John M. Wentworth

Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia

Congenital hypothyroidism occurs in one of every three to four thousand newborns, owing to complete or partial failure of thyroid gland development. Although thyroid hypoplasia has recently been associated with mutations in the thyrotropin (TSH) receptor, the cause of thyroid agenesis is unknown. Proteins including thyroid transcription factors 1 (TTF-1; refs 4, 5) and 2 (TTF-2; refs 6, 7) and Pax8 (refs 8, 9) are abundant in the developing mouse thyroid and are known to regulate genes expressed during its differentiation (for example, thyroid peroxidase and thyroglobulin genes). TTF-2 is a member of the forkhead/winged-helix domain transcription factor family, many of which are key regulators of embryogenesis. Here we report that the transcription factor FKHL15 (ref. 11) is the human homologue of mouse TTF-2 (encoded by the Titf2 gene) and that two siblings with thyroid agenesis, cleft palate and choanal atresia are homozygous for a missense mutation (Ala65Val) within its forkhead domain. The mutant protein exhibits impaired DNA binding and loss of transcriptional function. Our observations represent the first description of a genetic cause for thyroid agenesis.

Pro-Inflammatory CD11c+CD206+ Adipose Tissue Macrophages Are Associated With Insulin Resistance in Human Obesity

OBJECTIVE Insulin resistance and other features of the metabolic syndrome have been causally linked to adipose tissue macrophages (ATMs) in mice with diet-induced obesity. We aimed to characterize macrophage phenotype and function in human subcutaneous and omental adipose tissue in relation to insulin resistance in obesity. RESEARCH DESIGN AND METHODS Adipose tissue was obtained from lean and obese women undergoing bariatric surgery. Metabolic markers were measured in fasting serum and ATMs characterized by immunohistology, flow cytometry, and tissue culture studies. RESULTS ATMs comprised CD11c+CD206+ cells in “crown” aggregates and solitary CD11c−CD206+ cells at adipocyte junctions. In obese women, CD11c+ ATM density was greater in subcutaneous than omental adipose tissue and correlated with markers of insulin resistance. CD11c+ ATMs were distinguished by high expression of integrins and antigen presentation molecules; interleukin (IL)-1β, -6, -8, and -10; tumor necrosis factor-α; and CC chemokine ligand-3, indicative of an activated, proinflammatory state. In addition, CD11c+ ATMs were enriched for mitochondria and for RNA transcripts encoding mitochondrial, proteasomal, and lysosomal proteins, fatty acid metabolism enzymes, and T-cell chemoattractants, whereas CD11c− ATMs were enriched for transcripts involved in tissue maintenance and repair. Tissue culture medium conditioned by CD11c+ ATMs, but not CD11c− ATMs or other stromovascular cells, impaired insulin-stimulated glucose uptake by human adipocytes. CONCLUSIONS These findings identify proinflammatory CD11c+ ATMs as markers of insulin resistance in human obesity. In addition, the machinery of CD11c+ ATMs indicates they metabolize lipid and may initiate adaptive immune responses.

The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells

Foxp3+ regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.

Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy.

Objective  Androgen deprivation therapy (ADT) for prostate cancer is associated with increases in fat mass and risk of type 2 diabetes; however, the relationship between sex steroid deficiency and abdominal fat distribution remains controversial.

Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: a randomized controlled trial.

