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Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus
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Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2017) xxx–xxx
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Original Article
Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus Rajendran Jayanthi, Abu Raghavan Srinivasan* , Niranjan Gopal, Ramesh Ramaswamy Department of Biochemistry, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India
A R T I C L E I N F O
A B S T R A C T
Article history: Available online xxx
Aim: The study was primarily aimed at investigating the association of Magnesium and Zinc levels in the serum of adult Non- obese and Obese type 2 diabetic patients, with particular reference to thyroid comorbidity. Methods: 108 patients with T2DM of both genders (24 Non obese and 84 Obese) were enrolled from a tertiary health care unit in Puducherry. The cardio-metabolic risk factors were assessed through body mass index, Waist hip ratio, blood pressure, fasting blood glucose, lipid profile and glycated haemoglobin. Zinc and Magnesium were quantitated. Insulin resistance was by Homeostasis model assessment. Serum free T4, T3 and TSH were also measured. Results: In non-obese type 2 diabetic group, Glycated haemoglobin had a strong positive correlation with free T4(r = 0.784; p = 0.003).TSH also depicted a positive association with HOMA-IR (r = 0.924; p < 0.001); whereas,T3 and Insulin had negative correlation with Magnesium (r = 0.599* and r = 0.620*; p 0.04 and 0.031). The levels of Zinc and Magnesium in the serum of obese diabetic patients had a positive correlation among them (r = 0.565#; p < 0.001). TAG/HDL ratio a measure of small dense LDL is positively correlated with LDL in both groups (r = 0.881 and 0.912) with p value < 0.001 for both. Conclusion: Correlation among Glycemic control, Insulin resistance, Thyroid hormones, divalent cations and dyslipidemia depict differential characteristics in obese and non–obese type2 diabetes with Thyroid comorbidity. © 2017 Published by Elsevier Ltd on behalf of Diabetes India.
Keywords: Serum zinc Serum magnesium Type 2 diabetes Glycated haemoglobin Insulin resistance Thyroid hormones Dyslipidemia
1. Introduction Diabetes mellitus, a common endocrine abnormality affects the metabolism of ions including zinc and magnesium [1]. Diabetes affects nearly 170 million people worldwide or 2% of the world’s population [2,3]. The proposed mechanism of trace elements enhancing insulin action includes activation of insulin receptor sites, serving as cofactors or components for enzyme systems implicated in glucose homeostasis [4,5]. This increases insulin sensitivity and also act as antioxidants [6]. Lower serum levels of magnesium and zinc are observed in patients suffering from type-2 diabetes [7]. It remains to be seen whether difference in trace element status is a cause or effect. The objective of this study was to assess the levels of Zinc and Magnesium in serum in adult non obese and obese type 2 diabetics, but with reference to thyroid comorbidity, in the light of insulin resistance. This dimension has been envisaged, as thyroid comorbidity is frequently linked to
insulin resistance in type2 diabetics and also very few reports from South India are available implicating in obese, overweight and non- obese type 2 diabetes, as the case may be. 2. Methodology 2.1. Inclusion criteria 108 patients with T2DM of both genders (24 Non obese and 84 Obese based on Waist circumference for men 85 cm and for women 80 cm) were enrolled from a tertiary health care unit in Puducherry, during the latter half of 2016, with age in the range 30–75 years. Informed consent was obtained from all the participants. This study was conducted with the approval of the Institutional Human Ethics committee (IHEC). 2.2. Exclusion criteria
* Corresponding author at: Department of Biochemistry, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed University accredited by NAAC with A Grade), Puducherry 607403, India. E-mail address: [email protected] (A.R. Srinivasan). http://dx.doi.org/10.1016/j.dsx.2017.07.010 1871-4021/© 2017 Published by Elsevier Ltd on behalf of Diabetes India.
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
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The patients suffering from liver disease, kidney disease, and severe congestive heart failure were excluded from the study. Expecting mothers were also excluded from the study. 3. Biochemical assessment Fasting blood glucose was estimated by glucose oxidaseperoxidase method (GOD/POD); Fasting insulin was quantitated by automated chemiluminiscence and Glycated hemoglobin by HPLC method. Insulin resistance was measured based on the formula HOMA – IR (Fasting plasma glucose (m mol/l) plasma fasting insulin (m IU/l)/22.5) [9]. Triacylglycerols in serum was measured by glycerol kinase method; Total cholesterol by enzymatic method; HDL cholesterol was enabled by polyanion precipitation. LDL cholesterol was computed by Friedwald equation, LDL cholesterol = Total cholesterol-(HDL cholesterol + VLDL) where VLDL = TAG/5, Small dense LDL particles were quantitated using the surrogate marker (TAG/HDL); Zinc and Magnesium were estimated using spectrophotometry and T3, T4 & TSH were quantitated based on automated electro chemiluminiscence method. High HOMA-IR was defined as HOMA-IR 2.69 [10]. Venous blood was collected from the subjects following an overnight fast. The blood samples (fasting) were analyzed for plasma glucose, insulin resistance by HOMA-IR, lipid profile, glycated haemoglobin, Zinc, Magnesium and T3, T4, TSH. Diabetes mellitus was diagnosed as per American Diabetes Association (ADA) criteria. Glycated haemoglobin less than 7% denoted good Control. For serum lipid reference level, National Cholesterol Education Programme (NCEP) Adult Treatment Panel III (ATP III) guidelines were promulgated [8]. Reference range for Magnesium (serum): 0.7–1 mmol/L i.e. 1.7–2.4 mg/dL; Zinc (serum): 70– 100 mmol/L. T4: 0.8–1.8 ng/dL; T3: 2.3–4.2 pg/mL. TSH: 0.4– 4.0 mIU/L. All biochemical investigations were performed based on IFCC approved procedures. Internal quality control was enabled. External quality check was facilitated through the External Quality Assessment Scheme (EQAS) scheme promulgated by the Clinical Biochemistry Laboratory, Christian Medical College (CMC), Vellore. 4. Statistical analysis The statistical tests employed the present study mean SD and categorical data enumerated as number (%) percentage. The Pearson correlation coefficient was calculated among the study parameters. The p-value <0.05 was considered statistically significant. 5. Results Table 1 depicts the correlation coefficient of Key parameters as observed in both non obese and obese type 2 diabetics.
The serum Zn and Mg levels were statistically correlated with r value being 0.565, p value <0.001, in obese type 2 diabetic subject as compared to non obese individuals (Table 1). Fasting glycated haemoglobin level had significant positive correlation with serum level of thyroxine (p 0.003), in non obese type 2 diabetics;while tri iodothyronine had negative correlation (r = 0.599, p 0.04) with Magnesium in the same group; but there was no significant correlation found in obese type 2 diabetics excepting TAG/HDL ratio and Zinc, Magnesium. Insulin was negatively correlated with Magnesium (r = 0.620, p 0.03) in non–obese type 2 diabetics and TSH had strong positive association with HOMA-IR (r = 0.924, p < 0.001) in the same group (non obese). Our study further implies that insulin correlates positively with T3 in non obese. For the sake of clarity, the key parameters are listed on Table 2. 6. Discussion Type 2 DM is a major global health problem. [11]. It is characterised by insulin resistance in peripheral tissues and an insulin secretory defect of beta cells of the pancreas. The relationship of DM with minerals has been well documented [12–15]. Additionally, zinc may be involved not only in the protection of islet cells, but may also be cardinal to glucose metabolism and insulin signalling. Zinc enables the translocation of insulin into the cells [16]. Additionally, zinc activates the insulinresponse amino peptidase (IRAP) molecule, which enables the translocation of GLUT4 to the cell surface for glucose transport into the insulin responsive cells [17]. The clinical significance of trace elements Zinc and Magnesium are of particular interest. Numerous studies have also demonstrated the essential roles of trace elements as chromium, zinc, magnesium, selenium, vanadium, molybdenum and manganese in insulin action and carbohydrate metabolism [18]. In the study undertaken by Almaroof et al., it was observed that mean serum zinc level was significantly low in diabetics as compared to control subjects [19]. A few other studies have also reported lower serum and plasma zinc levels in diabetics [20]. Magnesium is required for insulin sensitivity and also for deiodinase activity. Hypomagnesaemia can increase the platelet reactivity, increase vascular and adrenal responses to angiotensin II Table 2 Key biochemical parameters in the differential manifestation of obese and non obese type 2 diabetes with reference to Thyroid comorbidity. Parameters
Non obese T2DM
Obese T2DM
T3Vs Mg Insulin vs Mg TSH vs HOMA-IR Zn vs Mg
r = 0.599* r = -0.620* r = 0.924* r = 0.204
r = 0.015 r = -0.265 r = 0.019 r = 0.565*
T3-Triiodothyronine; TSH-Thyroid stimulating hormone; HOMA-IR-Homeostasis model assessment-Insulin resistance; Zn-Zinc; Mg-Magnesium. *pvalue < 0.05.
Table 1 Correlation coefficient between adult non obese and obese type 2 diabetic patients. Non obese Type 2 diabetic patients
Obese Type 2 diabetic patients
Parameters
Correlation coefficient (r)
P value
Correlation coefficient (r)
P value
TAG/HDL vs LDL HbA1c vs T4 T3Vs Mg T3Vs Insulin Insulin vs Mg TSH vs HOMA-IR Zn vs Mg
0.881# 0.784* 0.599* 0.620* 0.620* 0.924# 0.204
<0.001 0.003 0.04 0.031 0.031 <0.001 0.525
0.912# 0.283 0.015 0.22 0.265 0.019 0.565#
<0.001 0.069 0.923 0.155 0.089 0.904 <0.001
TAG-Triacylglycerol; HbA1c-Glycated haemoglobin; HDL- High density lipoprotein; LDL-Low density lipoprotein; T3-Triiodothyronine; T4-Thyroxine; TSH-Thyroid stimulating hormone; HOMA-IR-Homeostasis model assessment-Insulin resistance; Zn-Zinc;Mg-Magnesium. * Indicates statistically significant p value <0.05. # Indicates statistically significant p value <0.001.
