Mediators of energy homeostasis in hyperthyroidism

ABSTRACT Objective: The aim of this study was to assess the effect of hyperthyroidism and its treatment on body weight and composition, insulin resistance, and mediators of appetite and energy homeostasis, namely ghrelin, leptin, adiponectin, and fibroblast growth factor 21 (FGF21). Subjects and methods: Thirty-five adult patients (27 female and 8 male, aged 39.63 ± 9.70 years) with overt hyperthyroidism were evaluated for leptin, ghrelin, adiponectin, and FGF21 levels; insulin resistance; and body composition using DEXA both at baseline and a minimum of two months following normalization of serum thyroxin on carbimazole treatment. Comparison of means between the baseline and post treatment values was performed by the paired t test for normally distributed parameters and by the Wilcoxon signed-rank test for non-normally distributed data. Results: Hyperthyroidism correction resulted in an increase in weight from 51.15 ± 8.50 kg to 55.74 ± 8.74 kg (P < 0.001), paradoxically accompanied by a decrease in insulin resistance as measured by HOMA-IR from 1.35 (1.02-1.72) to 0.73 (0.52-0.93) ( P < 0.001). Correction of hyperthyroidism was also associated with a decrease in FGF21 from 58 (55-64) to 52 (47-58) pg/mL ( P < 0.001) and in leptin levels from 17 (7-36) to 11 (4.6-28) ng/mL ( P = 0.03). Conclusion: Despite lower body weight, thyrotoxicosis is associated with insulin resistance. High levels of thermogenic hormones, leptin, and FGF21 were observed in thyrotoxicosis and may be partly responsible for the excessive heat production typical of this condition.

Urinary brush border enzymes for early diagnosis of tubular dysfunction in patients with type 2 diabetes mellitus

Background: Diabetic nephropathy is a major cause of premature morbidity and mortality in type 1 and type 2 diabetes mellitus (T2DM) and hence new markers with better sensitivities are being investigated. The study was taken up to investigate whether urinary activities of N-acetyl-β-D-glycosaminidase (NAG), alkaline phosphatase (ALP), lactate dehydrogenase LDH) and Gamma glutamyl transferase (γ-GT) can be used as screening markers of renal dysfunction in patients suffering from T2DM.Methods: One hundred and four patients with T2DM along with 30 age- and gender-matched healthy individuals were included in the study. Patients were divided into three groups based on their u-MA levels i.e. normoalbuminuric (group1), micro albuminuric (group 2) and macroalbuminuric (group 3).Results: Urinary enzymes activity was significantly higher in patients with T2DM compared to controls (p<0.05). NAG, ALP, LDH, and GGT were significantly higher in group 3 compared to group1 and group 2 (p<0.0001). NAG, ALP, LDH and GGT showed significant positive correlation with MA (p=0.0001, r=0.308; p=0.0001, r=0.369; p=0.002, r=0.304, p=0.044, r=0.202 respectively). GGT and LDH showed highest sensitivity (86.21%, 84.00% respectively) and specificity (78.57%,53.49% respectively) for diagnosing renal dysfunction in patients with normoalbuminuria.Conclusions: The study suggests that u-GGT and LDH can be useful markers for assessing renal dysfunction in T2DM patients even before microalbuminuria manifests.

Role of adipokines, oxidative stress, and endotoxins in the pathogenesis of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus

