glycemic control upon testosterone administration. When combined with proper nutrition, physical activity and resistance training, administration of testosterone may improve body composition (reduction of fat mass / increase of lean body mass) and may thus contribute to better metabolic control and reduction of cardiovascular risks.     

Anti-Müllerian hormone and inhibin B levels reflect altered Sertoli cell function in men with metabolic syndrome

The aim of the present study was to investigate the Sertoli cell markers inhibin B and anti-Müllerian hormone (AMH) in men with metabolic syndrome (MS). Twenty patients with MS according to the criteria of the International Diabetes Federation and 20 non obese age-matched men were investigated. The levels of testosterone, sex hormone binding globulin (SHBG), gonadotropins, inhibin B and AMH were measured in all of them. In obese patients with MS total testosterone (15.74 ± 6.95 versus 27.84 ± 12.80 nmol l(-1), P = 0.001), SHBG (21.71 ± 11.08 versus 38.80 ± 17.51 nmol l(-1), P = 0.001) and free testosterone (430.35 ± 237.40 versus 613.85 ± 303.65 pmol l(-1), P = 0.040) were significantly lower than in the controls. Interestingly, the inhibin B (103.64 ± 56.77 versus 149.88 ± 68.31 pg ml(-1), P = 0.025) and AMH levels (30.84 ± 13.14 versus 43.14 ± 9.66 pmol l(-1), P = 0.002) were also significantly lower in MS group in comparison to the other participants. The lowest levels of AMH were found in patients with MS and carbohydrate disturbances. The decreased concentrations of testosterone, inhibin B and AMH in patients with MS could reflect an impaired Leydig and Sertoli cell function. Further studies in men with obesity, insulin resistance and diabetes type 2 could reveal more information about the interrelations between the metabolic disturbances and reproductive function in men.     

Erectile dysfunction is associated with low bioactive testosterone levels and visceral adiposity in men with type 2 diabetes

Low testosterone levels in men are associated with type 2 diabetes mellitus. Erectile dysfunction (ED) is a frequent complication of type 2 diabetes. The aim of our cross-sectional study was to investigate the relationship between ED and total, bioavailable and free testosterone levels in 198 men with type 2 diabetes. In addition, we examined the associations of various cardiovascular risk factors involved in the development of ED in type 2 diabetic men. We found that bioavailable and free testosterone levels were significantly lower in men with ED (p = 0.006 and 0.027 respectively) than those without ED. Sex hormone-binding globulin levels were also reduced, but there was no significant difference in total testosterone (TT) levels between men with and without ED. The severity of ED as assessed by International Index of Erectile Function scores was significantly associated with TT (r = 0.32; p < 0.001), bioavailable testosterone (r = 0.32; p < 0.001) and calculated free testosterone (r = 0.35; p < 0.001) levels. ED was more frequently observed in men with hypertension and a higher waist circumference (p = 0.03). There was also a higher prevalence of ED among smokers (p = 0.06), but there were no significant associations between ED and alcohol consumption or with BMI > 30. This study has shown that ED is associated with low bioavailable and free testosterone levels, age, visceral adiposity and hypertension in type 2 diabetic men.     

Hypogonadism and diabetes

Clinicians have been aware of the increased prevalence of low testosterone levels in patients with type II diabetes for several years, but how these two conditions are associated is difficult to determine. Older age and obesity may be factors, as both are associated with type II diabetes and both decrease testosterone levels. Sex hormone-binding globulin (SHBG), the major serum carrier protein for testosterone, also may have an impact. SHBG levels fall with obesity and increase with aging. Some studies indicate lower SHBG levels in type II diabetes. Most of the differences in testosterone levels between diabetic and nondiabetic patients may be due to reduced SHBG, rather than reduced testosterone production. However, free testosterone levels fall with increasing age and obesity, rendering many type II diabetic patients testosterone deficient. Testosterone replacement may improve insulin sensitivity in hypogonadal, overweight men with type II diabetes by altering body composition, but studies are conflicting.     

