Low T3 Syndrome is Associated with Imbalance of Bone Turnover Biomarker in Patients with Type 2 Diabetes

Introduction

Type 2 diabetes (T2D) is a chronic medical condition characterized by uncontrolled high blood sugar levels, which ultimately result in dysfunction of the thyroid and an imbalance in bone metabolism. Research has emerged in recent decades suggesting that T2D may be associated with a higher incidence of complications such as thyroid dysfunction^1–3 and diabetic osteoporosis.⁴ Osteoporosis and diabetic osteopenia may result from abnormal glucose metabolism, which is partially attributable to the microvascular pathological lesion that nourishes osteoblasts and osteoclasts,⁵ as well as inflammation,⁶ hepatic or renal insufficiency,^7–9 oxidative stress.¹⁰ Recent epidemiological studies have identified osteoporosis as a significant risk factor for frailty among elderly individuals with diabetes.¹¹ Additionally, our prior research indicated a correlation between HbA1c levels and bone mass density (BMD).¹² According to our previous research,¹³ in severe cases of diabetes, such as diabetic ketoacidosis (DKA), the activity of osteoblasts decreases as indicated by the serum level of the N-terminal middle molecular fragment of osteocalcin (NMID). In contrast, the activity of osteoclasts increases as indicated by β C-terminal cross-linking telopeptide of type 1 collagen (β-CTX). We also found that recurrent DKA is associated with an increased risk of osteoporosis and bone fracture in some patients with inadequate glycemic control. Consequently, it is critical to monitor bone mass and quality, particularly in patients with type 2 diabetes who are elderly or have inadequate blood glucose management.

However, the thyroid hormone, a sensitive hormone closely associated with blood glucose regulation, plays a substantial role in numerous physiological processes, including energy and hormone homeostasis, stress management, cardiovascular equilibrium, neuronal production and excitability, and bone metabolism.^14,15 It has been discovered that abnormal thyroid function, including hyperthyroidism and hypothyroidism, is associated with abnormal bone turnover biomarker activity and increases the risk of developing osteoporosis and bone fracture.^16,17 Recent research indicates that abnormalities in thyroid function among patients with T2D may be correlated with serum iron levels; gender, age, kidney function, and intestinal flora may be the most influential factors.³ Additionally, our prior research indicated that low TSH levels are correlated with reduced bone mineral density (BMD) at the femoral neck and hip joint in postmenopausal female T2D patients who are euthyroid.² However, it was observed that substantial changes referred to as non-thyroidal illness syndrome (NTIS) were common among severe patients who also had systemic diseases, such as sepsis, respiratory failure, uremia, heart failure, acute diabetic complications (DKA), or hyperosmolar hyperglycemic state (HHS). While many patients with these conditions did not have thyroidal disease, the alteration in thyroid function could potentially serve as an indicator of mortality and severity.¹⁸

Thyroid dysfunction may be caused by T2D through a variety of mechanisms. It has been found that a hyperglycemic state may affect the production of triiodothyronine from thyroxine by attenuating the activity of deiodinase 1 (D1), which promotes reverse T3 (r-T3) conversion by D3.^1,19 About 77% of circulation thyroxine in normal individuals could be converted into T3 (35%) and rT3 (42%), while only 6.8%-12% to T3 in DM. A comparative clinical study reveals that metabolic control but not aging was one intimate factor of low T3 condition in T2DM.²⁰ The index of T3/T4 is negatively correlated with the level of blood glucose and could be remission with the improvement of diet control and insulin therapy. In addition, it is also demonstrated that the receptor of T3 could also be downregulated in DM,²¹ which could be passively attributed to the accumulated by-product in DM, such as ketone. Lower T3 may be associated with the change in insulin resistance.^22,23 In our previous investigation, we demonstrated that impaired T3 was positively linked with the severity of DKA, but elevated bodyweight represented by BMI could be a protected factor for both bone turnover biomarkers and thyroid function.²⁴ In DKA, the response to the thyrotropin hormone (TRH) by TSH may be suppressed and even retarded after recovery. Other pathological changes of low T3 in DM may be related to: 1) the disorder of specific transporters responsible for T4 into the certain cells that generate T3;²⁵ 2) decreased ATP production by the liver due to hyperbilirubinemia or increased non-esterified fatty acids;²⁶ 3) decreased TRH mRNA expression within the hypothalamus.²⁷ It has been determined that the TRH expression within hypothalamus could be regulated by the ratio of T3/T4 via T3β2 receptor and phosphorylated cAMP response element bound protein (CREB), wherein low T3 level decreases T3β2 binding to the targeted gene loci of TRH, and TRH may be downregulated by the competition binding of CREB and other regulatory factors, including arcuate nucleus (ARC) released peptide: α-melanin stimulating hormone (α-MSH), cocaine- and amphetamine-regulated transcript (CART), agouti-related protein (AgRP), and neuropeptide Y (NPY), etc;^28,29 4) inflammatory cytokine expression which suppress the T3 conversion such as IL-6, IL-1, TNF-α, IFN-γ.³⁰ Furthermore, lower T3 is even a progression index in diabetic complications, such as diabetic nephropathy (DN),³¹ diabetic neuropathy (DPN),³² and frailty,³³ as demonstrated by multiple clinical studies.