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
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enhanced thromboxane A2 release and lead to organ damage attribute to free radicals [21]. Magnesium itself has been reported to possess antioxidant properties by scavenging oxygen radicals, probably by affecting the rate of spontaneous dismutation of superoxide anions. Increased free radical formation and reduction in antioxidant potential contributes to the development of oxidative stress in type 2 DM [22]. The cause of hypomagnesaemia may be attributed to osmotic renal loss from glycosuria, and also decrease in net tubular reabsorption of magnesium [23]. Sharma has reported an inverse correlation between serum magnesium level and poor glycemic control; and a strong association with retinopathy [24]. Altered levels of Magnesium and zinc in diabetes mellitus remains yet to be ascertained, but its strong association with type 2 diabetes mellitus signifies the role played by magnesium and zinc in glucose disposal. The poor glycemic control and the association with type 2 diabetes mellitus strongly suggest that serum magnesium and zinc estimation should be a part of the screening panel in the risk detection for type 2 diabetic patients. Furthermore, Thyroid comorbidity is an accompanying feature in T2 DM. We feel that there must be also be other factors that effect insulin resistance in the light of the expected fact that hypomagnesmia should correlate with decreased T3 which is the active form of thyroid hormone. Many workers have documented that the magnesium and zinc supplementation, in addition to the other nutritional treatments, play an important role in delay and prevention of the complication of type 2 diabetes mellitus. However, the role of these ions in Thyroid morbidity associated with T2DM remains unclear and not very many reports are also available. When the status of zinc and magnesium is poor in patients with type 2 diabetes mellitus, supplementation of these minerals probably may be beneficial [25]. A recent study by Mamza et al. did not show statistically significant difference in magnesium levels between diabetics and controls. However, a positive correlation existed between magnesium levels and age. The study depicted higher levels of Zinc in diabetics, in comparison to controls. Though such studies have documented the role of divalent cations in insulin resistance and type 2 diabetes mellitus in populations, not many studies are available from India, in particular citing the influence of divalent cations in insulin resistance associated with thyroid comorbidity [26]. The effect of zinc on insulin secretion is biphasic, that is very high or very low zinc plasma concentrations impair insulin secretion [27]. The plasma magnesium level is reduced in diabetes mellitus. Our data reveals significant differences in T2DM non obese group versus the obese group, for serum magnesium and Zinc (Table 2). In accordance with other authors, our data reveals the existence of serum low total magnesium level in patients with non obese T2DM [28]. Hypomagnesaemia is also involved in T2DM pathogenesis and its complications. Earlier studies have correlated the levels of thyroid hormone T4 as a function of glycemic control (intervent comorbidity). However our present study indicates the thyroxine levels positively correlates with poor glycemic control in non obese, but insignificant in obese type 2 diabetics. This could be explained probably on the basis of down regulation of insulin receptors in obese type 2 diabetics. An interesting point that emerges from this study is the inverse correlation between serum magnesium levels and T3. This is a paradox since in the physiological state divalent magnesium ions promote deiodinase activity that is implicated in the formation of T3 from T4. Our study shows a very intense positive correlation with TSH as against HOMA-IR. This further explains that the divalent cations may have both direct and indirect action on hypothalamus – pituitary thyroid axis, besides the known function in insulin sensitivity and action. Porta et al. in 1994 showed with T3 and Mg, an inverse correlation as observed in type 2 diabetics exposed to stress [29]. This opens up an interesting proposition that the counter regulatory
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hormones to insulin, especially cortisol might have an effect on peripheral deiodinase activity. Also more well planned and detail studies have to be necessitated so as to include the role of counter regulatory hormones on divalent cation status in T2DM with associated thyroid comorbidity. We feel that magnesium and zinc occupy a pivotal position in regulating insulin sensitivity in T2DM, in general and with reference to thyroid comorbidity. This implies that Mg and Zn in addition to the role on insulin sensitivity and action might possess an additional influence on hypothalamus anterior pituitary thyroid axis in the presence of other key biochemical parameters. This further could imply why different investigators on the biochemistry of T2DM have come up with both hypo- and hyperthyroidism. An earlier study by Dolev et al. highlighted the status of Magnesium (Mg) and zinc (Zn) in subjects with reference to thyroid diseases. According to this report, Plasma and RBC Mg concentrations were low in half of the hyperthyroid subjects, but mean values were not significantly different from controls. Plasma Zn was lower in hypothyroid subjects and correlated with serum albumin. Plasma Zn concentration was however normal and serum albumin significantly lower in the hyperthyroid group than in the control group [30]. It is well understood that Obesity is a chronic disease characterized by excessive accumulation of body fat and the presence of insulin resistance. In this regard, zinc is an important nutrient that stimulates insulin secretion and increases sensitivity to insulin [31]. Zinc is an essential trace element involved in thyroid hormone metabolism. Our results suggest direct correlation between Zinc and Magnesium as related to thyroid comorbidity, but only in obese T2 diabetics. This further explains the role of insulin receptor in modulating thyroid comorbidity, especially as down regulation of insulin receptor is bound to occur in obese type 2 diabetics, but not in non- obese type 2 diabetics. A study done in Saudi Arabia compared lipid and mineral profiles in hypothyroid patients receiving thyroxine therapy. The authors found out that serum magnesium and lipid levels decreased in overt hyperthyroid [32]. Hyperthyroidism has been implicated in hypomagnesaemia and is frequently linked to enhanced renal excretion of magnesium [33]. Our results suggest that in non- obese type 2 diabetics, T3 inversely correlates with magnesium, whereas positive correlation was obtained with insulin. This showed that the pattern of thyroid comorbidity would vary with the phase of insulin resistance. The concept of beta cell mass and function assumes great relevance in insulin resistance. A recent paper published this year has implicated thyroid strongly in inter organ cross talks related to pancreatic beta cell function. However, the same paper has cited an inherent limitation, namely the availability of sparse published data in different ethnic groups [34]. We feel that mobilisation of magnesium from the intracellular may be a crucial factor in differentiating biochemical based predictors of thyroid comorbidity as related to insulin resistance in obese and non obese type 2 diabetics. Our results in Table 1 show that an inverse correlation was observed between insulin and magnesium only in the non obese group, but not in the obese group which further would support the direct role of insulin receptors in mobilising Magnesium from intracellular stage. Differences in trace elements levels between individuals with type 2 diabetes and controls have been reported in several studies in various body fluids and tissues, but results have been inconsistent and controversial [35]. Diabetes mellitus is a chronic physiological glucose metabolic disorder. Its high prevalence globally has a significant impact on the quality of life. We feel that the management of diabetes thus includes nonpharmacological and glucose lowering agents. Magnesium and Zinc are excellent candidates which would not only alleviate insulin resistance but also would improve thyroid status. Though mechanisms of these elements (Zinc and Magnesium) are well known, the synergetic effects of their combinations are still
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
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obscure as well as with reference to thyroid comorbidity and therapeutically safe doses are not available. It is suggested that detailed research which may be carried out on the basis of evidence based research that would certainly provide newer insights into the role of Mg and Zinc in thyroid comorbidity associated with insulin resistance and frank T2DM. The use of first phase insulin secretion in the early diagnosis of thyroid diabetes and T2DM. According to the study, the beta cell function in thyroid diabetes mellitus is much better than that in T2DM. Hence, this could be used as an early marker in differential diagnosis [36]. A study on thyroid signalling, insulin resistance and T2DM suggested no evidence of a causal association between circulatory levels of TSH, free thyroxine with insulin resistance, but deiodinase affects glucose metabolism [37]. However, the prevalence of non thyroidal causes of low T3 concentration and the frequency of normal T3 concentration in hypothyroid patients makes the use of deiodinase estimation dubious in establishing thyroid disease [38]. However, our present study has outlined the diagnostic efficacy of the levels of TSH, HOMA-IR, T4 and T3, without resorting to the use of deiodinase, in assessing diabetes mellitus with associated thyroid comorbidity. Furthermore, the same parameters could be used to evaluate comorbidity in adult non obese and obese type 2 diabetics that would assume additional clinical relevance. Wolide et al. studied the relationship between thyroid hormones dyslipidemia and T2DM and concluded that TSH was positively associated with serum triglycerides and BMI. Our study was primarily focussed on studying the role played by small dense LDL particles and its relevance in non obese and type 2 diabetics. Small dense LDL was characterised by taking TAG/HDL ratio is a surrogate marker. Quite surprisingly, a significant correlation was found out between TAG/HDL and LDL in both non obese and obese type 2 diabetics. This assumes relevance especially not only with reference to insulin resistance but also with associated thyroid comorbidity (Table 1). We strongly feel that small dense LDL particles have a leading role in the pathogenesis of T2DM with associated thyroid comorbidity. In other words, we may not be able to use TAG/HDL ratio, a surrogate marker of small dense LDL to distinguish thyroid comorbidity with associated insulin resistance in obese and non obese type 2 diabetics. An earlier paper published from our laboratory implicated TAG/HDL ratio and thyroid hormone levels in IR as observed in T2DM. We had concluded from that study that small dense LDL could be used as a reliable marker for IR, with thyroid comorbidity in overweight type 2 diabetics. However in the present study the classification of obese and non obese diabetics was performed based on waist circumference. This is a much more objective and reliable anthropometric measure since type 2 diabetics with a normal BMI can still retained abdominal adiposity, a forerunner to IR. This has been corroborated by earlier workers [39]. However, controversy still exists with reference to thyroid comorbidity as perceived in T2DM/IR and that pertaining to hypoand hyperthyroidism [40]. Maxzud et al. in a recent paper gave an account of the prevalence of thyroid dysfunction in type 2 diabetics in an Argentina population. They submitted that subclinical hypothyroidism was prevalent at a rate of 8% and thyroid dysfunction early detection should be performed especially in newly diagnosed T2DM patients in order to delay the entry into pronounced cardiovascular risk [41,42]. However, a recent paper has implicated oral hypoglycaemic agents in T2DM with associated hypothyroidism. Among other causes, the prevalence of hypothyroidism was lower in subjects with type 2 diabetics who were receiving metformin therapy. This would lead to speculation as to whether metformin would affect the hypothalamic pituitary thyroid axis in patients with T2DM. As per our report all the study subjects were on oral hypoglycaemic agents which