Testosterone and obesity in men under the age of 40 years

The study assessed anthropometric and laboratory variables, in particular testosterone (T) in a group of obese men of <40 years. Of 60 men with a body mass index (BMI) of >27 kg m^?2, 34 met the criteria of the metabolic syndrome (MS). Twenty men <40 years (with a BMI <25 kg m^?2) were studied for comparison. It was found that with increasing BMI, levels of serum leptin, triglycerides, insulin, the ratio high‐density lipoprotein (HDL) cholesterol/low‐density liporotein (LDL) cholesterol, the waist circumference (WC), the area of visceral fat and systolic/diastolic blood pressure were higher, whereas insulin sensitivity (HOMA) and serum T were lower. Obesity (BMI 27–30 kg m^?2) was associated with a decline in plasma T, but not with a decline in plasma sex hormone‐binding globulin (SHBG). The latter was the case in more severe obesity (>30 kg m^?2) qualifying as MS. In patients with MS, 58% variability of T levels could be predicted by combination of independent factors – SHBG, ratio LDL/HDL, insulin and leptin. On the other hand, in men with MS, 80% variance of concentrations of SHBG were predicted by triglycerides, HDL, glucose, leptin and surface of visceral adipose tissue. It is concluded that plasma T is significantly correlated with a number of features of the MS and, therefore, plasma T could serve as a marker of the MS.     

Testosterone,diabetes mellitus,and the metabolic syndrome

Metabolic syndrome is characterized by insulin insensitivity, central obesity dyslipidemia, and hypertension. It is recognized as a risk factor for cardiovascular disease in men; by the time metabolic syndrome is diagnosed, however, most men already have entrenched cardiovascular disease. A reliable early warning sign is needed to alert physicians to those at risk for metabolic syndrome and cardiovascular disease. Low serum testosterone level has emerged as a reliable prognosticator of metabolic syndrome in men whose testosterone deficiency is genetic (Klinefelter syndrome), iatrogenic following surgery for testicular cancer, pharmacologically induced by gonadotropin-releasing hormone during prostate cancer treatment, or a natural consequence of aging. One third of men with type 2 diabetes mellitus are now recognized as testosterone deficient. Emerging evidence suggests that testosterone therapy may be able to reverse some aspects of metabolic syndrome.     

Testosteron und das metabolische Syndrom

Abdominal obesity as a key cardiovascular risk factor as well as metabolic syndrome and type 2 diabetes mellitus are associated with low testosterone levels. In line with these facts, investigations of patients undergoing androgen ablation therapy for prostate cancer have shown a negative effect of this treatment approach on insulin sensitivity and body fat mass. The effects of physiological doses of testosterone seem to have less impact on the parameters of lipid metabolism. However, supraphysiological levels of testosterone can lower HDL levels. At present data on glycemic control in patients with type 2 diabetes are not yet uniform, but negative effects on glycemic control in type 2 diabetics have not been reported. In fact two studies were able to demonstrate a positive effect of testosterone on glycemic control in patients with type 2 diabetes. It is currently not yet possible to conclusively evaluate the significance of testosterone treatment in patients with metabolic syndrome and type 2 diabetes mellitus. Only larger, randomized prospective trials will show whether testosterone therapy is helpful in metabolic syndrome or type 2 diabetes. However, administration of testosterone in hypogonadal men with metabolic syndrome appears to be a promising treatment option to improve metabolic control.     

Testosterone in men's health: a new role for an old hormone

Testosterone is an anabolic hormone with a wide range of beneficial effects on men's health. A considerable body of evidence suggests that testosterone (T) deficiency contributes to the onset and/or progression of type 2 diabetes mellitus (T2D), insulin resistance (IR), metabolic syndrome (MetS), cardiovascular disease (CVD), and erectile dysfunction (ED). Low testosterone precedes elevated fasting insulin, glucose, and hemoglobin A1c (HbA1C) values and may even predict the onset of diabetes. Low testosterone also produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low density lipoprotein (LDL), increased production of pro-inflammatory factors, increased thickness of the arterial wall, and contributes to endothelial dysfunction. Testosterone therapy of hypogonadal men improves insulin sensitivity, fasting glucose, and hemoglobin A1c levels. Testosterone supplementation restores arterial vaso-reactivity, reduces pro-inflammatory cytokines, total cholesterol, and triglyceride levels and improves endothelial function and high density lipoprotein (HDL) levels. The therapeutic role of testosterone in men's health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for MetS, T2D, IR, CVD, and ED, androgen replacement therapy in hypogonadal men may potentially reduce the risk for these pathologies.     

