Evaluating remission of type 2 diabetes using a metabolic intervention including fixed-ratio insulin degludec and liraglutide: A randomized controlled trial.

AIM: To evaluate the effect on type 2 diabetes remission of short-term intensive metabolic intervention consisting of frequent dietary, exercise and diabetes management coaching, metformin and fixed-ratio insulin degludec/liraglutide. METHODS: In a multicentre open-label randomized controlled trial, insulin-naïve participants within 5 years of diabetes diagnosis were assigned to a 16-week remission intervention regimen or standard care, and followed for relapse of diabetes and sustained remission for an additional year after stopping glucose-lowering drugs. RESULTS: A total of 159 participants aged 57 ± 10 years, with diabetes duration 2.6 ± 1.5 years, body mass index 33.5 ± 6.5 kg/m2, and glycated haemoglobin (HbA1c) level 53 ± 7 mmol/mol were randomized and analysed (79 intervention, 80 control). At the end of the 16-week intervention period, compared to controls, intervention participants achieved lower HbA1c levels (40 ± 4 vs. 51 ± 7 mmol/mol; p < 0.0001), and lost more weight (3.3 ± 4.4% vs. 1.9 ± 3.0%; p = 0.02). There was a lower hazard of diabetes relapse overall in the intervention group compared to controls (hazard ratio 0.63, 95% confidence interval [CI] 0.45, 0.88; p = 0.007), although this was not sustained over time. Remission rates in the intervention group were not significantly higher than in the control group at 12 weeks (17.7% vs. 12.5%, relative risk [RR] 1.42, 95% CI 0.67, 3.00; p = 0.36) or at 52 weeks (6.3% vs. 3.8%, RR 1.69, 95% CI 0.42, 6.82) following the intervention period. CONCLUSIONS: An intensive remission-induction intervention including fixed-ratio insulin degludec/liraglutide reduced the risk of type 2 diabetes relapse within 1 year without sustained remission.

Diabetes remission and relapse following an intensive metabolic intervention combining insulin glargine/lixisenatide, metformin and lifestyle approaches: Results of a randomised controlled trial.

AIM: Non-surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short-term intensive glucose-lowering therapy. METHODS: In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) <7.3% (56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for an additional 52 weeks. The primary outcome was diabetes relapse defined as HbA1c ≥6.5% (48 mmol/mol) at 24 weeks or thereafter, capillary glucose ≥10 mmol/L on ≥50% of readings, or use of diabetes medications, analysed as time-to-event. Main secondary outcomes included complete or partial diabetes remission at 24, 36, 48 and 64 weeks defined as HbA1c <6.5% (48 mmol/mol) off diabetes medications since 12 weeks after randomisation. A hierarchical testing strategy was applied. RESULTS: The intervention significantly reduced the hazard of diabetes relapse by 43% (adjusted hazard ratio 0.57, 95% confidence interval 0.40-0.81; p = .002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14-3.24) and 1.83 (1.03-3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00-3.53) at 48 weeks and 2.05 (0.98-4.29) at 64 weeks. CONCLUSIONS: A 12-week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes.

PREDICTIVE MARKERS FOR POSTSURGICAL MEDICAL MANAGEMENT OF ACROMEGALY: A SYSTEMATIC REVIEW AND CONSENSUS TREATMENT GUIDELINE.