contained metformin mandatorily. Hence more studies have to be done with regard to glycemic control mediated effects on hypothyroid pituitary axis in patients with T2DM. A study undertaken by Koonareddy et al. assessed thyroid function in metabolic syndrome in obese and overweight patients [43]. According to the study, serum TSH level does not appear to be a modifiable risk factor in obese and overweight subjects with metabolic syndrome. This prompted us as to whether the divalent cations, namely Mg and Zn modify TSH levels with reference to insulin resistance associated thyroid comorbidity. Our study wanted to include the effect of Mg and Zn (Divalent Cations) more so because of the following reasons. Mg is involved in carbohydrate metabolism as well as insulin action. Zinc is required for insulin function besides a cofactor required for super oxide dismutase which detoxifies oxygen free radicals. Furthermore studies have documented dyslipidemia with associated hypomagnesaemia in enhanced insulin resistance. We wanted to extend this profile in the light of thyroid comorbidity associated with T2DM. Our study showed a significant negative correlation in nonobese type 2 diabetics between T3 and Mg. Normally, Mg is required for the peripheral deiodinase activity responsible for the formation of T3 from T4. However, we would reaffirm that our study indicates negative correlation between T3 and Mg in non obese. We suspect that there could be a direct interaction between extracellular Mg and Insulin receptors which would influence peripheral deiodinase activity. In non- obese type 2 diabetics, it is quite clear that down regulation of insulin receptors does not take place which leads to less of control on extracellular Mg per se but will have a possible influence in mobilizing Mg from within the cells to the extra cellular mileu. This explains the negative correlation between T3 and Mg and is quite possible that enhanced Mg exodus from within the cells to the extracellular fluid occurs in non- obese type 2 diabetics. This may be a probable adaptation mechanism envisaged in non- obese type 2 diabetics to still synthesise the active form of thyroid hormone despite insulin resistance. However, Zinc in the divalent cationic state is a major regulator of insulin action. Our results suggest that the divalent cations assume significance in obese T2DM in comparison to the non obese. A study done by Zhang et al. on type 2 diabetics revealed a study on serum trace elements in type 2 diabetics; there was a decline in serum Mg levels in T2DM [44]. A recent report on the association between thyroid hormones and insulin resistance in healthy individuals suggested high levels of free T3 [45]. Metformin is one of the most trusted hypoglycaemic agents used in diabetes therapy [46]. The present study was done on Type 2 diabetics who were on Metformin therapy as a rational drug prescribed on the basis of institute drug policy. Earlier studies have shown that metformin treatment decreases serum TSH levels, probably by enhancing the availability of thyroid hormone local levels in anterior pituitary and activating adenosine monophosphate activated protein kinase. We suggest that the dosage of metformin therapy could be optimised in such a manner that Type 2 diabetics would have a near euthyroid state. An earlier study undertaken at our laboratory suggested that small dense LDL particles evaluated through the surrogate TAG/HDL ratio and thyroid hormone levels could be used as objective markers for insulin resistance with thyroid comorbidity in overweight and obese type 2 diabetics [47]. Furthermore several mechanisms have been proposed to implicate thyroid function in human obesity that include adaptive changes to energy expenditure, hyper lipidemia, activity of deiodinase etc. [48]. A recent study on the role of thyroid hormones and TSH associated with IR and cardiometabolic risks even in euthyroid subjects revealed that fasting insulin and HOMAIR positively correlated with free T3 and TSH and negatively with free T4 [49]. Our present study has confirmed these findings, namely positive correlation between free T3 and insulin in non
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
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obese type 2 diabetics and a positive correlation was also observed between TSH and HOMA-IR in the same group (Non obese type 2 diabetics). However, our present study did not reveal any correlation among the same parameters in obese type 2 diabetics. It is well known that adiponectin elaborated by the adipocytes protects against development of insulin resistance. A study done by Briggs et al. an experimental model revealed that zinc enhances adiponectin oligomerisation to octadecamers, a mechanism probably considered important in the light of adiponectin with reference to insulin resistance [50]. We predict that zinc may have a central role not only with reference to insulin action, but also with reference to adiponectin activity that may assume additional relevance with respect to thyroid comorbidity (Results not shown here). Magnesium, another divalent cation considered absolutely essential for insulin action and carbohydrate metabolism is also involved in deiodinase activity leading to the formation of T3 from T4. Our present study suggests a positive correlation between Zinc and magnesium in obese type 2 diabetics, but not in non obese T2DM. This would essentially mean that there is an important role for insulin receptor mediated action in the action of divalent cations, because down regulation of insulin receptors occurs in obese type 2 diabetics. Our results depict that glycated haemoglobin, an index of glycemic control positively correlated with free T4 only in non obese T2DM, but not in obese T2DM. But, a negative correlation was observed between free T3 and Mg in non obese T2DM. This implies that there may be some other mechanisms involved that override the normal biochemistry in thyroid hormone synthesis, for magnesium is required in the conversion of T4–T3. Our results depict a negative correlation between insulin and magnesium in non obese type 2 diabetics. Earlier studies have categorically linked hypomagnesemia in type 2 diabetes mellitus. The hypomagnesemia could be attributed to defective intestinal absorption of the divalent cation or/and increased excretion of urinary magnesium. We explain our results as follows; Insulin resistance is a progressive condition. The hyperinsulinism that is observed in T2DM progresses as Insulin resistance, eventually leading to beta cell depletion. Hypomagnesemia could be perceived as the end result of insulin resistance nearing beta cell depletion. However, such a phenomenon (Hypomagnesemia) may not be observed in the phase of insulin resistance where insulin levels are high. It is in this scenario that a positive correlation exists between free T3 and Insulin, glycated haemoglobin and T4 and TSH Vs HOMA-IR. However, as per our study all these results have been observed only in non obese T2DM, but not in obese T2DM. Hence, we feel that there must be an additional role for Insulin receptor or receptor mediated obligatory biochemical events that may not occur in obese type 2 diabetics, where down- regulation of insulin receptors would have occurred. Hence, we suggest that it may be an interesting proposition to carryout studies on thyroid comorbidity as perceived in insulin resistance, but with reference to the intermediate group, namely overweight. 7. Conclusion Insulin resistance as seen in Type 2 DM is associated with Thyroid comorbidity. Routinely used biochemical parameters are associated with thyroid hormones and insulin can be used to predict the magnitude and variation in thyroid comorbidity as observed in obese and non obese type 2 diabetics. TAG/HDL, a surrogate marker of small dense LDL cannot be used to differentiate obese from non obese type 2 dibetics with associated comorbidity. The levels of T3, T4, TSH, HbA1C and HOMA-IR, a measure of insulin resistance should be checked with the levels of Mg and Zn in serum to differentially predict the course of thyroid
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comorbidity as related to insulin resistance in obese and non obese type 2 diabetics. 7.1. Limitations of the study We did not measure small dense LDL by direct assay. Oxidative stress mediated insulin resistance has been reported by earlier workers. But, we did not biochemically quantitate the markers of Oxidative stress. Anthropometric measures (WHR, BMI) were used only to segregate study participants into obese and non obese type 2 diabetics, but we did not perform correlation/association with physiological and biochemical parameters as linked to thyroid comorbidity in insulin resistance. Funding No funding from external agencies. Conflicts of interest The authors declare that there is no conflict of interest in this study. Acknowledgments The authors wish to express appreciation to the study participants and thank Prof. N. Ananthakrishnan, Dean Research, Sri Balaji Vidyapeeth, Puducherry. References [1] Quilliot D, Dousset B, Guerci B, Dubois F, Drouin P, Ziegler O. Evidence that diabetes mellitus favor impaired metabolism of zinc, copper, selenium in chronic pancreatitis. Pancreas 2001;22:299–306. [2] Souad Belmadani, Khalid Matrougui. The Unraveling Truth About IRE1 and MicroRNAs in Diabetes. Diabetes 2017;66(Jan (1)):23–4, doi:http://dx.doi.org/ 10.2337/dbi16-0058. [3] Unwin N, Sobngwi E, Albert KGMM. Type-2 diabetes: the challenge of preventing a global epidemic. Diabet Int 2001;11:3–8. [4] Vincent JB. Quest for the molecular mechanism of chromium action and its relationship to diabetes. Nutr Rev 2000;58:67–72. [5] Murray RK, Granner PA, Rodwell VW. Metabolism of carbohydrates. Harpers biochemistry, 25th. Appleton and Lange; 2000. p. 190–5. [6] Kruse-Jarres JD, Rukgauer M. Trace elements in diabetes mellitus. Peculiarities and clinical validity of determinations in blood cells. J Trace Elem Med Biol 2000;14:21–7. [7] Puri M, Gujral U, Nayyar SB. Comparative study of serum zinc, magnesium and copper levels among patients of type 2 diabetes mellitus with and without microangiopathic complications. Innovative J Med. Health 2013;3:274–8. [8] National Cholesterol Education Program (NCEP) Lipid Panel Reference Ranges: Pathology, inc., 2011, 2. [9] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. [10] Zhong Y, Miao Y, Jia WP, Yan H, Wang BY, Jin J. Hyperinsulinemia, insulin resistance and cognitive decline in older cohort. Biomed Environ Sci 2012;25:8–14. [11] Yang WY, Li GW, Xin XY. Prediction of metabolic syndrome with combination of waist-to-hip raio or waist circumference and blood pressure measurements. Chin J Endocrinol Metab 2005;21:227–9. [12] Sarkar A, Dash S, Barik BK, Muttigi MS, Kedage V, Shetty JK, et al. Copper and Ceruloplasmin levels in relation to total thiols and GST in type 2 diabetes mellitus patients. Ind J Clin Biochem 2010;25:74–6. [13] Viktorínová A, Toserová E, Krizko M, Durackova Z. Altered metabolism of copper, zinc, and magnesium is associated with increased levels of glycated hemoglobin in patients with diabetes mellitus. Metabolism 2009;58:1477–82. [14] Zargar AH, Shah NA, Masoodi SR, Laway BA, Dar FA, Khan AR, et al. Copper, zinc, and magnesium levels in non-insulin dependent diabetes mellitus. Postgrad Med J 1998;74:665–8. [15] Evliyaoglu O, Kebapcilar L, Uzuncan N, Kılıçaslan N, Karaca B, Kocaçelebi R, et al. Correlations of serum Cu + 2, Zn + 2, Mg + 2 and HbA1c in type 1 and type 2 diabetes mellitus. Turk J Endocrinol Metab 2004;2:75–9. [16] Keller SR. Role of the insulin-regulated aminopeptidase IRAP in insulin action and diabetes. Biol Pharm Bull 2004;27:761–4.