OBJECTIVE To determine whether testosterone therapy improves glucose metabolism in men with type 2 diabetes (T2D) and lowered testosterone. RESEARCH DESIGN AND METHODS We conducted a randomized, double-blind, parallel, placebo-controlled trial in 88 men with T2D, aged 35–70 years with an HbA1c ≤8.5% (69 mmol/mol), and a total testosterone level, measured by immunoassay, of ≤12.0 nmol/L (346 ng/dL). Participants were randomly assigned to 40 weeks of intramuscular testosterone undecanoate (n = 45) or matching placebo (n = 43). All study subjects were included in the primary analysis. Seven men assigned to testosterone and six men receiving placebo did not complete the study. Main outcome measures were insulin resistance by homeostatic model assessment (HOMA-IR, primary outcome) and glycemic control by HbA1c (secondary outcome). RESULTS Testosterone therapy did not improve insulin resistance (mean adjusted difference [MAD] for HOMA-IR compared with placebo −0.08 [95% CI −0.31 to 0.47; P = 0.23]) or glycemic control (MAD HbA1c 0.36% [0.0–0.7]; P = 0.05), despite a decrease in fat mass (MAD −2.38 kg [−3.10 to −1.66]; P < 0.001) and an increase in lean mass (MAD 2.08 kg [1.52–2.64]; P < 0.001). Testosterone therapy reduced subcutaneous (MAD −320 cm3 [−477 to −163]; P < 0.001) but not visceral abdominal adipose tissue (MAD 140 cm3 [−89 to 369]; P = 0.90). CONCLUSIONS Testosterone therapy does not improve glucose metabolism or visceral adiposity in obese men with moderately controlled T2D and modest reductions in circulating testosterone levels typical for men with T2D.

Multidisciplinary diabetes care with and without bariatric surgery in overweight people: a randomised controlled trial.

BACKGROUND Bariatric surgery improves glycaemia in obese people with type 2 diabetes, but its effects are uncertain in overweight people with this disease. We aimed to identify whether laparoscopic adjustable gastric band surgery can improve glucose control in people with type 2 diabetes who were overweight but not obese. METHODS We did an open-label, parallel-group, randomised controlled trial between Nov 1, 2009, and June 30, 2013, at one centre in Melbourne, Australia. Patients aged 18-65 years with type 2 diabetes and a BMI between 25 and 30 kg/m2 were randomly assigned (1:1), by computer-generated random sequence, to receive either multidisciplinary diabetes care plus laparoscopic adjustable gastric band surgery or multidisciplinary diabetes care alone. The primary outcome was diabetes remission 2 years after randomisation, defined as glucose concentrations of less than 7.0 mmol/L when fasting and less than 11.1 mmol/L 2 h after 75 g oral glucose, at least two days after stopping glucose-lowering drugs. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12609000286246. FINDINGS 51 patients were randomised to the multidisciplinary care plus gastric band group (n=25) or the multidisciplinary care only group (n=26), of whom 23 participants and 25 participants, respectively, completed follow-up to 2 years. 12 (52%) participants in the multidisciplinary care plus gastric band group and two (8%) participants in the multidisciplinary care only group achieved diabetes remission (difference in proportions 0.44, 95% CI 0.17-0.71; p=0.0012). One (4%) participant in the gastric band group needed revisional surgery and four others (17%) had a total of five episodes of food intolerance due to excessive adjustment of the band. INTERPRETATION When added to multidisciplinary care, laparoscopic adjustable gastric band surgery for overweight people with type 2 diabetes improves glycaemic control with an acceptable adverse event profile. Laparoscopic adjustable gastric band surgery is a reasonable treatment option for this population. FUNDING Monash University Centre for Obesity Research and Education and Allergan.

Type 1 diabetes: Lessons for other autoimmune diseases?

Type 1 diabetes (T1D) satisfies many of the criteria for an autoimmune disease. The impact of the environment to promote the development of T1D and the ability to identify individuals at risk for T1D years before clinical presentation afford lessons for other autoimmune diseases, in regard to gene-environment interactions and the potential for rational approaches to pre-clinical diagnosis and prevention. Public health measures aimed at the modern pro-inflammatory environment are required to stem the rising tide not only of T1D but other autoimmune and chronic inflammatory disorders. In the non-obese diabetic (NOD) model of spontaneous autoimmune diabetes, compelling evidence indicates that adaptive autoimmunity to the pancreatic beta cell is initially targeted against proinsulin. Proof-of-principle studies in the NOD mouse, which established that insulin and proinsulin peptides could be applied as tools to induce immune tolerance and protect against diabetes development, await successful translation to at-risk humans. Initial trials of insulin-specific immunotherapy in humans show promise and reveal ways of optimising this approach that are also applicable to other autoimmune diseases.

IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome

Interleukin-18 (IL-18) is activated by Caspase-1 in inflammasome complexes and has anti-obesity effects; however, it is not known which inflammasome regulates this process. We found that mice lacking the NLRP1 inflammasome phenocopy mice lacking IL-18, with spontaneous obesity due to intrinsic lipid accumulation. This is exacerbated when the mice are fed a high-fat diet (HFD) or a high-protein diet, but not when mice are fed a HFD with low energy density (high fiber). Furthermore, mice with an activating mutation in NLRP1, and hence increased IL-18, have decreased adiposity and are resistant to diet-induced metabolic dysfunction. Feeding these mice a HFD further increased plasma IL-18 concentrations and strikingly resulted in loss of adipose tissue mass and fatal cachexia, which could be prevented by genetic deletion of IL-18. Thus, NLRP1 is an innate immune sensor that functions in the context of metabolic stress to produce IL-18, preventing obesity and metabolic syndrome.

Exercise training increases adipose tissue GLUT4 expression in patients with type 2 diabetes.

We investigated the effects of exercise training on adipose tissue and skeletal muscle GLUT4 expression in patients with type 2 diabetes (T2D). Muscle and adipose tissue samples were obtained before and after 4‐weeks of exercise training in seven patients with T2D [47 ± 2 years, body mass index (BMI) 28 ± 2]. Seven control subjects (54 ± 4, BMI 30 ± 2) were recruited for baseline comparison. Adipose tissue GLUT4 protein expression was 43% lower (p < 0.05) in patients with T2D compared with control subjects and exercise training increased (p < 0.05) adipose tissue GLUT4 expression by 36%. Skeletal muscle GLUT4 protein expression was not different between control subjects and patients with T2D. Exercise training increased (p < 0.05) skeletal muscle GLUT4 protein expression by 20%. In conclusion, 4‐weeks of exercise training increased GLUT4 expression in adipose tissue and skeletal muscle of patients with T2D, although the functional benefits of this adaptation appear to be dependent on an optimal β‐cell function.

A randomised controlled trial of high dose vitamin D in recent-onset type 2 diabetes

AIMS Vitamin D insufficiency has been associated with impaired pancreatic beta-cell function. We aimed to determine if high dose oral vitamin D3 (D) improves beta-cell function and glycaemia in type 2 diabetes. METHODS Fifty adults with type 2 diabetes diagnosed less than 12 months, with normal baseline serum 25-OH D (25D), were randomised to 6000 IU D (n=26) or placebo (n=24) daily for 6 months. Beta-cell function was measured by glucagon-stimulated serum C-peptide (delta C-peptide [DCP], nmol/l). Secondary outcome measures were fasting plasma glucose (FPG), post-prandial blood glucose (PPG), HbA1c and insulin resistance (HOMA-IR). RESULTS In the D group, median serum 25D (nmol/l) increased from 59 to 150 (3 months) and 128 (6 months) and median serum 1,25D (pmol/l) from 135 to 200 and 190. After 3 months, change in DCP from baseline in D (+0.04) and placebo (-0.08) was not different (P=0.112). However, change in FPG (mmol/l) was significantly lower in D (-0.40) compared to placebo (+0.1) (P=0.007), as was the change in PPG in D (-0.30) compared to placebo (+0.8) (P=0.005). Change in HbA1c (%) between D (-0.20) and placebo (-0.10) was not different (P=0.459). At 6 months, changes from baseline in DCP, FPG, PPG and HbA1c were not different between groups. CONCLUSION Oral D3 supplementation in type 2 diabetes was associated with transient improvement in glycaemia, but without a measurable change in beta-cell function this effect is unlikely to be biologically significant. High dose D3 therefore appears to offer little or no therapeutic benefit in type 2 diabetes.