Background: Type 2 diabetes mellitus (T2DM) is associated with chronic inflammation and oxidative stress, implicated in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Present study aimed to assess the role of adipokines, oxidative stress, and endotoxins in the pathogenesis of NAFLD in T2DM.Methods: Present cross-sectional observational study included healthy controls (n=50; group 1); T2DM patients without NAFLD (n=50; group 2), T2DM patients with NAFLD (n=50; group 3). Study subjects were age and gender matched.Results: Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high sensitive C-reactive protein (hs-CRP), endotoxin, malondialdehyde (MDA) were significantly elevated and adiponectin, ferric reducing ability of plasma (FRAP), and glutathione (GSH) were significantly lower (p<0.001) in T2DM patients with NAFLD when compared to T2DM patients without NAFLD and controls. Endotoxin showed significant positive correlation with TNF-α (r=0.304; p<0.001), hs-CRP (r=0.193; p=0.018), and MDA (r=0.420; p<0.001), and significant negative correlation with adiponectin (r=-0.406; p<0.001). TNF-α and IL-6 showed significant positive correlation with MDA (r=0.526; p<0.001, r=0.229; p=0.005) and significant negative correlation with adiponectin (r=-0.396; p<0.001, r=-0.318; p<0.001), FRAP (r=-0.418; p<00.001, r=-0.170; p=0.038), and GSH (r=-0.353; p<0.001, r=-0.301; p<0.001).Conclusions: Authors observed elevated endotoxin, oxidative stress, inflammation and lower adiponectin levels in T2DM subjects compared to controls. These changes were more pronounced in T2DM with NAFLD when compared to T2DM without NAFLD.  Lower adiponectin levels were found to be a better predictor of NALFD in T2DM and is associated with oxidative stress and systemic inflammation.

Evaluation of activity of hypothalamo-pituitary-gonadal axis in postmenopausal women suffering from severe acute illness.

Background & objectives: Postmenopausal women constitute an ideal model for studying the extent of hypothalamo-pituitary gonadal (HPG) axis suppression in critical illness as the gonadotropins are normally high and non-cyclical in them. The objective was to assess the impact of acute severe illness in postmenopausal women on the HPG axis and the activities of the hypothalamo-pituitary-adrenal (HPA), the hypothalamo- pituitary-thyroid (HPT) axes; and levels of serum prolactin, by comparison between critically ill postmenopausal women and otherwise healthy postmenopausal women. Methods: Thirty five consecutive postmenopausal women older than 60 yr admitted to medical intensive care with a Simplified Acute Physiology Score II (SAPS II) more than 30 were included. On day five of their in-hospital stay, blood samples were collected for oestradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol, androstenedione, prolactin and thyroid profile. Thirty five apparently healthy postmenopausal women were selected as controls. Results: Levels of LH, FSH, thyrotropin, free thyroxin (fT4) and free tri-iodothyronine (fT3) were lower while oestradiol, cortisol and dehydroepiandrosterone were higher among patients in comparison to healthy controls. Prolactin levels were similar in patients and controls. Among sick patients both FSH and fT4 showed a negative correlation (P<0.05) with the SAPS II score. Interpretation & conclusions: In critically ill postmenopausal women, paradoxically elevated oestrogen levels despite gonadotropin suppression suggests a non-ovarian origin. Prolactin remained unaltered in patients despite their illness, possibly reflecting atrophy of lactotrophs in menopause.

Effects of thyroid hormone replacement on glycated hemoglobin levels in non diabetic subjects with overt hypothyroidism

Objective Glycated hemoglobin (HbA1c) may not accurately reflect the level of glycemia in conditions of altered erythrocyte turnover. Hypothyroidism is one condition associated with sluggish erythropoesis. To assess changes in HbA1c, independent of changes in plasma glucose after initiation of thyroxine replacement in patients with overt hypothyroidism. Materials and methods In this prospective longitudinal study carried out in a tertiary care centre, adult non-diabetic patients with overt hypothyroidism recruited between March 2012 to August 2013 were rendered euthyroid on thyroxine. They underwent testing for hemoglobin, HbA1c, reticulocyte count, thyroxine, thyrotropin and a standard oral glucose tolerance test, both before and at 3 months after restoration to the euthyroid state. Main outcome assessed was the change in HbA1c independent of the change in glucose parameters. Results Thirty eight patients (35 female and 3 male) aged 37.8 ± 10.2 years with overt hypothyroidism (thyroxine 12.6 ± 13.4 ng/mL and thyrotropin -98.1 ± 63.7 µIU/mL respectively) were recruited. While HbA1c fell from 5.8 ± 0.7% to 5.6 ± 0.5% (p = 0.009) at 3 months following the correction of hypothyroidism, there were no changes in the fasting and the 2 hr post oral glucose tolerance test glucose (p = 0.67 and 0.56 respectively). The number of patients with dysglycemia diagnosed by HbA1c (i.e HbA1c≥ 5.7%) fell from 25 (65.78%) to 17 (44.7%) after treatment (p = 0.008). There were 7 (18.4%) patients with HbA1c ≥ 6.5% at baseline, but this fell to just 4 (10.5%) (p < 0.001) after 3 months of euthyroidism. Conclusion HbA1c is not a reliable diagnostic test for diabetes in the presence of hypothyroidism.