To date, however, despite the possibility that thyroid function can be reversed with supplementing with thyroid hormone, such as Euthyrox (Levothyroxine), it remains debatable whether this supplementing could improve the outcome.³⁴ Therefore, identifying the factors and pathological mechanisms associated with this condition is crucial. We investigated the impact of low triiodothyronine (low T3) syndrome, a common form of non-thyroidal illness syndrome (NTIS), on bone turnover biomarker activity in patients with T2D. Our aim was to identify the bone outcome in these extremely sick patients and identify potential associated factors or determinants that could guide more effective therapeutic strategies. Our investigation will further analyze the severe T2D patients in low T3 condition without HHS or DKA and hypothyroidism or hyperthyroidism to explore its relationship with the bone metabolic markers, revealing its potential risks for deteriorated bone metabolism in the background of low T3.

Materials and Methods

Source of inpatient data

From the inpatient database, we collected information on 418 adult diabetic patients admitted to the Department of Endocrinology at Shanghai Pudong Hospital between 2018 and 2022. One hundred and three patients were diagnosed with low triiodothyronine (T3) syndrome, which is characterized by a decreased concentration of T3 without an elevated thyroid-stimulating hormone (TSH) level. Patients with primary or secondary hypothyroidism or hyperthyroidism were excluded from the study. In the control group of 314 diabetic patients with euthyroid function evident. All patients diagnosed with diabetes satisfied the T2D diagnostic criteria as established in the 1999 guidelines of the World Health Organization (WHO). The inclusion and exclusion process can be found in Figure 1. Although the patients with euthyroid function had a prior diagnosis of T2DM, none of them presented with diabetic ketoacidosis, hyperosmolar hyperglycemia, or other severe or acute comorbidities or complications. The patient’s demographic information, glucose metabolic status, and thyroid function are compared and summarized in Table 1.

Table 1 The Demographic and Metabolic Status of Patients in Euthyroid Vs Low T3 Syndrome

Figure 1 The inclusion and exclusion process of the current retrospective study. Abbreviations: T2D, type 2 diabetes mellitus; T1D, type1 diabetes; LADA, latent autoimmune diabetes in adults; DM, diabetes mellitus; T3, triiodothyronine; TSH, thyroid stimulating hormone; HHS, hyperglycemia hyperosmolar state; DKA, diabetic ketoacidosis; COPD, chronic obstructive pulmonary disease.