Objective: To clarify the selection of medical therapy following transsphenoidal surgery in patients with acromegaly, based on growth hormone (GH)/insulin-like growth factor 1 (IGF-1) response and glucometabolic control. Methods: We carried out a systematic literature review on three of the best studied and most practical predictive markers of the response to somatostatin analogues (SSAs): somatostatin receptor (SSTR) expression, tumor morphologic classification, and T2-weighted magnetic resonance imaging (MRI) signal intensity. Additional analyses focused on glucose metabolism in treated patients. Results: The literature survey confirmed significant associations of all three factors with SSA responsiveness. SSTR expression appears necessary for the SSA response; however, it is not sufficient, as approximately half of SSTR2-positive tumors failed to respond clinically to first-generation SSAs. MRI findings (T2-hypo-intensity) and a densely granulated phenotype also correlate with SSA efficacy, and are advantageous as predictive markers relative to SSTR expression alone. Glucometabolic control declines with SSA monotherapy, whereas GH receptor antagonist (GHRA) monotherapy may restore normoglycemia. Conclusion: We propose a decision tree to guide selection among SSAs, dopamine agonists (DAs), and GHRA for medical treatment of acromegaly in the postsurgical setting. This decision tree employs three validated predictive markers and other clinical considerations, to determine whether SSAs are appropriate first-line medical therapy in the postsurgical setting. DA treatment is favored in patients with modest IGF-1 elevation. GHRA treatment should be considered for patients with T2-hyperintense tumors with a sparsely granulated phenotype and/or low SSTR2 staining, and may also be favored for individuals with diabetes. Prospective analyses are required to test the utility of this therapeutic paradigm. Abbreviations: DA = dopamine agonist; DG = densely granulated; GH = growth hormone; GHRA = growth hormone receptor antagonist; HbA1c = glycated hemoglobin; IGF-1 = insulin-like growth factor-1; MRI = magnetic resonance imaging; SG = sparsely granulated; SSA = somatostatin analogue; SSTR = somatostatin receptor.

Thyroid-Stimulating Hormone-Stimulated Human Adipocytes Express Thymic Stromal Lymphopoietin.

When recombinant human (rh) thyroid-stimulating hormone (TSH) is administered to thyroid cancer survivors, an acute extra-thyroidal effect raises pro-inflammatory cytokines and activates platelets. Thymic stromal lymphopoietin (TSLP) is a cytokine recently implicated in platelet activation. Our aim was to measure platelet microparticle levels after rhTSH stimulation in vivo, and to investigate TSLP expression in TSH-stimulated human adipocytes in culture. Blood samples for total and platelet microparticle analysis were obtained from thyroid cancer survivors before (day 1) and after rhTSH administration (day 5). Adipocytes, differentiated from stromal preadipocytes isolated from adipose tissue from surgical patients, were stimulated with TSH. TSLP mRNA expression, protein expression, and protein release into the adipocyte medium were measured. The level of platelet microparticles in thyroid cancer patients rose 5-fold after rhTSH stimulation. TSH upregulated TSLP mRNA expression in adipocytes in culture through a pathway that was inhibited by 66% by H89, a protein kinase A inhibitor. TSLP protein expression rose in response to TSH, and TSH-stimulated TSLP release into the medium was completely blocked by dexamethasone. In conclusion, TSLP is a novel TSH-responsive adipokine. Future studies will be needed to address the potential role of adipocyte-derived TSLP and whether it is linked to TSH-dependent platelet activation.

Thyroid-stimulating hormone acutely increases monocyte gene expression in vivo.

OBJECTIVES: Thyroid-stimulating hormone (TSH) acts in an extra-thyroidal fashion and induces a pro-inflammatory, pro-coagulant state. Blood monocytes can be activated by vascular stress, but it is not known if this occurs upon TSH administration. Our aim was to determine if recombinant human (rh) TSH, administered acutely to patients being screened for thyroid cancer recurrence, alters blood monocyte gene expression. DESIGN AND SETTING: Patients (14 women, 1 man) had a mean (±SD) age of 48±10 years, a body mass index of 26±6 kg/m2, a history of total thyroidectomy and radioablation for thyroid cancer, and were on L-thyroxine therapy at a university teaching hospital. They received 2 intramuscular doses of rhTSH (0.9 mg), administered on days 1 and 2. Blood samples were obtained at baseline on day1, and on days 3 and 5. RESULTS: Monocyte MCP-1 mRNA (mean±SE) increased significantly by 1.7±0.3 fold on day 5 following rhTSH stimulation (p=0.03, n=15). IL-1ß and CD36 mRNA expression also increased on day 5 (1.9±0.4 fold, p=0.07, n=14) and 2.5±0.4 fold, p=0.1, n=10), respectively, although did not quite reach statistical significance. Significant correlations were detected between the BMI of patients and their TSH-stimulated monocyte mRNA responses at day 5 for CD11a, (r=0.66, n=14, p=0.01); CD14 (r=0.638, n=13, p=0.019), and CD16, r=0.84, n=13, p=0.0003). CONCLUSION: TSH administration increases pro-atherogenic monocyte gene expression.

Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial.

BACKGROUND: Hyperglycaemia could substantially increase the risk of ischaemic heart disease in patients with type 2 diabetes. We investigated whether intensive lowering of glucose concentrations affects risk. METHODS: We assessed 10,251 adults aged 40-79 years with established type 2 diabetes, mean glycated haemoglobin A1c (HbA1c) concentration of 67 mmol/mol (8·3%), and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or standard therapy (target HbA1c less than 42 or 53-63 mmol/mol [less than 6·0% or 7·0-7·9%], respectively). We assessed fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina, and new angina during active treatment (mean 3·7 years) plus a further mean 1·2 years. This trial is registered with ClinicalTrials.gov, number NCT00000620. FINDINGS: Myocardial infarction was less frequent in the intensive than in the standard therapy group during active treatment (hazard ratio [HR] 0·80, 95% CI 0·67-0·96; p=0·015) and overall (0·84, 0·72-0·97; p=0·02). Findings were similar for combined myocardial infarction, coronary revascularisation, and unstable angina (active treatment HR 0·89, 95% CI 0·79-0·99, overall 0·87 0·79-0·96) and for coronary revascularisation alone (0·84, 0·75-0·94) and unstable angina alone (0·81, 0·67-0·97) during full follow-up. With lowest achieved HbA1C concentrations included as a time-dependent covariate, all hazards became non-significant. INTERPRETATION: Raised glucose concentration is a modifiable risk factor for ischaemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors. FUNDING: National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Eye Intitute, and Centers for Disease Control and Prevention.

Serum fetuin-A levels following recombinant human thyroid-stimulating hormone stimulation.

PURPOSE: Fetuin-A is a hepatokine that is linked to lipid metabolism, obesity, insulin resistance, type 2 diabetes and cardiovascular disease. Elevated thyroid-stimulating hormone (TSH) levels are associated with metabolic and cardiovascular disturbances. Our aim was to determine if TSH can regulate fetuin-A levels. METHODS: Fetuin-A serum levels were examined in 26 subjects (19 women; previous thyroidectomy and radioactive iodine ablation) undergoing recombinant human TSH (rhTSH) stimulation to screen for thyroid cancer recurrence. Their age was 49±10 years, and body mass index (BMI) was 28±6 (both expressed as mean±SD). The patients received two doses of rhTSH (0.9 mg), administered 24 hours apart on days 1 and 2, without discontinuation of ongoing L-thyroxine therapy. Morning blood samples were obtained on days 1 (prior to the first dose of rhTSH), 3 and 5. RESULTS: The baseline value of fetuin-A (mean±SD) for all participants was 527±186 mg/L. Values of fetuin-A did not change in response to rhTSH administration. The lack of response was not dependent on gender, age, baseline free thyroxine level or BMI. CONCLUSION: Fetuin-A has been implicated in metabolic and inflammatory conditions, but there have been no reports on whether fetuin-A is influenced by TSH. Within the context of rhTSH administration for surveillance of thyroid cancer recurrence, there was no effect on serum levels of fetuin-A.

Gastrointestinal Symptoms in Type 1 Diabetes: Relationship With Autoimmune and Microvascular Complications.

PURPOSE: To assess reported rates of gastrointestinal (GI) symptoms and their association with autoimmune diseases and microvascular complications in adults and children with type 1 diabetes. METHODS: The Gastrointestinal Symptom Scale was used to assess GI symptom type and severity in 2370 patients with type 1 diabetes aged 8 to 45 years evaluated as part of a clinical trial screening for celiac disease (CD). The presence and severity of GI symptoms and relationships with demographic, clinical, and other diabetes-related factors were evaluated. RESULTS: Overall, 1368 adults (57.7%) aged 19 to 45 years and 1002 (42.3%) pediatric patients aged 8 to 18 years were studied. At least 1 GI symptom was reported in 34.1% of adults as compared with 21.7% of children (P < 0.0001). Common symptoms in children included upper and lower abdominal pain while adults more frequently reported lower GI symptoms. Participants with GI symptoms had higher hemoglobin A1c (HbA1c) levels (68 ±â€…14mmol/mol; 8.35 ±â€…1.37%) than those without symptoms (66 ±â€…15mmol/mol; 8.22 ±â€…1.40%; P = 0.041). Patients with microvascular complications (nephropathy, retinopathy, and/or neuropathy) were 1.8 times more likely to report GI symptoms (95% CI: 1.26-2.60; P < 0.01) after adjusting for age and sex. No association was observed between GI symptoms and the presence of autoimmune conditions, including thyroid and biopsy-confirmed CD (odds ratio = 1.1; 95% CI: 0.86-1.42; P = 0.45). MAIN CONCLUSIONS: These results highlight that GI symptoms are an important clinical morbidity and are associated with increasing age, duration of type 1 diabetes, HbA1c, and microvascular complications but not with autoimmune comorbidities including CD.