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
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[17] Tang XH, Shay NF. Zinc has an insulin-like effect on glucose transport mediated by phosphoinositol-3-kinase and Akt in 3T3-L1 fibroblasts and adipocytes. J Nutr 2001;131:1414–20. [18] Zargar AH, Bashir MI, Masoodi SR, Laway BA, Wani AI, Khan AR, et al. Copper, zinc and magnesium levels in type-1 diabetes mellitus. Saudi Med J 2002;23:539–42. [19] Al-Maroof RA, Al-Sharbatti SS. Serum zinc levels in diabetic patients and effect of zinc supplementation on glycemic control of type-2 diabetics. Saudi Med J 2006;27:344–50. [20] Anetor JI, Senjobi A, Ajose OA, Agbedana EO. Decreased serum magnesium and zinc levels: artherogenic implications in type-2 diabetes mellitus in Nigerians. Nutr Health 2002;16:291–300. [21] Diwan AG, Pradhan AB, Lingojwar D, Krishna KK, Singh P, Almelkar SI. Serum zinc, chromium and magnesium levels in type-2 diabetes. Int J Diabet Dev Ctries 2006;26:122–3. [22] Ankush RD, Suryakar AN, Ankush NR. Hypomagnesaemia in type-2 diabetes mellitus patients: a study on the status of oxidative and nitrosative stress. Ind J Clin Biochem 2009;24:184–9. [23] Tripathy S, Sumathi S, Raj GB. Minerals nutritional status of type-2 diabetic subjects. Int J Diab Dev Ctries 2004;24:27–8. [24] Sharma A, Dabla S, Agrawal RP, Barjatya H, Kothari RP, Kochar DK. Serum magnesium: an early predictor of course complications of diabetes mellitus. J Indian Med Assoc 2007;105:16–20. [25] Kaur Jaswant, Singh Tajinder. Estimation of serum magnesium and zinc levels In type-2 diabetes mellitus. Int J Bioassays 2015;4:3654–6. [26] Mamza YP, Abdullahi ZB, Gali RM, Mshelia DS, Genesis RY, Habu SA. Status of serum zinc and magnesium among type 2 diabetic subjects in maiduguri. IOSR-JDMS 2016;15:66–70. [27] Mishra S, Padmanaban P, Deepti GN, Sarkar G, Sumathi S, Toora BD. Serum magnesium and dyslipidemia in type-2 diabetes mellitus. Biomed Res 2012;23:295–306. [28] Walti MK, Zimmermann MB, Giatgen A, Spinas A, Hurrell RF. Swiss Med Wkly 2003;133:289–92. [29] Porta S, Epple A, Leitner G, Frise E, Liebmann P, Vogel WH, et al. Impact of stress and triiodothyronine on plasma magnesium fractions. Life Sci 1994;55:327– 32. [30] DolevE. Deuster PA, Solomon B, Trostmann UH, Wartofsky L, Burman KD. Alterations in magnesium and zinc metabolism in thyroid disease. Metabolism 1988;37:61–7. [31] Cruz KJ, Morais JB, de Oliveira AR, Severo JS, Marreiro DD. The effect of zinc supplementation on insulin resistance in obese subjects: a systematic review. Biol Trace Elem Res 2017;176:239–43. [32] Abdel-Gayoum AA. Dyslipidemia and serum mineral profiles in patients with thyroid disorders. Saudi Med J 2014;35(December):1469–76. [33] Lam HC, Ho LT, Tang KT, Ching KN. Concurrent hyperthyroidism and hyperparathyroidism: influence of hyperthyroidism on serum magnesium, free calcium and parathyroid hormone. Taiwan Yi Xue Hui ZaZhi 1989;886:601–5. [34] Shirakawa J, De Jesus DF, Kulkarni RN. Exploring inter-organ crosstalk to uncover mechanisms that regulate b-cell function and mass. Eur J Clin Nutr 2017;(March)15, doi:http://dx.doi.org/10.1038/ejcn.2017.13 Epub ahead of print.
[35] Hansen AF, Simi c A, Åsvold BO, Romundstad PR, Midthjell K, Syversen T, et al. Trace elements in early phase type 2 diabetes mellitus – a population-based study. Biol Trace Elem Res 2017;175:65–71. [36] Meng LH, Huang Y, Zhou J, Liang XH, Xian J, Li L, Qin Chin YF. Use of First-phase Insulin Secretion in Early Diagnosis of Thyroid Diabetes and Type 2 Diabetes Mellitus. Med J (Engl) 2017;130(7)798–804, doi:http://dx.doi.org/10.4103/ 0366-6999.202739 Apr 5. [37] Walker HK, Hall WD, Hurst JW. Clinical Methods. 3 edn Boston: Butter worths; 1990 ISBN-10:0-409-90077-X. [38] Chimeddamba O, Gearon E, Brilleman SL, Tumenjargal E, Peeters A. Increases in waist circumference independent of weight in Mongolia over the last decade: the Mongolian STEPS surveys. BMC Obes 2017;8(4):19. [39] Luz RH, Barbosa AR, d'Orsi E. Waist circumference, body mass index and waistheight ratio: are two indices better than one for identifying hypertension risk in older adults. Prev Med 2016;93:76–81. [40] Wang C. The relationship between type 2 DM and related thyroid diseases. J Diabetes Res 2013, doi:http://dx.doi.org/10.1155/2013/390534 Epub 2013 Apr 4J 390534. [41] Centeno Maxzud M, Gómez Rasjido L, Fregenal M, Arias Calafiore F, Córdoba Lanus M, D'Urso M, Luciardi H, et al. Prevalence of thyroid dysfunction in patients with type 2 diabetes mellitus. Medicina (B Aires) 2016;76:355–8. [42] Sarfo-Kantanka Osei, Stephen Sarfo Fred, Oparebea Ansah Eunice, Yorke Ernest, Akpalu Josephine, C. Nkum Bernard, et al. Frequency and determinants of thyroid autoimmunity in ghanaian type 2 diabetes patients: a case-control study. A BMC Endocr Disord 201717(2). [43] Kommareddy S, Lee SY, braverman LE, Pearce EN. Thyroid function and metabolic syndrome: a cross-sectional study in obese and overweight patients. Endocr Pract 2015;21:1204–10. [44] Wang Y, Lin M, Gao X, Pedram P, Du J, Vikram C, et al. High dietary selenium intake is associated with less insulin resistance in the Newfoundland population. PLoS One 201712:, doi:http://dx.doi.org/10.1371/journal. pone.0174149. [45] Benites-Zapata VA, Urrunaga-Pastor D, Torres-Mallma C, Prado-Bravo C, Guarnizo-Poma M, Lázaro-Alcántara H. Is free triiodothyronine important in the development of insulin resistance in healthy people? Diabetes Metab Syndr 201728(April), doi:http://dx.doi.org/10.1016/j.dsx.2017.04.022. [46] Meng X, Xu S, Chen G, Derwahl M, Liu C. Metformin and thyroid disease. J Endocrinol 2017;233(1)R43–51, doi:http://dx.doi.org/10.1530/JOE-16-0450 Epub 2017 Feb 14. [47] Jayanthi R, Srinivasan AR, Hanifah M, Maran AL. Associations among insulin resistance, triacylglycerol/high density lipoprotein (TAG/HDL ratio) and thyroid hormone levels – a study on type 2 diabetes mellitus in obese and overweight subjects. Diabetes Metab Syndr 2016, doi:http://dx.doi.org/ 10.1016/j.dsx.2016.12.020s pii: S1871-4021(16)30259-4 Dec 23. [48] Fontenelle LCFeitosa MM1, Severo JS1, Freitas TE1, Morais JB1, Torres-Leal FL2, et al. Thyroid function in human obesity: underlying mechanisms. Horm Metab Res 2016;48(December):787–94. [49] Hainer V, Zamrazilová H, Aldhoon Hainerová I. Are the thyroid hormones and thyrotropin associated with cardiometabolic risks and insulin resistance even in euthyroid subjects. Vnitrni Lekarstvi 2016;62:63–7. [50] Briggs DB, Giron RM, Schnittker K, Hart MV, Park CK, Hausrath AC, et al. Zinc enhances adiponectin oligomerization to octadecamers but decreases the rate of disulfide bond formation. Biometals 2012;25:469–86.