Blood sampling and methods of laboratory assessment

All patients admitted to the ward were conscious with a Glasgow Coma Scale (GCS) score of 15. Patients with type 2 diabetes (T2D) received oral anti-diabetic medication, such as metformin, Sulfonylurea, glinides, pioglitazone, SGLT-2 inhibitors, α-glucosidase inhibitors, dipeptidyl peptidase inhibitors (DPP-IV inhibitors), or injectables including GLP-1 receptor agonists, insulin therapy (basal insulin or combined with prandial insulin or premixed insulin). Calcium or vitamin D supplements were not administered to patients unless being diagnosed with osteoporosis or severe osteopenia after blood sampling. Biomarkers of bone turnover, including 25-hydroxyvitamin D3 (25 OH VitD3), N-MID, and β-CTX, were collected from all DM patients. The measurement of bone formation biomarker NMID was processed using a Fluorescence immunochromatography assay on the Dry Fluorescence Immunoassay Analyzer (AFS2000A), while the bone resorption biomarker β-CTX was processed using an Enzyme-linked immunosorbent assay on the Enzyme label analyzer (RT-6100). Parathyroid hormone (PTH) was measured using the Chemiluminescence method on the ADVIA Centaur XP device from Siemens, and blood calcium was analyzed using colorimetry on the ADVIA Chemistry XPT device, also from Siemens. The following parameters were examined: fasting blood glucose, lipid parameters, hepatic function, and kidney function indicators: estimated glomerular filtration rate (eGFR), creatinine, and uric acid (UA) were analyzed via full-automatic biochemical analyzer (ADVIA chemistry XPT, SIEMENS, USA). Hemoglobin A1C (HbA1C) was analyzed by an HbA1C analyzer (TOSOH G8), which reflects the level of glycemic control in the past 3 months. C-peptide and thyroid function indicators: thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (TT3), total thyroxine (TT4), and anti-thyroid peroxidase antibody (TPOAb), anti-thyroid globin antibody (TgAb), two biomarkers of chronic lymphatic thyroiditis, were processed via chemiluminescence methods, in a full-automatic chemiluminescence immunoassay analyzer (ADIVA Centaur XPT, SIEMENS, USA).

Statistical analyses

The statistical analysis was performed using SPSS (IBM, version 26.0) and Prism (GraphPad, version 9.0) software. Laboratory data, including bone turnover biomarkers, were analyzed using non-parametric tests or independent sample t-tests to compare the low T3 and DM groups. The comparison of bone turnover biomarkers between the low T3 group and DM group was analyzed using independent sample t-tests or non-parametric tests. The relationship between the metabolic parameters and bone turnover biomarkers was analyzed using parametric Pearson or nonparametric Spearman correlation analyses according to the characteristics of parameter data. Multivariate linear regression analyses were conducted to identify the best predictors of bone turnover biomarker change in the low T3 group. A significance level of p<0.05 was used for all statistical analyses.

Results

The comparisons of bone turnover biomarkers between patients with low T3 syndrome and euthyroid function

The results showed that compared with the group, the concentration of serum Ca²⁺(LowT3 vs euthyroid: 2.12±0.14 vs 2.21±0.11 mmol/L, p<0.0001; reference level: 2.08~2.65mmol/L), 25 OH VitD3 (LowT3 vs euthyroid: 15.32±6.61 vs 20.32±8.73ng/mL, p<0.0001; reference level: >30.0ng/ml, and NMID (LowT3 vs euthyroid: 1.51±3.59 vs 12.72±6.41ng/mL, p<0.0001; reference level: female: pre-menopause: 11–43 ng/ml, post-menopause: 15–46 ng/ml; male 18–30 years old: 24–70 ng/ml, 31–47 years old : 14–46 ng/ml) were significantly lower in the low T3 group (p<0.05), which was in contrast with the level of β-CTX (LowT3 vs euthyroid: 8.64±15.32 vs 0.37±0.21ng/mL, p<0.0001; reference level: pre-menopause: ≤0.57 ng/ml, post-menopause: ≤1.01 ng/ml; male: >50 years old : ≤ 0.85 ng/ml); however, no obvious disparity was observed in PTH (LowT3 vs euthyroid: 6.85±5.81 vs 8.49±33.98 pmol/L, p=0.66; reference level: 1.96–9.33 pmol/L) between the low T3 and euthyroid group. (Figure 2)

Figure 2 The comparisons between low T3 and euthyroid showed the disparity in the concentration of serum Ca2+ (p<0.0001) (A), 25 OH Vit D3 (p<0.0001) (B), PTH (p>0.05) (C), β-CTX (p<0.0001) (D), and NMID (p<0.0001) (E). Abbreviations: ns, no significance; Ca2+, calcium; 25 OH Vit D3, 25-hydroxyvitamin D3; β-CTX, βC-terminal cross-linking telopeptide of type 1 collagen; NMID, N-terminal middle molecular fragment of osteocalcin. Note: ****p<0.0001.