Impact of a Gluten-Free Diet on Quality of Life and Health Perception in Patients With Type 1 Diabetes and Asymptomatic Celiac Disease.

CONTEXT: Celiac disease (CD) is a common comorbidity seen in patients with type 1 diabetes (T1D) and is frequently asymptomatic. As chronic conditions requiring significant lifestyle changes, there are limited reports assessing changes in health-related quality of life (HRQoL) during transition to a gluten-free diet (GFD) in patients with T1D who are asymptomatic for CD. OBJECTIVE: This work aims to prospectively assess HRQoL and health perception in children and adults with T1D and asymptomatic CD after random assignment to GFD vs usual diet. METHODS: Patients with T1D aged 8 to 45 years without CD symptoms were serologically screened for CD, with positive results confirmed with intestinal biopsy. Participants were randomly assigned in an open-label fashion to a GFD or gluten-containing diet (GCD) for 12 months. Generic and diabetes-specific HRQoL and self-perceived wellness (SPW) were assessed longitudinally. RESULTS: A total of 2387 T1D patients were serologically screened. CD was biopsy-confirmed in 82 patients and 51 participants were randomly assigned to a GFD (N = 27) or GCD (N = 24). Excellent adherence to the assigned diets was observed. Overall, no changes in generic (P = .73) or diabetes-specific HRQoL (P = .30), or SPW (P = .41) were observed between groups over 12 months. Hemoglobin A1c (HbA1c) and gastrointestinal symptoms were consistent predictors of HRQoL and SPW. CONCLUSION: HRQoL and SPW were not significantly affected by the adoption of a GFD over 12 months, but worsened with symptom onset and increased HbA1c. Our findings indicate that transition to a GFD can be made successfully in this population without adversely affecting quality of life.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.

A web-based simulation of a longitudinal clinic used in a 4-week ambulatory rotation: a cohort study.

BACKGROUND: Residency training takes place primarily on inpatient wards. In the absence of a resident continuity clinic, internal medicine residents rely on block rotations to learn about continuity of care. Alternate methods to introduce continuity of care are needed. METHODS: A web-based tool, Continuity of Care Online Simulations (COCOS), was designed for use in a one-month, postgraduate clinical rotation in endocrinology. It is an interactive tool that simulates the continuing care of any patient with a chronic endocrine disease. Twenty-three residents in internal medicine participated in a study to investigate the effects of using COCOS during a clinical rotation in endocrinology on pre-post knowledge test scores and self-assessment of confidence. RESULTS: Compared to residents who did the rotation alone, residents who used COCOS during the rotation had significantly higher improvements in test scores (% increase in pre-post test scores +21.6 [standard deviation, SD, 8.0] vs. +5.9 [SD 6.8]; p < .001). Test score improvements were most pronounced for less commonly seen conditions. There were no significant differences in changes in confidence. Residents rated COCOS very highly, recommending its use as a standard part of the rotation and throughout residency. CONCLUSION: A stand-alone web-based tool can be incorporated into an existing clinical rotation to help residents learn about continuity of care. It has the most potential to teach residents about topics that are less commonly seen during a clinical rotation. The adaptable, web-based format allows the creation of cases for most chronic medical conditions.

Using Clinical Questions Asked by Primary Care Providers Through eConsults to Inform Continuing Professional Development.