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Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2017) xxx–xxx
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Original Article
Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus Rajendran Jayanthi, Abu Raghavan Srinivasan* , Niranjan Gopal, Ramesh Ramaswamy Department of Biochemistry, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India
A R T I C L E I N F O
A B S T R A C T
Article history: Available online xxx
Aim: The study was primarily aimed at investigating the association of Magnesium and Zinc levels in the serum of adult Non- obese and Obese type 2 diabetic patients, with particular reference to thyroid comorbidity. Methods: 108 patients with T2DM of both genders (24 Non obese and 84 Obese) were enrolled from a tertiary health care unit in Puducherry. The cardio-metabolic risk factors were assessed through body mass index, Waist hip ratio, blood pressure, fasting blood glucose, lipid profile and glycated haemoglobin. Zinc and Magnesium were quantitated. Insulin resistance was by Homeostasis model assessment. Serum free T4, T3 and TSH were also measured. Results: In non-obese type 2 diabetic group, Glycated haemoglobin had a strong positive correlation with free T4(r = 0.784; p = 0.003).TSH also depicted a positive association with HOMA-IR (r = 0.924; p < 0.001); whereas,T3 and Insulin had negative correlation with Magnesium (r = 0.599* and r = 0.620*; p 0.04 and 0.031). The levels of Zinc and Magnesium in the serum of obese diabetic patients had a positive correlation among them (r = 0.565#; p < 0.001). TAG/HDL ratio a measure of small dense LDL is positively correlated with LDL in both groups (r = 0.881 and 0.912) with p value < 0.001 for both. Conclusion: Correlation among Glycemic control, Insulin resistance, Thyroid hormones, divalent cations and dyslipidemia depict differential characteristics in obese and non–obese type2 diabetes with Thyroid comorbidity. © 2017 Published by Elsevier Ltd on behalf of Diabetes India.
Keywords: Serum zinc Serum magnesium Type 2 diabetes Glycated haemoglobin Insulin resistance Thyroid hormones Dyslipidemia
1. Introduction Diabetes mellitus, a common endocrine abnormality affects the metabolism of ions including zinc and magnesium [1]. Diabetes affects nearly 170 million people worldwide or 2% of the world’s population [2,3]. The proposed mechanism of trace elements enhancing insulin action includes activation of insulin receptor sites, serving as cofactors or components for enzyme systems implicated in glucose homeostasis [4,5]. This increases insulin sensitivity and also act as antioxidants [6]. Lower serum levels of magnesium and zinc are observed in patients suffering from type-2 diabetes [7]. It remains to be seen whether difference in trace element status is a cause or effect. The objective of this study was to assess the levels of Zinc and Magnesium in serum in adult non obese and obese type 2 diabetics, but with reference to thyroid comorbidity, in the light of insulin resistance. This dimension has been envisaged, as thyroid comorbidity is frequently linked to
insulin resistance in type2 diabetics and also very few reports from South India are available implicating in obese, overweight and non- obese type 2 diabetes, as the case may be. 2. Methodology 2.1. Inclusion criteria 108 patients with T2DM of both genders (24 Non obese and 84 Obese based on Waist circumference for men 85 cm and for women 80 cm) were enrolled from a tertiary health care unit in Puducherry, during the latter half of 2016, with age in the range 30–75 years. Informed consent was obtained from all the participants. This study was conducted with the approval of the Institutional Human Ethics committee (IHEC). 2.2. Exclusion criteria
* Corresponding author at: Department of Biochemistry, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed University accredited by NAAC with A Grade), Puducherry 607403, India. E-mail address: [email protected] (A.R. Srinivasan). http://dx.doi.org/10.1016/j.dsx.2017.07.010 1871-4021/© 2017 Published by Elsevier Ltd on behalf of Diabetes India.
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
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The patients suffering from liver disease, kidney disease, and severe congestive heart failure were excluded from the study. Expecting mothers were also excluded from the study. 3. Biochemical assessment Fasting blood glucose was estimated by glucose oxidaseperoxidase method (GOD/POD); Fasting insulin was quantitated by automated chemiluminiscence and Glycated hemoglobin by HPLC method. Insulin resistance was measured based on the formula HOMA – IR (Fasting plasma glucose (m mol/l) plasma fasting insulin (m IU/l)/22.5) [9]. Triacylglycerols in serum was measured by glycerol kinase method; Total cholesterol by enzymatic method; HDL cholesterol was enabled by polyanion precipitation. LDL cholesterol was computed by Friedwald equation, LDL cholesterol = Total cholesterol-(HDL cholesterol + VLDL) where VLDL = TAG/5, Small dense LDL particles were quantitated using the surrogate marker (TAG/HDL); Zinc and Magnesium were estimated using spectrophotometry and T3, T4 & TSH were quantitated based on automated electro chemiluminiscence method. High HOMA-IR was defined as HOMA-IR 2.69 [10]. Venous blood was collected from the subjects following an overnight fast. The blood samples (fasting) were analyzed for plasma glucose, insulin resistance by HOMA-IR, lipid profile, glycated haemoglobin, Zinc, Magnesium and T3, T4, TSH. Diabetes mellitus was diagnosed as per American Diabetes Association (ADA) criteria. Glycated haemoglobin less than 7% denoted good Control. For serum lipid reference level, National Cholesterol Education Programme (NCEP) Adult Treatment Panel III (ATP III) guidelines were promulgated [8]. Reference range for Magnesium (serum): 0.7–1 mmol/L i.e. 1.7–2.4 mg/dL; Zinc (serum): 70– 100 mmol/L. T4: 0.8–1.8 ng/dL; T3: 2.3–4.2 pg/mL. TSH: 0.4– 4.0 mIU/L. All biochemical investigations were performed based on IFCC approved procedures. Internal quality control was enabled. External quality check was facilitated through the External Quality Assessment Scheme (EQAS) scheme promulgated by the Clinical Biochemistry Laboratory, Christian Medical College (CMC), Vellore. 4. Statistical analysis The statistical tests employed the present study mean SD and categorical data enumerated as number (%) percentage. The Pearson correlation coefficient was calculated among the study parameters. The p-value <0.05 was considered statistically significant. 5. Results Table 1 depicts the correlation coefficient of Key parameters as observed in both non obese and obese type 2 diabetics.
The serum Zn and Mg levels were statistically correlated with r value being 0.565, p value <0.001, in obese type 2 diabetic subject as compared to non obese individuals (Table 1). Fasting glycated haemoglobin level had significant positive correlation with serum level of thyroxine (p 0.003), in non obese type 2 diabetics;while tri iodothyronine had negative correlation (r = 0.599, p 0.04) with Magnesium in the same group; but there was no significant correlation found in obese type 2 diabetics excepting TAG/HDL ratio and Zinc, Magnesium. Insulin was negatively correlated with Magnesium (r = 0.620, p 0.03) in non–obese type 2 diabetics and TSH had strong positive association with HOMA-IR (r = 0.924, p < 0.001) in the same group (non obese). Our study further implies that insulin correlates positively with T3 in non obese. For the sake of clarity, the key parameters are listed on Table 2. 6. Discussion Type 2 DM is a major global health problem. [11]. It is characterised by insulin resistance in peripheral tissues and an insulin secretory defect of beta cells of the pancreas. The relationship of DM with minerals has been well documented [12–15]. Additionally, zinc may be involved not only in the protection of islet cells, but may also be cardinal to glucose metabolism and insulin signalling. Zinc enables the translocation of insulin into the cells [16]. Additionally, zinc activates the insulinresponse amino peptidase (IRAP) molecule, which enables the translocation of GLUT4 to the cell surface for glucose transport into the insulin responsive cells [17]. The clinical significance of trace elements Zinc and Magnesium are of particular interest. Numerous studies have also demonstrated the essential roles of trace elements as chromium, zinc, magnesium, selenium, vanadium, molybdenum and manganese in insulin action and carbohydrate metabolism [18]. In the study undertaken by Almaroof et al., it was observed that mean serum zinc level was significantly low in diabetics as compared to control subjects [19]. A few other studies have also reported lower serum and plasma zinc levels in diabetics [20]. Magnesium is required for insulin sensitivity and also for deiodinase activity. Hypomagnesaemia can increase the platelet reactivity, increase vascular and adrenal responses to angiotensin II Table 2 Key biochemical parameters in the differential manifestation of obese and non obese type 2 diabetes with reference to Thyroid comorbidity. Parameters
Non obese T2DM
Obese T2DM
T3Vs Mg Insulin vs Mg TSH vs HOMA-IR Zn vs Mg
r = 0.599* r = -0.620* r = 0.924* r = 0.204
r = 0.015 r = -0.265 r = 0.019 r = 0.565*
T3-Triiodothyronine; TSH-Thyroid stimulating hormone; HOMA-IR-Homeostasis model assessment-Insulin resistance; Zn-Zinc; Mg-Magnesium. *pvalue < 0.05.
Table 1 Correlation coefficient between adult non obese and obese type 2 diabetic patients. Non obese Type 2 diabetic patients
Obese Type 2 diabetic patients
Parameters
Correlation coefficient (r)
P value
Correlation coefficient (r)
P value
TAG/HDL vs LDL HbA1c vs T4 T3Vs Mg T3Vs Insulin Insulin vs Mg TSH vs HOMA-IR Zn vs Mg
0.881# 0.784* 0.599* 0.620* 0.620* 0.924# 0.204
<0.001 0.003 0.04 0.031 0.031 <0.001 0.525
0.912# 0.283 0.015 0.22 0.265 0.019 0.565#
<0.001 0.069 0.923 0.155 0.089 0.904 <0.001
TAG-Triacylglycerol; HbA1c-Glycated haemoglobin; HDL- High density lipoprotein; LDL-Low density lipoprotein; T3-Triiodothyronine; T4-Thyroxine; TSH-Thyroid stimulating hormone; HOMA-IR-Homeostasis model assessment-Insulin resistance; Zn-Zinc;Mg-Magnesium. * Indicates statistically significant p value <0.05. # Indicates statistically significant p value <0.001.