How to optimise treatment of erectile dysfunction above and beyond the beneficial effects of a phosphodiesterase type 5 inhibitor

The introduction in 1998 of the phosphodiesterase type 5 (PDE-5) inhibitors has changed the landscape of diagnosis and, in particular, the treatment of erectile dysfunction (ED). It has paved the road for a more profound insight into ED. ED and other ailments of elderly men, such as atherosclerosis, hypertension, diabetes mellitus and lower urinary tract symptoms were usually regarded as distinct diagnostic/therapeutic entities, but there is growing evidence that they are interrelated and are factors in ED. To optimise the treatment of ED, an integral approach to the health of the ageing male is required. There is an interdependence between the metabolic syndrome, ED and patterns of testosterone in ageing men. The main features of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia, significant factors in the aetiology of erectile function. The metabolic syndrome is associated with lower-than-normal testosterone levels. Testosterone is a determinant of glucose homeostasis and lipid metabolism. Testosterone is not only a factor in libido but also exerts essential effects on the anatomical and physiological substrate of penile erection. With these recent insights, the health problems of elderly men must be placed in a context that allows an integral approach. While PDE-5 inhibitors are the mainstay of treatment of men with ED, treatment of testosterone deficiency is becoming part and parcel of a new approach to both ED and the metabolic syndrome. The diagnostic work-up of ED should comprise measurement of plasma testosterone. If proven deficient, treatment with testosterone is indicated.     

Testosterone and the metabolic syndrome

There is convincing evidence that abdominal obesity, a key factor in the metabolic syndrome, is associated with low testosterone levels and, conversely, low levels of testosterone are a risk factor for development of the metabolic syndrome, thus producing a vicious circle. The mechanisms by which the metabolic syndrome induces hypogonadism are increasingly being elucidated. It is now clear that insulin resistance decreases Leydig cell responsiveness to stimulation with human chorionic gonadotropin.Androgen depletion in men with prostate cancer has demonstrated an impressive increase in insulin resistance and the risk of developing type 2 diabetes mellitus. Androgens have direct (membrane) effects on pancreatic β-cells thus stimulating insulin production.The relationship between circulating testosterone levels and the metabolic syndrome has been demonstrated in elderly men, but, paradoxically, there is a lack of effect of testosterone insulin sensitivity or glucose tolerance in healthy young men.Interventions with testosterone in men with the metabolic syndrome lead to improvements of body composition (decreasing fat mass and increasing lean body mass) and improve insulin sensitivity.     

Cardiovascular diseases and erectile dysfunction: the two faces of the coin of androgen deficiency

Traditionally, clinical conditions synonymous with the ageing male included cardiovascular disease (CVD), type 2 diabetes mellitus (DM) and sexual dysfunction, and were widely regarded as independent clinical entities. Over the last decade, interrelationship of clinical conditions has been convincingly demonstrated. Declining testosterone levels in the elderly, once regarded as an academic endocrinological question, appear to be central to the listed pathologies. It is now clear that erectile dysfunction is an expression of endothelial dysfunction. Testosterone deficiency is associated with an increased incidence of CVD and DM. The latter is often the sequel of the metabolic syndrome. Visceral obesity, a pivotal characteristic of the metabolic syndrome, suppresses the hypothalamic-pituitary-testicular axis leading to diminished testosterone production. Conversely, substantial androgen deficiency leads to signs and symptoms of metabolic syndrome. It is erroneous not to include testosterone measurements in the progress of the CVD, DM and erectile dysfunction. These conditions correlate strongly with testosterone deficiency.     

Is serum sex hormone-binding globulin a dominant risk factor for metabolic syndrome?

This multi-center, cross-sectional study investigated the association between serum testosterone (T) levels, serum sex hormone-binding globulin (SHBG) levels, and the risk of metabolic syndrome (MS) in 3332 adult Chinese men. The prevalence of MS was 34.7%, and men with MS had lower serum levels of total T (TT) and SHBG than those without MS (P < 0.001). There was no significant difference in serum free T (FT) levels between subjects with and without MS (P = 0.627). In logistic regression analysis, the association between MS and serum SHBG levels persisted after adjusting for age, body mass index (BMI), smoking and drinking status, and serum TT (odds ratio [OR] 0.962, 95% confidence interval [95% CI] 0.954−0.969, P< 0.01). However, the association between serum TT level and the risk of MS was weak after adjusting for age, BMI, SHBG level, and smoking and drinking status (OR 0.981, 95% CI 0.960−1.007). Our study reveals that both serum TT and SHBG levels, but not serum FT, are inversely associated with the prevalence of MS and that serum SHBG is an independent and dominant risk factor for MS.     