The comparisons of hepatic and renal function between low T3 and euthyroid

Step further, we observed the disparity in hepatic and renal function and only found a significantly lower level of serum albumin (Alb: LowT3 vs euthyroid: 35.65±3.79 vs 38.72±4.63 g/L, p<0.0001; reference level: 40–55 g/L; TP: LowT3 vs euthyroid: 62.05±6.34 vs 63.97±8.43 g/L, p=0.0125; reference level: 65–85 g/L) in the hepatic function test, whereas there were increased Scr (LowT3 vs euthyroid: 91.98±65.11 vs 66.19±26.15 μmol/L, p=0.0002; reference level: 45–84 μmol/L) and decreased eGFR (LowT3 vs euthyroid: 79.29±26.61 vs 90.94±21.28 mL/min*1.73m², p=0.0001) detected in renal function (p<0.05). (Figure 3)

Figure 3 The analyses showed that serum albumin (p<0.0001) (A), bilirubin (p>0.005) (B), Transferase (p>0.05) (C), BUN(p>0.05)(D), Scr (p<0.001)(E), and eGFR (p<0.001) (F), UA(p>0.05) (G) were different between the low T3, and euthyroid groups. Abbreviations: ns, no significant; DBil, direct bilirubin; SBil, indirect bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; SCr, serum creatinine; eGFR, estimated glomerular infiltration; UA, uric acid. Note: *p<0.05; ***p<0.001; ****p<0.0001.

Correlational Relationships Between Bone Turnover Biomarker and Other Parameters

We in advance tested the relationship between bone turnover biomarkers and other assessed parameters in low T3 group and euthyroid group, and found a significant correlational relationship between bone turnover biomarkers and metabolic parameters. The results are shown in Table 2.

Table 2 The Correlational Relationship Between the Bone Turnover Biomarkers and Parameters Related to Metabolism

Multilinear regression analyses of bone turnover biomarkers in the state of low FT3 state and euthyroid group

Thereafter, we assessed the multivariate linear regression relationship between the bone turnover biomarkers change and the multiple metabolic parameters. The results are shown in Tables 3–13.

Table 3 The Multilinear Regression Model of Variables to the NMID Change in Low T3

Table 4 The Multilinear Regression Model of Variables to the NMID Change in Euthyroid Function

Table 5 The Multilinear Regression Model of Variables to the β-CTX Change in Low T3

Table 6 The Multilinear Regression Model of Variables to the β-CTX Change in Euthyroid Function

Table 7 The Multilinear Regression Model of Variables to the 25 OH VitD3 Change in Low T3

Table 8 The Multilinear Regression Model of Variables to the 25 OH VitD3 Change in Euthyroid Function

Table 9 The Multilinear Regression Model of Variables to the PTH Change in Low T3 but Showed No Significant Variables Was Associated with PTH of Euthyroid Function Group

Table 10 The Multilinear Regression Model of Variables to the Ca2+ Change in Low T3

Table 11 The Multilinear Regression Model of Variables to the Ca2+ Change in Euthyroid Function

Table 12 The Multilinear Regression Model of Variables to the FT3 Change in Low T3

Table 13 The Multilinear Regression Model of Variables to the FT3 Change in Euthyroid Function

Discussion

Our findings show that in T2D patients with low T3 syndrome, there is a significant alteration in bone metabolism-related markers change. This tendency reveals the activity of bone formation (NMID) decreases, whereas the marker for bone reabsorption (β-CTX) increase, and this alteration is not directly caused by the disarrangement of calcium-related regulatory hormones such as PTH and 25-OH Vit D3, suggested by the regression analyses. Our study reveals that in T2D patients with low T3 syndrome, due to multiple severe diabetic complications, there may be significant changes in bone metabolism, if untreated they would experience higher risk of osteoporosis or bone fractures compared with normal T2D. Our analyses also show a range of another metabolic parameters could be served as risk factors associated with aberrant bone metabolic markers in low T3 including renal function, bodyweight, pancreatic function (Figure 4).

Figure 4 An illustration of the impact that variation has on the homeostasis of biomarkers for bone turnover (β--CTX and NMID). In T2D patients with low T3 syndrome, β-CTX levels demonstrated an increase as determined by eGFR and free plasma c-peptide (FPCP), whereas NMID levels declined exclusively in association with increased body weight. Conversely, in euthyroid T2D patients, the change of NMID was concurrently in line with that of β-CTX, although a tendency of increase in bone reabsorption activity was observed, and a few factors such as sex, albumin, FT4, eGFR, and 25 OH VitD3 influenced their activities.