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enhanced thromboxane A2 release and lead to organ damage attribute to free radicals [21]. Magnesium itself has been reported to possess antioxidant properties by scavenging oxygen radicals, probably by affecting the rate of spontaneous dismutation of superoxide anions. Increased free radical formation and reduction in antioxidant potential contributes to the development of oxidative stress in type 2 DM [22]. The cause of hypomagnesaemia may be attributed to osmotic renal loss from glycosuria, and also decrease in net tubular reabsorption of magnesium [23]. Sharma has reported an inverse correlation between serum magnesium level and poor glycemic control; and a strong association with retinopathy [24]. Altered levels of Magnesium and zinc in diabetes mellitus remains yet to be ascertained, but its strong association with type 2 diabetes mellitus signifies the role played by magnesium and zinc in glucose disposal. The poor glycemic control and the association with type 2 diabetes mellitus strongly suggest that serum magnesium and zinc estimation should be a part of the screening panel in the risk detection for type 2 diabetic patients. Furthermore, Thyroid comorbidity is an accompanying feature in T2 DM. We feel that there must be also be other factors that effect insulin resistance in the light of the expected fact that hypomagnesmia should correlate with decreased T3 which is the active form of thyroid hormone. Many workers have documented that the magnesium and zinc supplementation, in addition to the other nutritional treatments, play an important role in delay and prevention of the complication of type 2 diabetes mellitus. However, the role of these ions in Thyroid morbidity associated with T2DM remains unclear and not very many reports are also available. When the status of zinc and magnesium is poor in patients with type 2 diabetes mellitus, supplementation of these minerals probably may be beneficial [25]. A recent study by Mamza et al. did not show statistically significant difference in magnesium levels between diabetics and controls. However, a positive correlation existed between magnesium levels and age. The study depicted higher levels of Zinc in diabetics, in comparison to controls. Though such studies have documented the role of divalent cations in insulin resistance and type 2 diabetes mellitus in populations, not many studies are available from India, in particular citing the influence of divalent cations in insulin resistance associated with thyroid comorbidity [26]. The effect of zinc on insulin secretion is biphasic, that is very high or very low zinc plasma concentrations impair insulin secretion [27]. The plasma magnesium level is reduced in diabetes mellitus. Our data reveals significant differences in T2DM non obese group versus the obese group, for serum magnesium and Zinc (Table 2). In accordance with other authors, our data reveals the existence of serum low total magnesium level in patients with non obese T2DM [28]. Hypomagnesaemia is also involved in T2DM pathogenesis and its complications. Earlier studies have correlated the levels of thyroid hormone T4 as a function of glycemic control (intervent comorbidity). However our present study indicates the thyroxine levels positively correlates with poor glycemic control in non obese, but insignificant in obese type 2 diabetics. This could be explained probably on the basis of down regulation of insulin receptors in obese type 2 diabetics. An interesting point that emerges from this study is the inverse correlation between serum magnesium levels and T3. This is a paradox since in the physiological state divalent magnesium ions promote deiodinase activity that is implicated in the formation of T3 from T4. Our study shows a very intense positive correlation with TSH as against HOMA-IR. This further explains that the divalent cations may have both direct and indirect action on hypothalamus – pituitary thyroid axis, besides the known function in insulin sensitivity and action. Porta et al. in 1994 showed with T3 and Mg, an inverse correlation as observed in type 2 diabetics exposed to stress [29]. This opens up an interesting proposition that the counter regulatory
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hormones to insulin, especially cortisol might have an effect on peripheral deiodinase activity. Also more well planned and detail studies have to be necessitated so as to include the role of counter regulatory hormones on divalent cation status in T2DM with associated thyroid comorbidity. We feel that magnesium and zinc occupy a pivotal position in regulating insulin sensitivity in T2DM, in general and with reference to thyroid comorbidity. This implies that Mg and Zn in addition to the role on insulin sensitivity and action might possess an additional influence on hypothalamus anterior pituitary thyroid axis in the presence of other key biochemical parameters. This further could imply why different investigators on the biochemistry of T2DM have come up with both hypo- and hyperthyroidism. An earlier study by Dolev et al. highlighted the status of Magnesium (Mg) and zinc (Zn) in subjects with reference to thyroid diseases. According to this report, Plasma and RBC Mg concentrations were low in half of the hyperthyroid subjects, but mean values were not significantly different from controls. Plasma Zn was lower in hypothyroid subjects and correlated with serum albumin. Plasma Zn concentration was however normal and serum albumin significantly lower in the hyperthyroid group than in the control group [30]. It is well understood that Obesity is a chronic disease characterized by excessive accumulation of body fat and the presence of insulin resistance. In this regard, zinc is an important nutrient that stimulates insulin secretion and increases sensitivity to insulin [31]. Zinc is an essential trace element involved in thyroid hormone metabolism. Our results suggest direct correlation between Zinc and Magnesium as related to thyroid comorbidity, but only in obese T2 diabetics. This further explains the role of insulin receptor in modulating thyroid comorbidity, especially as down regulation of insulin receptor is bound to occur in obese type 2 diabetics, but not in non- obese type 2 diabetics. A study done in Saudi Arabia compared lipid and mineral profiles in hypothyroid patients receiving thyroxine therapy. The authors found out that serum magnesium and lipid levels decreased in overt hyperthyroid [32]. Hyperthyroidism has been implicated in hypomagnesaemia and is frequently linked to enhanced renal excretion of magnesium [33]. Our results suggest that in non- obese type 2 diabetics, T3 inversely correlates with magnesium, whereas positive correlation was obtained with insulin. This showed that the pattern of thyroid comorbidity would vary with the phase of insulin resistance. The concept of beta cell mass and function assumes great relevance in insulin resistance. A recent paper published this year has implicated thyroid strongly in inter organ cross talks related to pancreatic beta cell function. However, the same paper has cited an inherent limitation, namely the availability of sparse published data in different ethnic groups [34]. We feel that mobilisation of magnesium from the intracellular may be a crucial factor in differentiating biochemical based predictors of thyroid comorbidity as related to insulin resistance in obese and non obese type 2 diabetics. Our results in Table 1 show that an inverse correlation was observed between insulin and magnesium only in the non obese group, but not in the obese group which further would support the direct role of insulin receptors in mobilising Magnesium from intracellular stage. Differences in trace elements levels between individuals with type 2 diabetes and controls have been reported in several studies in various body fluids and tissues, but results have been inconsistent and controversial [35]. Diabetes mellitus is a chronic physiological glucose metabolic disorder. Its high prevalence globally has a significant impact on the quality of life. We feel that the management of diabetes thus includes nonpharmacological and glucose lowering agents. Magnesium and Zinc are excellent candidates which would not only alleviate insulin resistance but also would improve thyroid status. Though mechanisms of these elements (Zinc and Magnesium) are well known, the synergetic effects of their combinations are still
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
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obscure as well as with reference to thyroid comorbidity and therapeutically safe doses are not available. It is suggested that detailed research which may be carried out on the basis of evidence based research that would certainly provide newer insights into the role of Mg and Zinc in thyroid comorbidity associated with insulin resistance and frank T2DM. The use of first phase insulin secretion in the early diagnosis of thyroid diabetes and T2DM. According to the study, the beta cell function in thyroid diabetes mellitus is much better than that in T2DM. Hence, this could be used as an early marker in differential diagnosis [36]. A study on thyroid signalling, insulin resistance and T2DM suggested no evidence of a causal association between circulatory levels of TSH, free thyroxine with insulin resistance, but deiodinase affects glucose metabolism [37]. However, the prevalence of non thyroidal causes of low T3 concentration and the frequency of normal T3 concentration in hypothyroid patients makes the use of deiodinase estimation dubious in establishing thyroid disease [38]. However, our present study has outlined the diagnostic efficacy of the levels of TSH, HOMA-IR, T4 and T3, without resorting to the use of deiodinase, in assessing diabetes mellitus with associated thyroid comorbidity. Furthermore, the same parameters could be used to evaluate comorbidity in adult non obese and obese type 2 diabetics that would assume additional clinical relevance. Wolide et al. studied the relationship between thyroid hormones dyslipidemia and T2DM and concluded that TSH was positively associated with serum triglycerides and BMI. Our study was primarily focussed on studying the role played by small dense LDL particles and its relevance in non obese and type 2 diabetics. Small dense LDL was characterised by taking TAG/HDL ratio is a surrogate marker. Quite surprisingly, a significant correlation was found out between TAG/HDL and LDL in both non obese and obese type 2 diabetics. This assumes relevance especially not only with reference to insulin resistance but also with associated thyroid comorbidity (Table 1). We strongly feel that small dense LDL particles have a leading role in the pathogenesis of T2DM with associated thyroid comorbidity. In other words, we may not be able to use TAG/HDL ratio, a surrogate marker of small dense LDL to distinguish thyroid comorbidity with associated insulin resistance in obese and non obese type 2 diabetics. An earlier paper published from our laboratory implicated TAG/HDL ratio and thyroid hormone levels in IR as observed in T2DM. We had concluded from that study that small dense LDL could be used as a reliable marker for IR, with thyroid comorbidity in overweight type 2 diabetics. However in the present study the classification of obese and non obese diabetics was performed based on waist circumference. This is a much more objective and reliable anthropometric measure since type 2 diabetics with a normal BMI can still retained abdominal adiposity, a forerunner to IR. This has been corroborated by earlier workers [39]. However, controversy still exists with reference to thyroid comorbidity as perceived in T2DM/IR and that pertaining to hypoand hyperthyroidism [40]. Maxzud et al. in a recent paper gave an account of the prevalence of thyroid dysfunction in type 2 diabetics in an Argentina population. They submitted that subclinical hypothyroidism was prevalent at a rate of 8% and thyroid dysfunction early detection should be performed especially in newly diagnosed T2DM patients in order to delay the entry into pronounced cardiovascular risk [41,42]. However, a recent paper has implicated oral hypoglycaemic agents in T2DM with associated hypothyroidism. Among other causes, the prevalence of hypothyroidism was lower in subjects with type 2 diabetics who were receiving metformin therapy. This would lead to speculation as to whether metformin would affect the hypothalamic pituitary thyroid axis in patients with T2DM. As per our report all the study subjects were on oral hypoglycaemic agents which