Visceral adiposity index is useful for evaluating obesity effect on erectile dysfunction

Studies show that erectile dysfunction (ED) is associated with obesity, and it has been shown that the possibility of developing sexual dysfunction in obese men is 30% higher compared to those with normal weight. Obesity is measured using various methods, for example waist circumference (WC) measurement or body mass index (BMI), but recently, visceral adiposity index (VAI) has also been utilised to better assess obesity and metabolic syndrome. In our study, the potential link between VAI and ED was investigated. The data of 176 patients who presented to the urology outpatient clinic with erection complaints were retrospectively screened. A control group was also established with 122 men without complaints of erectile dysfunction. The erectile functions of all participants were determined using the International Erectile Function Index‐5 (IIEF‐5) scoring. In addition, their serum fasting blood glucose, total testosterone (TT), triglyceride (TG), low‐density lipoprotein (LDL) cholesterol and high‐density lipoprotein (HDL) cholesterol levels were measured. The physical examination comprised the measurement of WC, height and weight, and BMI. The mean age of the participants was 58.7 ± 8.4 for the ED group and 57.1 ± 7.5 for the control group. The mean VAI was statistically significantly higher in the ED group (5.32 ± 2.77) compared to the control group (4.11 ± 1.93) (p < 0.001). Since VAI contains both physical and metabolic parameters, our findings suggest that it discloses the effects of WC, BMI, HDL and TG more clearly. VAI is considered useful for the assessment of the effect of obesity on ED patients.     

Relationship between BMI, total testosterone, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men

The objective of this work was to evaluate the relationship between sex steroid hormones, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men. Anthropometrical indexes, total testosterone (Tt), free testosterone (fT), estradiol (E), sex hormone-binding-globulin (SHBG), glucemia, insulin and leptin were measured in 77 men, with ages between 20 and 60 years. According to their body mass index (BMI), subjects were grouped into three categories: normal body weight (< 24.9 kg/m2), overweight (25-29.9 kg/m2) and obese group (> 30 kg/m2). Insulin resistance index was obtained by the homeostasis assessment model for insulin resistance (HOMA-IR). Total testosterone and SHBG concentrations were lower in the obese group compared with normal and overweight subjects (p < 0.05). The mean insulin concentration was significantly higher in the obese group compared with the other groups (p < 0.05). T was negatively correlated with the BMI (r = -0.447; p < .01), WC (r = -0.464); p < .01, leptin (r = -0.382; p < .01), insulin (r = -0.391; p < 0.01) and also with the HOMA-IR (r = -0.416; p < 0.01). The SHBG negatively and significantly correlated with BMI (r = -0.334; p < 0.01) and WC index (= -0.322; p < 0.01), as well with insulin levels (r = -0.313; p < 0.01) and insulin resistance (= -0.266; p < 0.05). Our results shows that in a sample of men, Tt and SHBG concentrations proportionally diminished with both the increase of BMI and insulin resistance index.     

Insulin resistance and sex hormone‐binding globulin are independently correlated with low free testosterone levels in obese males

Male obesity is associated with decreased testosterone levels but the pathophysiological mechanisms behind this association are not completely understood. This study aimed to investigate the impact of hyperglycaemia/insulin resistance and sex hormone‐binding globulin (SHBG) levels on testosterone levels in a population of obese men. We investigated the impact of several clinical, anthropometric and analytic measures on testosterone levels in 150 obese males. Testosterone deficiency was present in 52.0% of the enrolled patients. This percentage dropped to 17.6% when only calculated free testosterone (FT) was accounted, as SHBG levels were correlated negatively with body mass index (r = ?.20; p < .05). Older age (p < .05) and higher homoeostasis model assessment of insulin resistance (HOMA‐IR) (p < .01) and lower SHBG levels (p < .05) were independently correlated with lower FT. Weight and fasting plasma glucose lost their statistical significance after multivariate adjustment. Patients with type 2 diabetes mellitus and pre‐diabetes had lower FT than those with normal glucose tolerance (p < .05 and p < .01 respectively). Insulin resistance, and not hyperglycaemia and weight per se, seems to be the main determinant of low testosterone levels in obese males. Low SHBG levels are correlated with low FT even after HOMA‐IR adjustment. This suggests that SHBG can be associated with testosterone deficiency beyond the influence of insulin resistance unlike previously reported.     