INTRODUCTION: Continuing professional development (CPD) offerings should address the educational needs of health care providers. Innovative programs, such as electronic consultations (eConsults), provide unique educational opportunities for practice-based needs assessment. The purpose of this study is to assess whether CPD offerings match the needs of physicians by coding and comparing session content to clinical questions asked through eConsults. METHODS: This study analyzes questions asked by primary care providers between July 2011 and January 2015 using a service that allows specialists to provide consultation over a secure web-based server. The content of these questions was compared with the CPD courses offered in the area in which these primary care providers are practicing over a similar period (2012-2014). The clinical questions were categorized by the content area. The percentage of questions asked about each content area was calculated for each of the 12 specialties consulted. CPD course offerings were categorized using the same list of content areas. Percentage of minutes dedicated to each content area was calculated for each specialty. The percentage of questions asked and the percentage of CPD course minutes for each content area were compared. RESULTS: There were numerous congruencies and discrepancies between the proportion of questions asked about a given content area and the CPD minutes dedicated to it. DISCUSSION: Traditional needs assessment may underestimate the need to address topics that are frequently the subject of eConsults. Planners should recognize eConsult questions as a valuable source of practice-associated challenges that can identify professional development needs of physicians.

Time is of the essence: an observational time-motion study of internal medicine residents while they are on duty.

BACKGROUND: The effects of changes to resident physician duty hours need to be measureable. This time-motion study was done to record internal medicine residents' workflow while on duty and to determine the feasibility of capturing detailed data using a mobile electronic tool. METHODS: Junior and senior residents were shadowed by a single observer during six-hour blocks of time, covering all seven days. Activities were recorded in real-time. Eighty-nine activities grouped into nine categories were determined a priori. RESULTS: A total of 17,714 events were recorded, encompassing 516 hours of observation. Time was apportioned in the following categories: Direct Patient Care (22%), Communication (19%), Personal tasks (15%), Documentation (14%), Education (13%), Indirect care (11%), Transit (6%), Administration (0.6%), and Non-physician tasks (0.4%). Nineteen percent of the education time was spent in self-directed learning activities. Only 9% of the total on duty time was spent in the presence of patients. Sixty-five percent of communication time was devoted to information transfer. A total of 968 interruptions were recorded which took on average 93.5 seconds each to service. CONCLUSION: Detailed recording of residents' workflow is feasible and can now lead to the measurement of the effects of future changes to residency training. Education activities accounted for 13% of on-duty time.

Time-motion studies of internal medicine residents' duty hours: a systematic review and meta-analysis.

BACKGROUND: Since the mid-1980s, medical residents' long duty hours have been under scrutiny as a factor affecting patient safety and the work environment for the residents. After several mandated changes in duty hours, it is important to understand how residents spend their time before proposing and implementing future changes. Time-motion methodology may provide reliable information on what residents do while on duty. PURPOSE: The purpose of this study is to review all available literature pertaining to time-motion studies of internal medicine residents while on a medicine service and to understand how much of their time is apportioned to various categories of tasks, and also to determine the effects of the Accreditation Council for Graduate Medical Education (ACGME)-mandated duty hour changes on resident workflow in North America. METHODS: Electronic bibliographic databases were searched for articles in English between 1941 and April 2013 reporting time-motion studies of internal medicine residents rotating through a general medicine service. RESULTS: Eight articles were included. Residents spent 41.8% of time in patient care activities, 18.1% communicating, 13.8% in educational activities, 19.7% in personal/other, and 6.6% in transit. North American data showed the following changes after the implementation of the ACGME 2003 duty hours standard: patient care activities from 41.8% to 40.8%, communication activities from 19.0% to 22.3%, educational activities from 17.7% to 11.6%, and personal/other activities from 21.5% to 17.1%. CONCLUSION: There was a paucity of time-motion data. There was great variability in the operational definitions of task categories reported in the studies. Implementation of the ACGME duty hour standards did not have a significant effect on the percentage of time spent in particular tasks. There are conflicting reports on how duty hour changes have affected patient safety. A low proportion of time spent in educational activities deserves further study and may point to a review of the educational models used.

Acute TSH stimulation in vivo does not alter serum PCSK9 levels.