contained metformin mandatorily. Hence more studies have to be done with regard to glycemic control mediated effects on hypothyroid pituitary axis in patients with T2DM. A study undertaken by Koonareddy et al. assessed thyroid function in metabolic syndrome in obese and overweight patients [43]. According to the study, serum TSH level does not appear to be a modifiable risk factor in obese and overweight subjects with metabolic syndrome. This prompted us as to whether the divalent cations, namely Mg and Zn modify TSH levels with reference to insulin resistance associated thyroid comorbidity. Our study wanted to include the effect of Mg and Zn (Divalent Cations) more so because of the following reasons. Mg is involved in carbohydrate metabolism as well as insulin action. Zinc is required for insulin function besides a cofactor required for super oxide dismutase which detoxifies oxygen free radicals. Furthermore studies have documented dyslipidemia with associated hypomagnesaemia in enhanced insulin resistance. We wanted to extend this profile in the light of thyroid comorbidity associated with T2DM. Our study showed a significant negative correlation in nonobese type 2 diabetics between T3 and Mg. Normally, Mg is required for the peripheral deiodinase activity responsible for the formation of T3 from T4. However, we would reaffirm that our study indicates negative correlation between T3 and Mg in non obese. We suspect that there could be a direct interaction between extracellular Mg and Insulin receptors which would influence peripheral deiodinase activity. In non- obese type 2 diabetics, it is quite clear that down regulation of insulin receptors does not take place which leads to less of control on extracellular Mg per se but will have a possible influence in mobilizing Mg from within the cells to the extra cellular mileu. This explains the negative correlation between T3 and Mg and is quite possible that enhanced Mg exodus from within the cells to the extracellular fluid occurs in non- obese type 2 diabetics. This may be a probable adaptation mechanism envisaged in non- obese type 2 diabetics to still synthesise the active form of thyroid hormone despite insulin resistance. However, Zinc in the divalent cationic state is a major regulator of insulin action. Our results suggest that the divalent cations assume significance in obese T2DM in comparison to the non obese. A study done by Zhang et al. on type 2 diabetics revealed a study on serum trace elements in type 2 diabetics; there was a decline in serum Mg levels in T2DM [44]. A recent report on the association between thyroid hormones and insulin resistance in healthy individuals suggested high levels of free T3 [45]. Metformin is one of the most trusted hypoglycaemic agents used in diabetes therapy [46]. The present study was done on Type 2 diabetics who were on Metformin therapy as a rational drug prescribed on the basis of institute drug policy. Earlier studies have shown that metformin treatment decreases serum TSH levels, probably by enhancing the availability of thyroid hormone local levels in anterior pituitary and activating adenosine monophosphate activated protein kinase. We suggest that the dosage of metformin therapy could be optimised in such a manner that Type 2 diabetics would have a near euthyroid state. An earlier study undertaken at our laboratory suggested that small dense LDL particles evaluated through the surrogate TAG/HDL ratio and thyroid hormone levels could be used as objective markers for insulin resistance with thyroid comorbidity in overweight and obese type 2 diabetics [47]. Furthermore several mechanisms have been proposed to implicate thyroid function in human obesity that include adaptive changes to energy expenditure, hyper lipidemia, activity of deiodinase etc. [48]. A recent study on the role of thyroid hormones and TSH associated with IR and cardiometabolic risks even in euthyroid subjects revealed that fasting insulin and HOMAIR positively correlated with free T3 and TSH and negatively with free T4 [49]. Our present study has confirmed these findings, namely positive correlation between free T3 and insulin in non
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
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obese type 2 diabetics and a positive correlation was also observed between TSH and HOMA-IR in the same group (Non obese type 2 diabetics). However, our present study did not reveal any correlation among the same parameters in obese type 2 diabetics. It is well known that adiponectin elaborated by the adipocytes protects against development of insulin resistance. A study done by Briggs et al. an experimental model revealed that zinc enhances adiponectin oligomerisation to octadecamers, a mechanism probably considered important in the light of adiponectin with reference to insulin resistance [50]. We predict that zinc may have a central role not only with reference to insulin action, but also with reference to adiponectin activity that may assume additional relevance with respect to thyroid comorbidity (Results not shown here). Magnesium, another divalent cation considered absolutely essential for insulin action and carbohydrate metabolism is also involved in deiodinase activity leading to the formation of T3 from T4. Our present study suggests a positive correlation between Zinc and magnesium in obese type 2 diabetics, but not in non obese T2DM. This would essentially mean that there is an important role for insulin receptor mediated action in the action of divalent cations, because down regulation of insulin receptors occurs in obese type 2 diabetics. Our results depict that glycated haemoglobin, an index of glycemic control positively correlated with free T4 only in non obese T2DM, but not in obese T2DM. But, a negative correlation was observed between free T3 and Mg in non obese T2DM. This implies that there may be some other mechanisms involved that override the normal biochemistry in thyroid hormone synthesis, for magnesium is required in the conversion of T4–T3. Our results depict a negative correlation between insulin and magnesium in non obese type 2 diabetics. Earlier studies have categorically linked hypomagnesemia in type 2 diabetes mellitus. The hypomagnesemia could be attributed to defective intestinal absorption of the divalent cation or/and increased excretion of urinary magnesium. We explain our results as follows; Insulin resistance is a progressive condition. The hyperinsulinism that is observed in T2DM progresses as Insulin resistance, eventually leading to beta cell depletion. Hypomagnesemia could be perceived as the end result of insulin resistance nearing beta cell depletion. However, such a phenomenon (Hypomagnesemia) may not be observed in the phase of insulin resistance where insulin levels are high. It is in this scenario that a positive correlation exists between free T3 and Insulin, glycated haemoglobin and T4 and TSH Vs HOMA-IR. However, as per our study all these results have been observed only in non obese T2DM, but not in obese T2DM. Hence, we feel that there must be an additional role for Insulin receptor or receptor mediated obligatory biochemical events that may not occur in obese type 2 diabetics, where down- regulation of insulin receptors would have occurred. Hence, we suggest that it may be an interesting proposition to carryout studies on thyroid comorbidity as perceived in insulin resistance, but with reference to the intermediate group, namely overweight. 7. Conclusion Insulin resistance as seen in Type 2 DM is associated with Thyroid comorbidity. Routinely used biochemical parameters are associated with thyroid hormones and insulin can be used to predict the magnitude and variation in thyroid comorbidity as observed in obese and non obese type 2 diabetics. TAG/HDL, a surrogate marker of small dense LDL cannot be used to differentiate obese from non obese type 2 dibetics with associated comorbidity. The levels of T3, T4, TSH, HbA1C and HOMA-IR, a measure of insulin resistance should be checked with the levels of Mg and Zn in serum to differentially predict the course of thyroid
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comorbidity as related to insulin resistance in obese and non obese type 2 diabetics. 7.1. Limitations of the study We did not measure small dense LDL by direct assay. Oxidative stress mediated insulin resistance has been reported by earlier workers. But, we did not biochemically quantitate the markers of Oxidative stress. Anthropometric measures (WHR, BMI) were used only to segregate study participants into obese and non obese type 2 diabetics, but we did not perform correlation/association with physiological and biochemical parameters as linked to thyroid comorbidity in insulin resistance. Funding No funding from external agencies. Conflicts of interest The authors declare that there is no conflict of interest in this study. Acknowledgments The authors wish to express appreciation to the study participants and thank Prof. N. Ananthakrishnan, Dean Research, Sri Balaji Vidyapeeth, Puducherry. References [1] Quilliot D, Dousset B, Guerci B, Dubois F, Drouin P, Ziegler O. Evidence that diabetes mellitus favor impaired metabolism of zinc, copper, selenium in chronic pancreatitis. Pancreas 2001;22:299–306. [2] Souad Belmadani, Khalid Matrougui. The Unraveling Truth About IRE1 and MicroRNAs in Diabetes. Diabetes 2017;66(Jan (1)):23–4, doi:http://dx.doi.org/ 10.2337/dbi16-0058. [3] Unwin N, Sobngwi E, Albert KGMM. Type-2 diabetes: the challenge of preventing a global epidemic. Diabet Int 2001;11:3–8. [4] Vincent JB. Quest for the molecular mechanism of chromium action and its relationship to diabetes. Nutr Rev 2000;58:67–72. [5] Murray RK, Granner PA, Rodwell VW. Metabolism of carbohydrates. Harpers biochemistry, 25th. Appleton and Lange; 2000. p. 190–5. [6] Kruse-Jarres JD, Rukgauer M. Trace elements in diabetes mellitus. Peculiarities and clinical validity of determinations in blood cells. J Trace Elem Med Biol 2000;14:21–7. [7] Puri M, Gujral U, Nayyar SB. Comparative study of serum zinc, magnesium and copper levels among patients of type 2 diabetes mellitus with and without microangiopathic complications. Innovative J Med. Health 2013;3:274–8. [8] National Cholesterol Education Program (NCEP) Lipid Panel Reference Ranges: Pathology, inc., 2011, 2. [9] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. [10] Zhong Y, Miao Y, Jia WP, Yan H, Wang BY, Jin J. Hyperinsulinemia, insulin resistance and cognitive decline in older cohort. Biomed Environ Sci 2012;25:8–14. [11] Yang WY, Li GW, Xin XY. Prediction of metabolic syndrome with combination of waist-to-hip raio or waist circumference and blood pressure measurements. Chin J Endocrinol Metab 2005;21:227–9. [12] Sarkar A, Dash S, Barik BK, Muttigi MS, Kedage V, Shetty JK, et al. Copper and Ceruloplasmin levels in relation to total thiols and GST in type 2 diabetes mellitus patients. Ind J Clin Biochem 2010;25:74–6. [13] Viktorínová A, Toserová E, Krizko M, Durackova Z. Altered metabolism of copper, zinc, and magnesium is associated with increased levels of glycated hemoglobin in patients with diabetes mellitus. Metabolism 2009;58:1477–82. [14] Zargar AH, Shah NA, Masoodi SR, Laway BA, Dar FA, Khan AR, et al. Copper, zinc, and magnesium levels in non-insulin dependent diabetes mellitus. Postgrad Med J 1998;74:665–8. [15] Evliyaoglu O, Kebapcilar L, Uzuncan N, Kılıçaslan N, Karaca B, Kocaçelebi R, et al. Correlations of serum Cu + 2, Zn + 2, Mg + 2 and HbA1c in type 1 and type 2 diabetes mellitus. Turk J Endocrinol Metab 2004;2:75–9. [16] Keller SR. Role of the insulin-regulated aminopeptidase IRAP in insulin action and diabetes. Biol Pharm Bull 2004;27:761–4.
