Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance

Abstract

Context: Brown adipose tissue (BAT) found by positron emission/computed tomography (PET-CT) using flouro-deoxyglucose (FDG) is inducible by cold exposure in men. Factors leading to increased BAT are of great interest for its potential role in the treatment of diabetes and obesity.

Objective: We tested whether thyroid hormone (TH) levels are related to the volume and activity of BAT in a patient with a mutation in the insulin receptor gene. DESIGN/SETTING/INTERVENTION: Our work was based on the case report of a patient in an observational study at the National Institutes of Health.

Patient: The patient discontinued insulin and oral antidiabetics after thyroidectomy and suppressive-dose levothyroxine therapy for thyroid cancer. PET-CT uptake in BAT was confirmed by histology and molecular analysis.

Outcomes: PET-CT studies were performed, and we measured hemoglobin A1c and resting energy expenditure before and after levothyroxine discontinuation for thyroid cancer testing. Molecular studies of BAT and white adipose samples are presented.

Result: Supraclavicular and periumbilical sc adipose tissue demonstrated molecular features of BAT including uncoupling protein-1, type 2 deiodinase, and PR domain containing 16 by quantitative PCR. Activity of type 2 deiodinase activity was increased. The discontinuation of levothyroxine resulted in decreased FDG uptake and diminished volume of BAT depots accompanied by worsening of diabetic control.

Conclusions: This case demonstrates the TH effect on BAT activity and volume in this patient and an association between BAT activity and glucose levels in this patient. Because the contribution of TH on skeletal muscle energy expenditure and fuel metabolism was not assessed, an association between BAT activity and glucose homeostasis can only be suggested.

Figures

Figure 1

FDG-PET scans normalized for intensity show the profound effect of TH status on uptake of glucose throughout the body. A, On levothyroxine suppression therapy; B, off levothyroxine; C, on levothyroxine therapy for 14 d. For the brown adipose volume calculations, a three-dimensional region of interest encompassing the areas with intense uptake on the PET image were marked, and a standardized uptake value was calculated for each pixel, corrected for body weight and injection dose. The 3-dimensional region of interest was copied from the PET image onto the CT scan (data not shown). Pixels within the region of interest were defined as BAT if the standardized uptake value was greater than 1.5 and the corresponding Hounsfield unit on CT was between −50 and −150, levels indicative of adipose tissue. The volume of designated brown fat pixels was calculated by multiplying the number of pixels by the volume of each pixel in cubic centimeters. BAT volume changed with TH levels: A, 29 cm3; B, 9 cm3; C, 27.5 cm3.

Figure 2

Histological and molecular studies on adipose from the patient with type A insulin resistance. A, Dif-quick staining at 120× magnification of BAT from the suprascapular needle biopsy showing multivesicular cells containing lipid. B, Hematoxylin and eosin staining at 200× magnification of adipose tissue from periumbilical sc abdominal needle biopsy showing an atypical appearance consistent with brown adipose. The adipocytes lacked features of white adipose (large empty cell with classical signet-ring morphology). C, Molecular signature of brown fat in the adipose depots of the patient: real-time PCR analysis of mRNA levels of the brown fat molecular markers UCP1, PRDM16, and D2 in abdominal sc fat tissue and of UCP1 in suprascapular fat depot in a control subject and the patient. D, Type 2 5′ deiodinase activity in adipose biopsies obtained from the patient’s suprascapular and sc abdominal depots compared with control sc abdominal adipose biopsy. The patient’s type 2 5′ deiodinase activity is higher in both abdominal (white adipose) and suprascapular (brown adipose) regions compared with control.