Individuals diagnosed with T2D are susceptible to developing a range of complications if their glycemia levels failing to achieve the intended goal. These complications may include but are not limited to cerebral impairment, emotional disorders, osteoporosis, cancer, and frailty. Relatively severe acute diabetic dysregulation, such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemia (HHS), was associated with decreased bone turnover biomarker activity in T2D, according to our recent research.²⁴ Impaired thyroid function was also observed in those patients, as indicated by a low T3 level.²⁴ In those patients with DKA and HHS, the adaptive modification in thyroid activity did not indicate the thyroid lesion per se, but rather potentially as a disruption in the functioning of the hypothalamic-pituitary-thyroid axis (HPA axis). In our current study, as indicated by the concentration adjustments of serum NMID and β-CTX, regression analyses indicated that the adaptive modification in thyroid activity was also associated with bone turnover biomarker activity in the patients without DKA and HHS, which provides further support for our hypothesis that thyroid function is closely associated with bone metabolism in T2D patients with severe conditions. There is a lack of research that examines the correlation between low T3 syndrome and alterations in bone metabolism in T2D patients with severe conditions. The current research provided prognostic values that can be utilized to evaluate and predict the bone prognosis of individuals diagnosed with severe type 2 diabetes (Figure 4).

Initially, we conducted a comparative analysis of demographic characteristics and metabolic status between the groups with low T3 and euthyroidism (Table 1). The age difference implies that elderly patients may have a slower rate of metabolism than younger patients, which may contribute to the higher prevalence of low T3 in this population. The medication history also suggests the advanced progression of T2D in low T3, though, the diabetic duration in two groups were comparable, in that there were more proportion of patients with drug naïve, administered oral anti-diabetic drugs rather than insulin utilization. Due to the possibility of malnutrition in aged low T3 patients, their bodyweight was slightly lower than euthyroid. We could also observe elevated mean fasting glucose (FPG) in low T3, as well the glycemic control level seems more higher than euthyroid. In terms of thyroid function, the thyroid hormones were also significantly lower in these cohorts.

Subsequently, we examined the bone turnover biomarkers in both groups and identified decreased serum calcium levels, 25(OH)D3, and NMID, which indicate calcium depletion and a disruption in the regulation of calcium-regulating hormones (Figure 2). This may be attributed to factors, such as malnutrition, aging, absorption disorders, and VitD3 metabolic disorder. A significant increase in the activity of β-CTX and a decrease in the activity of NMID were also observed, suggesting that the equilibrium between bone anabolism and catabolism was disrupted. Our data may indicate that low T3 participants may be more susceptible to developing osteoporosis and bone fractures compared to euthyroid individuals. Simultaneously, an analysis of the hepatic and renal functions in both groups was conducted. The results indicated malnutrition and impaired protein synthesis in the low T3 group, as well as increased catabolism and decreased renal filtration function as indicated by elevated SCr and lower eGFR (Figure 2).

Additionally, we investigated the association between bone turnover indicators and the metabolic parameters described previously (Table 3). β-CTX, a biomarker of catabolism, showed positive associations with total protein, SCr, TSH, PTH, and FPCP, but a negative correlation with eGFR. This indicates that β-CTX can be used as an indicator of catabolism, and any increase in SCr or decrease in eGFR can lead to higher levels of β-CTX. While there is no notable change in TSH levels in patients with low T3, an increase in TSH indicates a decrease in the feedback inhibition of thyroid hormones. This increase in TSH may result in an elevation of β-CTX, which is consistent with a previous study that observed TSH receptors expressed in bone osteoclasts.³⁵ It is possible that TSH regulates the activity of these osteoclasts. PTH is a hormone that stimulates the uptake of calcium in bones to balance the levels of circulating calcium. Therefore, we have additionally observed a positive correlation between them. Remarkably, our results indicate that FPCP serves not only as a criterion for pancreatic function but also has a correlation with the activity of bone catabolism. This suggests that pancreatic function could be considered an indicator of the quality of bone turnover status, which aligns with our clinical observation.³⁶ Regarding the NMID, we discovered a negative correlation between it and bodyweight and total bilirubin. This suggests that low T3 levels, being male, having higher bodyweight, and experiencing liver injury may impede the bone’s anabolism process. However, our findings indicate that the male gender, greater bodyweight, improved nutrition, and higher calcium concentration are significant factors in relation to 25 OH VitD3. Regarding PTH, the factors that significantly contribute to raised PTH levels include aging, increased SCr, reduced renal filtration and excretion of UA, decreased calcium levels, decreased TT3 levels, and increased β-CTX levels. These findings indicate that PTH may serve as a catabolic indicator. Furthermore, the serum calcium level had a positive correlation with total protein concentration, albumin level, raised FT3 level, and 25(OH) Vitamin D3(VitD3). Conversely, it exhibited a negative correlation with PTH, which serves as an indicator of nutritional status and disease severity. After conducting an analysis, we discovered that there is a negative association between aging and globin level with FT3. On the other hand, albumin and calcium concentration showed a positive relationship with FT3. This result indicates that the change in FT3 is closely related to the individual’s nutrition status, suggesting that FT3 can be considered an indicator of anabolism status.

