Abstract
Recent studies have described bone as an endocrine organ regulating glucose metabolism, with insulin signaling regulating osteocalcin secretion and osteocalcin regulating β cell function. We have previously demonstrated increased bone expression of TXNIP in patients with endogenous Cushing's syndrome (CS), and we hypothesized that TXNIP could contribute to the dysregulated glucose metabolism in CS. We studied 33 CS patients and 29 matched controls, with bone biopsies from nine patients, before and after surgical treatment. In vitro, the effect of silencing TXNIP (siTXNIP) in osteoblasts, including its effect on human islet cells, was examined. Our major findings were: (i) The high mRNA levels of TXNIP in bone from CS patients were significantly associated with high levels of glucose and insulin, increased insulin resistance, and decreased insulin sensitivity in these patients. (ii) Silencing TXNIP in osteoblasts enhanced their OC response to insulin and glucose and down-regulated interleukin (IL)-8 levels in these cells. (iii) Conditional media from siTXNIP-treated osteoblasts promoted insulin content and anti-inflammatory responses in human islet cells. We recently demonstrated that the thioredoxin/TXNIP axis may mediate some detrimental effects of glucocorticoid excess on bone tissue in CS. Here we show that alterations in this axis also may affect glucose metabolism in these patients.
Highlights
Glucose intolerance and overt diabetes mellitus are classical parts of endogenous Cushing’s syndrome (CS), and insulin resistance is a well known feature of cortisol excess [1]
While circulating Thioredoxin 1 (TRX) was correlated with insulin (r = 0.54, p = 0.008), insulin resistance (i.e. homeostasis model assessment index of IR (HOMA-IR), Figure 2C) and decreased insulin sensitivity (i.e. quantitative insulin sensitivity check index (QUICKI), Figure 2C) in controls, no associations with indices of glucose metabolism were found in CS patients (Figure 2C), potentially suggesting a dysregulated TRX/thioredoxin interacting protein 1 (TXNIP) axis in these patients
We recently demonstrated that the TRX/TXNIP axis may mediate some detrimental effects of glucocorticoid excess on bone tissue in CS
Summary
Glucose intolerance and overt diabetes mellitus are classical parts of endogenous Cushing’s syndrome (CS), and insulin resistance is a well known feature of cortisol excess [1]. Recent studies have shown a reciprocal relationship between bone and energy metabolism, whereby imbalance in bone remodeling seems to be of importance for glucose metabolism and insulin resistance and vice versa, at least in experimental models [5,6]. We and others have previously shown that CS patients have low levels of OC and display low bone mass [10,11,12]. While some clinical studies demonstrate associations between circulating OC or ucOC and glucose metabolism in different populations [13,14], the association between bone and glucose metabolism in CS is unknown
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