Combination Therapy for Hypothyroidism: Rationale, Therapeutic Goals, and Design.

Hypothyroidism is a common condition with a wide spectrum of etiologies and clinical manifestations. While the majority of patients affected by hypothyroidism respond well to levothyroxine, some patients do not and complain of symptoms despite adequate replacement. There is evidence in experimental models of hypothyroidism that levothyroxine alone may not be able to deliver an adequate amount of T3 to all the tissues targeted by the hormonal action, while liothyronine/levothyroxine combination therapy can. The results of clinical studies directed to assess the effectiveness of liothyronine/levothyroxine combination therapy on the amelioration of hypothyroid symptoms have been disappointing. Most of the trials have been short and underpowered, with several shortcomings in the study design. There is consensus that an adequately powered clinical trial should be developed to prove or disprove the efficacy and effectiveness of therapies other than LT4 alone for the treatment of hypothyroidism, and to assess which group of patients would benefit from them. Here we present some considerations on the technical aspects and necessary tradeoffs in designing such a study with a particular focus on study population selection, choice of endpoints, and study drugs formulation and regimen.

Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss - results of an exploratory study.

PURPOSE: Roflumilast (Daliresp, Daxas) is a FDA-approved phosphodiesterase 4 (PDE4) inhibitor for the treatment of moderate-to-severe chronic obstructive pulmonary disease. In mice and in limited human studies, this oral medication can cause weight loss and improve insulin sensitivity. We set out to determine the mechanism of its effect on insulin sensitivity. PATIENTS AND METHODS: Eight adults with overweight/obesity and prediabetes received roflumilast for 6 weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation, and mitochondria function. Dietary intake and physical activity were also assessed. Our primary outcome was the change in peripheral insulin sensitivity, as assessed by the hyper-insulinemic euglycemic clamp. RESULTS: This study was underpowered for the primary outcome. Pre- and post-roflumilast mean peripheral insulin sensitivity were 48.7 and 70.0 mg/g fat free mass/minute, respectively, (P-value=0.18), respectively. Among the mixed meal variables, roflumilast altered glucagon-like peptide 1 (GLP-1) hormone the most, although the average effect was not statistically significant (P=0.18). Roflumilast induced a trend toward significance in 1) decreased energy intake (from 11,095 KJ to 8,4555 KJ, P=0.07), 2) decreased fat mass (from 34.53 to 32.97 kg, P=0.06), 3) decreased total and LDL cholesterol (P=0.06 for both variables), and 4) increased plasma free fatty acids (from 0.40 to 0.50 mEq/L, P=0.09) The interval changes in adiposity and free fatty acid were significantly associated with the subject's age (P-value range= <0.001 to 0.02 for the correlations). Inflammatory and adhesion markers, though unchanged, significantly correlated with one another and with incretin hormones only after roflumilast. CONCLUSION: We demonstrate, for the first time in humans, increasing percentage of fat mass loss from roflumilast with increasing age in adults with prediabetes and overweight/obesity. We also demonstrate novel associations among roflumilast-induced changes in incretin hormones, inflammatory markers, peripheral insulin sensitivity, and adiposity. We conclude that roflumilast's early effects on insulin sensitivity is indirect and likely mediated through roflumilast's prioritization of lipid over glucose handling. CLINICAL TRIALS REGISTRATION: NCT01862029.

Effects of bottom water dissolved oxygen variability on copper and lead fractionation in the sediments across the oxygen minimum zone, western continental margin of India.

This study describes the effect of varying bottom-water oxygen concentration on geochemical fractionation (operational speciation) of Cu and Pb in the underneath sediments across the oxygen minimum zone (Arabian Sea) in the west coast of India. Both, Cu and Pb were redistributed among the different binding phases of the sediments with changing dissolved oxygen level (from oxic to hypoxic and close to suboxic) in the bottom water. The average lability of Cu-sediment complexes gradually decreased (i.e., stability increased) with the decreasing dissolved oxygen concentrations of the bottom water. Decreasing bottom-water oxygen concentration increased Cu association with sedimentary organic matter. However, Pb association with Fe/Mn-oxyhydroxide phases in the sediments gradually decreased with the decreasing dissolved oxygen concentration of the overlying bottom water (due to dissolution of Fe/Mn oxyhydroxide phase). The lability of Pb-sediment complexes increased with the decreasing bottom-water oxygen concentration. This study suggests that bottom-water oxygen concentration is one of the key factors governing stability and lability of Cu and Pb complexes in the underneath sediment. Sedimentary organic matter and Fe/Mn oxyhydroxide binding phases were the major hosting phases for Cu and Pb respectively in the study area. Increasing lability of Pb-complexes in bottom sediments may lead to positive benthic fluxes of Pb at low oxygen environment.