Testosterone and metabolic syndrome

Controversies surround the usefulness of identifying patients with the metabolic syndrome (MetS). Many of the components are accepted risk factors for cardiovascular disease (CVD). Although the MetS as defined includes many men with insulin resistance, insulin resistance is not universal. The low total testosterone (TT) and sex hormone binding globulin (SHBG) levels in these men are best explained by the hyperinsulinism and increased inflammatory cytokines that accompany obesity and increased waist circumference. It is informative that low SHBG levels predict future development of the MetS. Evidence is strong relating low TT levels to CVD in men with and without the MetS; however, the relationship may not be causal. The recommendations of the International Diabetes Federation for managing the MetS include cardiovascular risk assessment, lifestyle changes in diet, exercise, weight reduction and treatment of individual components of the MetS. Unfortunately, it is uncommon to see patients with the MetS lose and maintain a 10% weight loss. Recent reports showing testosterone treatment induced dramatic changes in weight, waist circumference, insulin sensitivity, hemoglobin A1c levels and improvements in each of the components of the MetS are intriguing. While some observational studies have reported that testosterone replacement therapy increases cardiovascular events, the Food and Drug Administration in the United States has reviewed these reports and found them to be seriously flawed. Large, randomized, placebo-controlled trials are needed to provide more definitive data regarding the efficacy and safety of this treatment in middle and older men with the MetS and low TT levels.     

Metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone

Until a decade ago the ailments of elderly men, such as atherosclerosis, hypertension, diabetes mellitus, lower urinary tract symptoms and erectile dysfunction (ED), were regarded as distinct diagnostic/therapeutic entities but there is a growing awareness that these entities are not disparate and, to improve the health of the ageing male, require an integral approach. There is an inter-dependence between the metabolic syndrome, ED and patterns of testosterone in ageing men. The main features of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia, significant factors in the aetiology of erectile function. The metabolic syndrome is associated with lower-than-normal testosterone levels. A new concept of the role of testosterone in male physiology suggests that testosterone plays also a significant role in the development and maintenance of bone and muscle mass and is a determinant of glucose homeostasis and lipid metabolism. Testosterone is not only a factor in libido but exerts also essential effects on the anatomical and physiological substrate of penile erection. With these recent insights, the health problems of elderly men must be placed in a context that allows an integral approach. Treatment of testosterone deficiency is to become part and parcel of this approach.     

Screening for metabolic syndrome and testosterone deficiency in patients with erectile dysfunction: results from the first UK prospective study

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To screen patients with erectile dysfunction (ED) for the presence of metabolic syndrome (MetS), testosterone deficiency and cardiovascular (CV) risk factors, in a secondary referral centre in the UK, as men with ED have a high incidence of CV risk factors that might amount to MetS, with obesity, increased risk of coronary heart disease and type II diabetes; testosterone deficiency has also been associated with both ED and MetS.

PATIENTS AND METHODS

We assessed 124 men presenting with ED between March 2007 and August 2008. Data were collected prospectively for patient demographics, risk factors associated with MetS, and hypogonadism. MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III Criteria 2005 (based on three or more of five criteria: waist circumference, high triglycerides, low levels of high‐density lipoprotein cholesterol, hypertension and impaired glucose tolerance).

RESULTS

The mean (range) age of the men was 50 (16–76) years; 50 of 124 (40%) patients had MetS and 27% had hypogonadism. The latter was also associated with a low testicular volume and decreased libido. Ninety‐seven patients (82%) were either overweight or obese, and 64 (52%) were current or ex‐smokers.

CONCLUSIONS

Our audit confirms a high incidence of MetS and hypogonadism in patients with ED in the UK. We recommend routine screening for CV risk factors, MetS and testosterone deficiency in all patients in the UK with ED.     

Duration of obesity increases the incidence of NIDDM.

The effect of duration of obesity on incidence of non-insulin-dependent diabetes mellitus (NIDDM) was determined among Pima Indians. Duration of obesity was defined as the time since body mass index (BMI) was first known to be at least 30 kg/m2. Among 1057 participants eligible for study, there were 224 incident cases of NIDDM in 5975 person-yr of follow-up. The association of duration of obesity with incidence of diabetes adjusted for age, sex, and current BMI was highly significant (P less than 0.0001). This adjusted incidence of diabetes in cases/1000 person-yr of obesity was 24.8 for people with less less than 5 yr of obesity, 35.2 for people with 5-10 yr of obesity, and 59.8 for people with at least 10 yr of obesity. There was no apparent excess risk of diabetes for people who had a BMI of at least 30 kg/m2 and then lost weight. They had a slightly nonsignificantly higher rate than people who had not attained a BMI of at least 30 kg/m2 and a lower rate than people whose BMI remained 30-35 kg/m2. The relationship of duration of obesity with serum insulin concentrations among nondiabetic people was determined controlling for sex and age, BMI, and plasma glucose concentrations at the time of a glucose tolerance test. Duration of obesity was inversely associated with fasting serum insulin concentration through most of the range of fasting plasma glucose concentrations (P less than 0.001) and tended to be inversely associated with 2-h postload serum insulin concentration through the entire range of postload plasma glucose concentrations (P = 0.058).