Effect of oral hypoglycaemic agents on bone metabolism in patients with type 2 diabetes mellitus & occurrence of osteoporosis.

Background & objectives: Type 2 diabetes mellitus (T2DM) is considered to be a protective factor against development of osteoporosis. But oral hypoglycaemic agents (OHA) are likely to increase the risk of osteoporosis. This study was carried out to evaluate the effect of various OHA on bone mineral density (BMD) in patients with T2DM. Methods: Forty one patients (study group) with T2DM (mean age 51.9±5.5 yr; 31 females) receiving treatment with oral hypoglycaemic agents (OHA) [thiazolidinediones alone (n=14) or in combination with other OHA (n=27)] for a period of at least three consecutive years and 41 age- and gender-matched healthy controls (mean age 51.4±5.1 yr) were included in the study. A detailed clinical history was taken and all were subjected to physical examination and recording of anthropometric data. BMD was assessed for both patients and controls. Results: The mean body mass index (kg/m2) (26.5±4.90 vs 27.3 ±5.33) and median [inter-quartile range (IQR)] duration of menopause (yr) among women [6(2-12) vs 6(1-13)] were comparable between both groups. The bone mineral density (BMD; g/cm2) at the level of neck of femur (NOF) (0.761±0.112 vs 0.762±0.110), lumbar spine antero-posterior view (LSAP) (0.849±0.127 vs 0.854±0.135); median Z-score NOF {0.100[(-0.850)-(0.550)] vs -0.200[(-0.800)-(0.600)]}, LSAP {-1.200[(-1.700)-(-0.200)] vs -1.300 [(-1.85)-(-0.400)]} were also similar in study and control groups. Presence of normal BMD (9/41 vs 8/41), osteopenia (16/41 vs 18/41) and osteoporosis (16/41 vs 15/41) were comparable between the study and control groups. No significant difference was observed in the BMD, T-scores and Z-scores at NOF and LSAP among T2DM patients treated with thiazolidinediones; those treated with other OHA and controls. Interpretation & conclusions: The present findings show that the use of OHA for a period of three years or more does not significantly affect the BMD in patients with T2DM.

Bone disease in thyrotoxicosis.

Thyrotoxicosis, a clinical syndrome characterized by manifestations of excess thyroid hormone, is one of the commonly-recognised conditions of the thyroid gland. Thyrotoxicosis causes acceleration of bone remodelling and though it is one of the known risk factors for osteoporosis, the metabolic effects of thyroxine on bone are not well discussed. Studies show that thyroid hormones have effects on bone, both in vitro and in vivo. Treatment of thyrotoxicosis leads to reversal of bone loss and metabolic alterations, and decreases the fracture risk. There are limited studies in India as to whether these changes are fully reversible. In this review we discuss about the effects of thyrotoxicosis (endogenous and exogenous) on bone and mineral metabolism, effects of subclinical thyrotoxicosis on bone and mineral metabolism and effects of various forms of treatment in improving the bone mineral density in thyrotoxicosis.