Myocardial Fat Accumulation Is Independent of Measures of Insulin Sensitivity.

BACKGROUND: Myocardial steatosis, an independent predictor of diastolic dysfunction, is frequently present in type 2 diabetes mellitus. High free fatty acid flux, hyperglycemia, and hyperinsulinemia may play a role in myocardial steatosis. There are no prior studies examining the relationship between insulin sensitivity (antilipolytic and glucose disposal actions of insulin) and cardiac steatosis. OBJECTIVE: Using a cross-sectional study design of individuals with and without metabolic syndrome (MetSyn), we examined the relationships between cardiac steatosis and the sensitivity of the antilipolytic and glucose disposal actions of insulin. METHODS: Pericardial fat (PF) volume, intramyocardial and hepatic fat (MF and HF) content, visceral fat (VF) and sc fat content were assessed by magnetic resonance imaging in 77 subjects (49 without MetSyn and 28 with MetSyn). In a subset of the larger cohort (n = 52), peripheral insulin sensitivity index (SI) and adipocyte insulin sensitivity (Adipo-SI) were determined from an insulin-modified frequently sampled iv glucose tolerance test. The Quantitative Insulin Sensitivity Check Index was used as a surrogate for hepatic insulin sensitivity. RESULTS: Individuals with the MetSyn had significantly higher body mass index, total body fat, and MF, PF, HF, and VF content. HF and VF, but not MF, were negatively correlated with the Quantitative Insulin Sensitivity Check Index, Adipo-SI, and SI. Stepwise regression revealed that waist circumference and serum triglyceride levels independently predicted MF and PF, respectively. Adipo-SI and serum triglyceride levels independently predict HF. CONCLUSION: Myocardial steatosis is unrelated to hepatic, adipocyte, or peripheral insulin sensitivity. Although it is frequently observed in insulin-resistant subjects, further studies are necessary to identify and delineate pathogenic mechanisms that differentially affect cardiac and hepatic steatosis.

Coagulation profile in diabetes and its association with diabetic microvascular complications.

OBJECTIVES: To investigate the haemostatic parameters and to assesss their relationship with microvascular complications in type 2 diabetes mellitus. MATERIALS AND METHODS: Coagulation and fibrinolysis parameters were measured in 60 type 2 diabetic patients (M:F 1:1) with (n=40) and without (n=20) diabetic microvascular complications and in 30 nondiabetic healthy subjects (M:F 1:1). RESULTS: The mean age of diabetic patients and healthy controls was 56.9 +/- 8.78 and 53.2 +/- 7.58 respectively (p = 0.05). The plasma levels of PAI-1 (22.6 +/- 6.85 vs 44.8 +/- 20.8, p = 0.00), serum fibrinogen (227.5 +/- 22.8 vs. 252.75 +/- 40.23, p = 0.002) and vWF activity (99.4 +/- 28.18 vs. 144.78 +/- 36.21, p = 0.00) were found to be increased in diabetics compared to healthy controls. Plasma PAI-1 levels (37.15 +/- 15.18 vs 48.65 +/- 22.29, p = 0.0) and vWF activity (123.19 +/- 29.63 vs. 155.57 +/- 34.61, p = 0.007) were significantly increased in diabetic patients with microvascular complications than those without microvascular complications.Amongst the diabetic patients, protein S activity (63.05 +/- 16.85 vs. 51.59 +/- 10.7, p = 0.002) was significantly lower in patients with microvascular complications than in patients without these complications. Diabetic retinopathy was associated with decreased protein S levels (63.05 +/- 16.85 vs. 48.48 +/- 8.72, p = 0.005) and vWF activity (123.19 +/- 29.63 vs. 151.85 +/- 29.74, p = 0.009). Diabetic nephropathy was associated with increased PAI-1 levels (39.55 +/- 13.20 vs. 51.69 +/- 26.53, p = 0.02) and vWF activity (134.99 +/- 32.54 vs. 157.57 +/- 37.37, p = 0.007). Diabetic neuropathy did not show any significant relationship with any of the haemostatic variables. CONCLUSION: Hypercoagulable state as indicated by decreased fibrinolysis and increased coagulability is responsible as one of the factors for the development of microvascular complications of diabetes mellitus.