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010
G Model DSX 812 No. of Pages 6
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R. Jayanthi et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2017) xxx–xxx
[17] Tang XH, Shay NF. Zinc has an insulin-like effect on glucose transport mediated by phosphoinositol-3-kinase and Akt in 3T3-L1 fibroblasts and adipocytes. J Nutr 2001;131:1414–20. [18] Zargar AH, Bashir MI, Masoodi SR, Laway BA, Wani AI, Khan AR, et al. Copper, zinc and magnesium levels in type-1 diabetes mellitus. Saudi Med J 2002;23:539–42. [19] Al-Maroof RA, Al-Sharbatti SS. Serum zinc levels in diabetic patients and effect of zinc supplementation on glycemic control of type-2 diabetics. Saudi Med J 2006;27:344–50. [20] Anetor JI, Senjobi A, Ajose OA, Agbedana EO. Decreased serum magnesium and zinc levels: artherogenic implications in type-2 diabetes mellitus in Nigerians. Nutr Health 2002;16:291–300. [21] Diwan AG, Pradhan AB, Lingojwar D, Krishna KK, Singh P, Almelkar SI. Serum zinc, chromium and magnesium levels in type-2 diabetes. Int J Diabet Dev Ctries 2006;26:122–3. [22] Ankush RD, Suryakar AN, Ankush NR. Hypomagnesaemia in type-2 diabetes mellitus patients: a study on the status of oxidative and nitrosative stress. Ind J Clin Biochem 2009;24:184–9. [23] Tripathy S, Sumathi S, Raj GB. Minerals nutritional status of type-2 diabetic subjects. Int J Diab Dev Ctries 2004;24:27–8. [24] Sharma A, Dabla S, Agrawal RP, Barjatya H, Kothari RP, Kochar DK. Serum magnesium: an early predictor of course complications of diabetes mellitus. J Indian Med Assoc 2007;105:16–20. [25] Kaur Jaswant, Singh Tajinder. Estimation of serum magnesium and zinc levels In type-2 diabetes mellitus. Int J Bioassays 2015;4:3654–6. [26] Mamza YP, Abdullahi ZB, Gali RM, Mshelia DS, Genesis RY, Habu SA. Status of serum zinc and magnesium among type 2 diabetic subjects in maiduguri. IOSR-JDMS 2016;15:66–70. [27] Mishra S, Padmanaban P, Deepti GN, Sarkar G, Sumathi S, Toora BD. Serum magnesium and dyslipidemia in type-2 diabetes mellitus. Biomed Res 2012;23:295–306. [28] Walti MK, Zimmermann MB, Giatgen A, Spinas A, Hurrell RF. Swiss Med Wkly 2003;133:289–92. [29] Porta S, Epple A, Leitner G, Frise E, Liebmann P, Vogel WH, et al. Impact of stress and triiodothyronine on plasma magnesium fractions. Life Sci 1994;55:327– 32. [30] DolevE. Deuster PA, Solomon B, Trostmann UH, Wartofsky L, Burman KD. Alterations in magnesium and zinc metabolism in thyroid disease. Metabolism 1988;37:61–7. [31] Cruz KJ, Morais JB, de Oliveira AR, Severo JS, Marreiro DD. The effect of zinc supplementation on insulin resistance in obese subjects: a systematic review. Biol Trace Elem Res 2017;176:239–43. [32] Abdel-Gayoum AA. Dyslipidemia and serum mineral profiles in patients with thyroid disorders. Saudi Med J 2014;35(December):1469–76. [33] Lam HC, Ho LT, Tang KT, Ching KN. Concurrent hyperthyroidism and hyperparathyroidism: influence of hyperthyroidism on serum magnesium, free calcium and parathyroid hormone. Taiwan Yi Xue Hui ZaZhi 1989;886:601–5. [34] Shirakawa J, De Jesus DF, Kulkarni RN. Exploring inter-organ crosstalk to uncover mechanisms that regulate b-cell function and mass. Eur J Clin Nutr 2017;(March)15, doi:http://dx.doi.org/10.1038/ejcn.2017.13 Epub ahead of print.
[35] Hansen AF, Simi c A, Åsvold BO, Romundstad PR, Midthjell K, Syversen T, et al. Trace elements in early phase type 2 diabetes mellitus – a population-based study. Biol Trace Elem Res 2017;175:65–71. [36] Meng LH, Huang Y, Zhou J, Liang XH, Xian J, Li L, Qin Chin YF. Use of First-phase Insulin Secretion in Early Diagnosis of Thyroid Diabetes and Type 2 Diabetes Mellitus. Med J (Engl) 2017;130(7)798–804, doi:http://dx.doi.org/10.4103/ 0366-6999.202739 Apr 5. [37] Walker HK, Hall WD, Hurst JW. Clinical Methods. 3 edn Boston: Butter worths; 1990 ISBN-10:0-409-90077-X. [38] Chimeddamba O, Gearon E, Brilleman SL, Tumenjargal E, Peeters A. Increases in waist circumference independent of weight in Mongolia over the last decade: the Mongolian STEPS surveys. BMC Obes 2017;8(4):19. [39] Luz RH, Barbosa AR, d'Orsi E. Waist circumference, body mass index and waistheight ratio: are two indices better than one for identifying hypertension risk in older adults. Prev Med 2016;93:76–81. [40] Wang C. The relationship between type 2 DM and related thyroid diseases. J Diabetes Res 2013, doi:http://dx.doi.org/10.1155/2013/390534 Epub 2013 Apr 4J 390534. [41] Centeno Maxzud M, Gómez Rasjido L, Fregenal M, Arias Calafiore F, Córdoba Lanus M, D'Urso M, Luciardi H, et al. Prevalence of thyroid dysfunction in patients with type 2 diabetes mellitus. Medicina (B Aires) 2016;76:355–8. [42] Sarfo-Kantanka Osei, Stephen Sarfo Fred, Oparebea Ansah Eunice, Yorke Ernest, Akpalu Josephine, C. Nkum Bernard, et al. Frequency and determinants of thyroid autoimmunity in ghanaian type 2 diabetes patients: a case-control study. A BMC Endocr Disord 201717(2). [43] Kommareddy S, Lee SY, braverman LE, Pearce EN. Thyroid function and metabolic syndrome: a cross-sectional study in obese and overweight patients. Endocr Pract 2015;21:1204–10. [44] Wang Y, Lin M, Gao X, Pedram P, Du J, Vikram C, et al. High dietary selenium intake is associated with less insulin resistance in the Newfoundland population. PLoS One 201712:, doi:http://dx.doi.org/10.1371/journal. pone.0174149. [45] Benites-Zapata VA, Urrunaga-Pastor D, Torres-Mallma C, Prado-Bravo C, Guarnizo-Poma M, Lázaro-Alcántara H. Is free triiodothyronine important in the development of insulin resistance in healthy people? Diabetes Metab Syndr 201728(April), doi:http://dx.doi.org/10.1016/j.dsx.2017.04.022. [46] Meng X, Xu S, Chen G, Derwahl M, Liu C. Metformin and thyroid disease. J Endocrinol 2017;233(1)R43–51, doi:http://dx.doi.org/10.1530/JOE-16-0450 Epub 2017 Feb 14. [47] Jayanthi R, Srinivasan AR, Hanifah M, Maran AL. Associations among insulin resistance, triacylglycerol/high density lipoprotein (TAG/HDL ratio) and thyroid hormone levels – a study on type 2 diabetes mellitus in obese and overweight subjects. Diabetes Metab Syndr 2016, doi:http://dx.doi.org/ 10.1016/j.dsx.2016.12.020s pii: S1871-4021(16)30259-4 Dec 23. [48] Fontenelle LCFeitosa MM1, Severo JS1, Freitas TE1, Morais JB1, Torres-Leal FL2, et al. Thyroid function in human obesity: underlying mechanisms. Horm Metab Res 2016;48(December):787–94. [49] Hainer V, Zamrazilová H, Aldhoon Hainerová I. Are the thyroid hormones and thyrotropin associated with cardiometabolic risks and insulin resistance even in euthyroid subjects. Vnitrni Lekarstvi 2016;62:63–7. [50] Briggs DB, Giron RM, Schnittker K, Hart MV, Park CK, Hausrath AC, et al. Zinc enhances adiponectin oligomerization to octadecamers but decreases the rate of disulfide bond formation. Biometals 2012;25:469–86.
Please cite this article in press as: R. Jayanthi, et al., Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus, Diab Met Syndr: Clin Res Rev (2017), http://dx.doi.org/10.1016/j.dsx.2017.07.010