In this study, we summarized clinical features of KS patients in a single Chinese hospital center and evaluated characteristics of islet β-cell function in KS and hyperglycemia patients, compared with hyperglycemia patients without KS and euglycemic subjects. The incidence of DM in PUMCH center was 35.3%, that was much higher than the prevalence of DM in the general population, which was 10.4% in China according to the guidelines of Chinese Diabetes Society published in 2017 and 14.3% in the United States[40]. KS was considered as a state of "pre-diabetes"[41], the associations between KS and impaired glucose tolerance and DM have been reported, several possible mechanisms of DM have been proposed. Low level of testosterone is proposed to correlate with the increased incidence of insulin resistance and DM in males[42, 43]. In several studies in KS patients, testosterone deficiency was identified as an independent predictor for insulin resistance and metabolic syndrome [10, 20], and the effects of testosterone replacement therapy (TRT) on ameliorating glycemic disorder and insulin resistance[44] were observed. The gene dosage effect from the extra copies of X chromosomes was speculated to be another factor[6], since the close relationship between karyotypes and DM [6, 9], and the level of insulin resistance[45] have been reported. Autoimmune abnormity may also involve, the incidence of type 1 diabetes mellitus (T1DM) and the presence of DM related auto-antibodies can be detected in some patients with KS[10, 46]. Other mechanisms, such as changes in body composition, inflammation status[11], socioeconomic factors[2], high triglyceride level, fatty liver and acute pancreatitis[6] might play important roles in the development of DM in KS patients as well. However, up to now the specific pathogenesis remains to be elucidated, further large, long-term, prospective, randomized, controlled studies are needed to clarify whether and how much above factors may affect the glycemic metabolism in KS patients.
We found KS patients develop hyperglycemia earlier in life than those without KS which was consistent with previous observations. Insulin sensitivity was lower in hyperglycemic KS patients compared with hyperglycemic patients without KS, whereas HOMA-β was significantly higher which indicated better competence of insulin compensatory secretion. Insulin resistance was considered as the major characteristic in KS patients with DM. Bojesen et al.[11] calculated insulin sensitivity by the HOMA model and showed a significant decreased insulin sensitivity but a significant increased islet β-cell secretion function in KS patients. Pei et al.[47] confirmed that insulin resistance was elevated in KS patients by area under the curve of serum insulin after a 75g oral glucose load and insulin suppression test. Using the gold standard, hyperinsulinemic euglycemic clamp test, Lee et al.[48] demonstrated impaired peripheral insulin resistance as the underlying mechanism of impaired glucose tolerance in Korean patients with KS, whereas Yesilova et al.[21] discovered that plasma insulin levels of KS patients were significantly elevated but without reduced insulin-mediated glucose disposal values compared with the controls, they concluded that hyperinsulinemia may be the primary metabolic abnormality rather than insulin resistance. Our results found that insulin resistance and compensatory increase in insulin secretion did exist in KS patients, and the increased islet β-cell secretion function was statistical significance compared to those of impaired glucose metabolism but without KS.
As for hypoglycemic therapy in hyperglycemic KS patients, best practices were still not established. The effects of TRT on the improvement of glucose control remained controversial, some clinical trials observed improvement of HbA1c level after TRT[44, 49], while others reported no improvement[50–52]. Especially, improvements of TRT in insulin sensitivity was observed in obese hypogonadal patients but not lean patients [53]. According to previous evidences, populations with lower level of testosterone tend to have higher proportion of body fat, which resulted in impaired insulin sensitivity. After TRT, improvement of ratio of fat and muscle composition could benefit glucose and lipid metabolism rather than the direct effects of TRT. Insulin therapy was a common strategy in KS patients with DM, in the cases review in Japanese, among 895 Japanese KS patients reported in literatures up to 2001, 61 patients was diagnosed of DM, and at least 20 patients were treated with insulin preparations but the glycemic control was poor with HbA1c level of 10.6%[23] which reflected less effective in glycemic control of insulin therapy among KS and DM patients. From the results of the changes of insulin sensitivity and islet β-cell secretion function in our study, we found those KS patients with hyperglycemia presented with similar insulin resistance level but better islet β-cell secretion function compared with those without KS, which suggested insulin preparations might not be the best choice for those KS patients with hyperinsulinemia, since hyperinsulinemia and insulin resistance would result in the increased dosage of insulin preparations and reduce the curative effects, further weight gain following the increased insulin dosage would aggravate insulin resistance. From this point of view, oral hypoglycemic drugs that target to improve insulin resistance might be considered first for those still with existed islet β-cell secretion function. For those KS patients with hyperglycemia, we recommended individualized hypoglycemia drugs choice after evaluating islet β-cell function rather than taking insulin therapy at first.
From the results of clinical features associated with KS, those patients with hyperglycemia were more likely to present gynecomastia, which accorded with the lower testosterone level than those with NGT. The incidence of cryptorchidism was lower in hyperglycemia patients, while the incidence of behavioral and intelligence problems was higher. We also found the higher frequency of development of other metabolic diseases in hyperglycemia and KS patients, including hypertension and dyslipidemia, which confirmed other metabolic factors including blood pressure and serum lipid levels may have effects on glycemic metabolism in KS patients.
This study has some limitations. First, KS is a rare disease and this is a retrospective study in a single Chinese center, so the sample size was small. Second, the clinical information was limited with missing data in some clinical features. Third, the age of patients in HG-KS group did not match with those in HG group because adolescents with type 2 diabetes mellitus were mostly obese which could not match BMI with KS patients.