BACKGROUND: It is now recognized that TSH can act on targets other than the thyroid, including the liver. Elevated serum TSH levels in euthyroid subjects were recently reported to correlate with high values of serum proprotein convertase subtilisin/kexin type 9 (PCSK9). This protein, expressed and secreted by hepatocytes, promotes higher LDL-cholesterol levels. We tested whether an acute increase of TSH levels following administration of TSH in vivo would raise PCSK9 levels in patients who had previously undergone total thyroidectomy and radioablation for thyroid cancer. FINDINGS: TSH levels rose from 0.64 ± 1.02 mU/L on day 1 to 98.66 ± 4.83 mU/L on day 3, following injections of recombinant human TSH (on days 1 and 2). PCSK9 levels were 330 ± 99 ng/ml on day 1, and did not change on days 3 or 5 in response to TSH stimulation. CONCLUSIONS: Although a positive correlation between TSH and PCSK9 in euthyroid subjects has raised the possibility that TSH might act on the liver to raise PCSK9 values, our data show that PCSK9 levels are not affected by acute elevations of TSH levels. Whether chronic elevations of TSH are needed to upregulate PCSK9 remains to be determined.

Pituitary hyperplasia: a complication of the pseudomalabsorption of thyroxine.

OBJECTIVE: "The pseudomalabsorption of thyroxine" has been used to describe patients with hypothyroidism who fail to comply with their treatment. We describe a unique case of a 32-year-old with hypothyroidism who developed pituitary hyperplasia and hyperprolactinemia secondary to the pseudomalabsorption of thyroxine. INVESTIGATIONS AND TREATMENT: After baseline thyroid-function tests were performed, the patient was administered levothyroxine 0.5 mg under the supervision of a registered nurse. Thyroid function testing was repeated at 30, 60, 120, and 180 minutes. Arrangements were made for further daily supervised loading of levothyroxine 0.1 mg. RESULTS: With the administration of 0.5 mg levothyroxine, free thyroxine levels increased by 120 minutes, and with daily supervised dosing of 0.1 mg there was normalization of the thyroid hormone levels and a reduction of thyroid-stimulating hormone levels. Maintenance of thyroid-stimulating hormone < 15 mU/L for 2 weeks led to a reduction in prolactin levels and regression in the size of the pituitary on magnetic resonance imaging. CONCLUSION: If left untreated, these patients face significant morbidity and are at risk of developing pituitary hyperplasia, complications from an increase in pituitary size, hyperprolactinemia, and potentially myxedema coma. Recognizing pituitary hyperplasia and hyperprolactinemia as a complication from the pseudomalabsorption of levothyroxine may prevent the potential of a misdiagnosis of a prolactinoma leading to unnecessary investigations and inappropriate treatment. Patient awareness of this serious complication and the rapid, demonstrable resolution with adequate thyroid hormone replacement may provide motivation to comply with supervised dosing of levothyroxine. It has also been suggested that supervised treatment enables the individual to maintain their patient status, which may be in part the motivation behind this disorder.

Thyroid-stimulating hormone stimulates lipolysis in adipocytes in culture and raises serum free fatty acid levels in vivo.

Thyroid-stimulating hormone (TSH) stimulates adipocyte lipolysis, but signal transduction pathways activated by TSH for this response have not been directly studied. Using differentiated 3T3-L1 adipocytes as well as primary human adipocytes, we characterized the lipolytic action of TSH with dose-response and time-course studies, and compared it with isoproterenol. Thyroid-stimulating hormone stimulated phosphorylation of perilipin and hormone-sensitive lipase (HSL). Inhibition of protein kinase A with H89 blocked TSH-stimulated lipolysis as well as phosphorylation of perilipin and HSL. Thyroid-stimulating hormone stimulated lipolysis in vivo, as indicated by an elevation in serum free fatty acid (FFA) levels after recombinant human TSH administration to thyroidectomized patients (42% increase, n = 19, P < .05). For patients with a body mass index less than 30 kg/m(2), the TSH-induced increase in serum FFA levels was 53% (n = 11, P < .05), whereas levels in patients with a body mass index of at least 30 kg/m(2) (n = 8) did not change after TSH treatment. In summary, TSH stimulates lipolysis and phosphorylation of perilipin and HSL in a protein kinase A-dependent manner in differentiated adipocytes in culture and raises serum FFA levels in vivo.