We have identified the factors that cause changes in bone turnover biomarker activities (Tables 3–13). Based on our research, we have determined that bodyweight has a negative impact on NMID. On the other hand, the change in β-CTX can be predicted by renal function, and pancreatic islet function. Through the examination of the factors influencing the levels of 25(OH) Vitamin D3(VitD3), we have discovered that being male, having higher blood calcium levels can lead to an increase its concentration. In addition, we found that uric acid (UA), aging, and reduced serum calcium were factors that influenced the PTH, the catabolic indicator. However, it was found that the storage of serum albumin is the only factor that affects the fluctuation of serum calcium, as the physiological function of calcium is intimately associated with level of albumin (ALB) and hepatic synthetic function.³⁷ Moreover, the regression analysis revealed that the changes in FT3, in addition to other thyroid function biomarkers, could be predicted with a confidence level of 62.7% based on the levels of ALB, and serum globin (GLO).

Non-thyroid illness syndrome (NTIS) is a bodily protective adaption to the stress condition, and Low T3 could be restoration as long as the stress be remission. Although, there were evidences that supplementation of thyroid hormone such as Euthyrox (Levothyroxine) in certain conditions may bestow benefits to the certain patients during caloric restriction, cardiovascular disorders, acute renal insufficiency, and burning patients; however, the outcome according to the previous comparative clinical trials proved no advantage with LT-4 supplementation. It is also reported that supplementation of TSH in chronic patients could normalize the rhythms of TRH release, while the power of the pertinent evidences seemed plausible. Some studies set out to examine the supplementation of T3 on the Low T3 patients also proved no better outcomes such as mortality despite the patients’ condition or certain parameters improved, in that T3 may physiologically possess more effective bioactive function than T4. There were also investigations proving that suppress TSH level may prevent osteoporosis in thyroid disorders, however the outcomes by different research group varied. Therefore, whether supplementation of Euthyrox could relive the aberrant bone turnover biomarkers in the diabetic patients with low T3 syndrome still remain debatable.

Limitation

Due to lack of multicenter cooperation and limitations on sample size, we could not further explore the characteristics of these low T3 population, such as other demographic information, and follow-up on their thyroid function and bone metabolism, as well as assessment of the ultimate bone outcome. Nevertheless, our findings also indicate that thyroid function indicators and pancreatic function may serve as metabolic prognostic factors for the bone metabolism and reveal the risk of osteoporosis in low T3 syndrome.

Conclusion

In the present study, we compared the demographic and metabolic characteristics of patients with T2D who had low levels of T3 hormone and those with normal thyroid function. This study demonstrated that T2D patients with condition of low T3 syndrome may experience an aberrant bone metabolism represented by the elevation of bone reabsorption marker and suppressed bone formation marker, which in long-term may be served as risk factors to predict major bone fractures. In addition, we identified other systemic and metabolic parameters as risk factors in low T3 including age, bodyweight, gender, hepatic and renal function, as well as pancreatic function. The impact of nutrient conditions, calcium supplementation and renal function as well as alleviate toxicity of hyperglycemia on pancreatic function may benefit on the regulation of bone turnover biomarkers in patients with low T3 syndrome who have T2D.