The Effect of Administration of Small Doses of Thyroxine on Glucose and Lipid Metabolism, in Type 2 Diabetes Mellitus.

Study Overview
=================
Brief Summary
-----------------
We investigated the effect of the administration of small doses of thyroxine to healthy humans and patients with type 2 diabetes on postprandial forearm muscle glucose uptake, insulin sensitivity indices, lipid metabolism, in vitro glucose uptake and GLUT4 recruitment in the plasma membrane of monocytes.

Detailed Description
-----------------
The present open-labeled, randomized and placebo-controlled study was undertaken in euthyroid type 2 diabetic patients and healthy humans, to examine the effect of administration of small doses of thyroxine within the euthyroid range, on muscle glucose disposal, postprandial insulin sensitivity, lipid metabolism, in vitro glucose uptake and GLUT4 recruitment in the plasma membrane of monocytes.This was investigated with the arteriovenous-difference technique after the consumption of a mixed meal and the in vitro study of a glucose analogue(6-NBDG) uptake by the peripheral monocytes. Subjects and Methods: Eleven euthyroid, treatment naive, type-2 diabetic patients with a micronodular texture of the thyroid gland and eleven healthy euthyroid subjects, were studied before and after administration of 50 μg of thyroxine once daily for 2 months. In parallel, a placebo group was also studied. Eleven euthyroid treatment-naïve subjects with type 2 diabetes and a micronodular texture of the thyroid gland, matched for age, sex, BMI, and basal thyroid function, were studied before and after administration of a placebo, once daily for 2 months. Experimental protocol: All subjects were admitted to the hospital at 0700 h after an overnight fast and had the radial artery (A) and a forearm deep vein (V) catheterized. A meal (730kcal, 50%carbohydrate, of which 38% was starch, 40% fat, and 10% protein) was given at least 1 h after catheter insertion and was consumed within 20 min. Blood samples were drawn from both sites before the meal (at -30 and 0 min) and at 30- to 60-min intervals for 300 min thereafter for measurements of thyroid hormones,glucose, total cholesterol, LDL Cholesterol, HDL Cholesterol, triglycerides, Apolipoprotein A1, Apolipoprotein BII and Lp(a).Forearm blood flow was measured with strain-gauge plethysmography. After the first meal tolerance test, treatment with 50μg of thyroxine or placebo, once daily, was initiated for a 2-month period. Then a second identical test was repeated. Special care was taken in order to avoid the induction of subclinical hyperthyroidism, that is suppression of TSH below 0.27 μU/ml, as it has recently been shown that the latter is also an insulin-resistant condition.

Official Title
-----------------
The Effect of Administration of Small Doses of Thyroxine on Glucose and Lipid Metabolism, at All Stages of Type 2 Diabetes Mellitus.

Conditions
-----------------
Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: thyroxine
* Drug: Placebo
* Other: A meal (730kcal, 50%carbohydrate, of which 38% was starch, 40% fat, and 10% protein)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy or treatment naive type 2 diabetes euthyroid subjects, with a micronodular texture of the thyroid gland. Recreationally active With stable body weight and diet during the last two months. Exclusion Criteria: Any systemic disease(besides glucose abnormalities) Any medication therapy Diabetic complications

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: thyroxine in eythyroid diabetics<br>50 μg of thyroxine once daily, for 2 months. | Drug: thyroxine<br>* treatment with 50μg of thyroxine once daily for two months.<br>* Other names: T4;Other: A meal (730kcal, 50%carbohydrate, of which 38% was starch, 40% fat, and 10% protein)<br> <br> |
| Active Comparator: thyroxine in euthyroid healthy humans<br>50 μg of thyroxine once daily, for 2 months. | Drug: thyroxine<br>* treatment with 50μg of thyroxine once daily for two months.<br>* Other names: T4;Other: A meal (730kcal, 50%carbohydrate, of which 38% was starch, 40% fat, and 10% protein)<br> <br> |
| Placebo Comparator: placebo in euthyroid diabetics<br>50 μg of placebo once daily, for 2 months. | Drug: Placebo<br>* treatment with 50μg of placebo, once daily, for two months.<br>Other: A meal (730kcal, 50%carbohydrate, of which 38% was starch, 40% fat, and 10% protein)<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| area under the glucose uptake versus time curve-AUC | Muscle glucose uptake following meal ingestion | Time Frame: 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma glucose levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma insulin levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma triglyceride levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma total cholesterol levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma LDL-cholesterol levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma HDL-cholesterol levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma Apo-A levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma Apo-B levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma Lp(α) levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma NEFA levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma glycerol levels following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Muscle blood flow following meal ingestion | area under the plasma concentration versus time curve-AUC | 0, 30, 60, 90, 120, 180, 240, 300 min postmeal | 
| Plasma thyroid hormones | measure of plasma concentration | baseline | 
| glucose uptake by peripheral monocytes by the usage of the fluorescent analogue 6-NBDG | area under the curve of 6-NBDG uptake by monocytes under insulin stimulation | baseline to 600 sec | 
| % GLUT4 increment from baseline (0mU/l) to maximal concentration (200mU/l) of insulin. |  | baseline | 
| Number of participants with adverse events |  | 300 min postmeal | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes mellitus, thyroxine