By Max Bingham, PhD

One of the biggest challenges faced by researchers interested in T cells and their autoimmune potential is that autoimmune T cells are very rare within blood and therefore incredibly hard to isolate from humans and animals. This makes routine study of T-cell responses in autoimmune diseases, including type 1 diabetes, difficult to follow with any confidence. And so, a biomaterial, described by Thelin et al. (p. 2220), that can trap and enrich circulating T cells to enable their isolation and further investigation is likely to attract attention from researchers involved in immune-tolerance–promoting drugs for type 1 diabetes and from those involved in many other autoimmune diseases. The method Thelin et al. describe involves subcutaneous implantation of biomaterial scaffolds loaded with specific antigens designed to attract and trap disease-specific T cells. The temporarily implanted device can then be extracted to isolate the enriched population of T cells. Using a series of experiments with various types of mice, the authors initially describe the effect of implanting the device laced with ovalbumin and the enrichment of ovalbumin-specific CD8+ and CD4+ T cells. To then demonstrate the utility of the scaffolds in a disease-specific manner, they report that scaffolds containing lysates from the NIT-1 pancreatic β-cell line implanted in NOD mice became enriched with β-cell–specific T cells. When these cells were implanted in other mice, the recipient mice developed diabetes, which the authors say indicates the pathogenicity of the scaffold-recruited cells. Subsequent sequencing of T-cell receptors in both the scaffolds and pancreas tissue suggested significant overlaps in sequences, which they say is further evidence that the scaffolds enrich disease-specific T cells. Commenting more widely on the study, author Omar A. Ali told Diabetes: “The ability to enrich and trap autoreactive T cells within a controlled environment may allow us to identify the antigenic determinants of type 1 diabetes and perhaps other autoimmune diseases. This platform may be utilized to identify targets or as a readout for drugs that may raise tolerance to the disease.”

Thelin et al. In vivo enrichment of diabetogenic T cells. Diabetes 2017;66:2220–2229

β-Cell lysate scaffolds recruit multiple hematopoietic lineages. Hematoxylin-eosin staining of sections of β-cell and control scaffolds at day 14 postimplantation in NOD mice. Scale bar = 1 mm.

β-Cell lysate scaffolds recruit multiple hematopoietic lineages. Hematoxylin-eosin staining of sections of β-cell and control scaffolds at day 14 postimplantation in NOD mice. Scale bar = 1 mm.

Acyl-CoA thioesterase (ACOT1) likely plays a central role in regulating hepatic fatty acid oxidation, oxidative stress, and inflammation during fasting, according to Franklin et al. (p. 2112)—a finding that might help explain the progression of nonalcoholic fatty liver disease and its close association with insulin resistance and metabolic syndrome. On the basis of mice and cell experiments, the authors initially report that fasting induced a marked increase in ACOT1 expression. After knocking down the gene Acot1 in the liver, they found reduced liver triglycerides, reportedly via enhanced triglyceride hydrolysis and subsequent fatty acid oxidation. They say that although fewer liver triglycerides are usually considered beneficial, the increased fatty acid oxidation led to oxidative stress and inflammation in the liver. The knockdown also reduced the expression of PPARα target genes, whereas overexpression led to increased PPARα activity. As PPARα activity and fatty acid oxidation typically parallel one another, the authors say that a major finding of the study is that ACOT1 appears to uncouple fatty acid oxidation from PPARα signaling. In further studies they report that a synthetic PPARα ligand could rescue all of the adverse outcomes of the knockdown and that ACOT1 translocates to the nucleus during fasting, suggesting that it may produce a local pool of fatty acids that serve as ligands for PPARα. They also report the effects of the knockdown in mice fed a high-fat diet, showing that it increased fatty acid oxidation and exacerbated inflammation leading to fibrosis, a key step in the development of nonalcoholic fatty liver disease. Author Douglas G. Mashek said: “ACOT1 appears to be an important protein that acts to slow fatty acid flow to the mitochondria and simultaneously increases PPARα, resulting in reduced oxidative stress and inflammation. It’s essentially acting like a switch that controls fatty acid flux and signaling. Moving forward, it will be interesting to further characterize the role of ACOT1 in numerous metabolic diseases in which altered lipid metabolism leads mitochondrial dysfunction.”

Franklin et al. Acyl-CoA thioesterase 1 (ACOT1) regulates PPARα to couple fatty acid flux with oxidative capacity during fasting. Diabetes 2017;66:2112–2123

Proposed mechanism of ACOT1 in fasting lipid metabolism in the liver. ACOT1 expression during fasting mitigates fatty acid (FA) flux toward oxidation in the cytosol. Under fasting and with elevated cAMP/PKA stimulation, nuclear ACOT1 is important in the activation of PPARα. Acsl, long-chain acyl-CoA synthetase; LD, lipid droplet.

Proposed mechanism of ACOT1 in fasting lipid metabolism in the liver. ACOT1 expression during fasting mitigates fatty acid (FA) flux toward oxidation in the cytosol. Under fasting and with elevated cAMP/PKA stimulation, nuclear ACOT1 is important in the activation of PPARα. Acsl, long-chain acyl-CoA synthetase; LD, lipid droplet.

The mechanisms underlying the release of glucagon-like peptide 1 (GLP-1) have been widely studied in animal and cellular models but much less so in humans. As a result, some lingering doubts still exist over how the intestine releases the glucoregulatory hormone in humans. Against this background, Sun et al. (p. 2144) detail a study into the mechanisms underlying the secretion of GLP-1 in humans and combine clinical studies with ex vivo secretion analyses from human intestinal tissues. The clinical arm focused on eight human volunteers who underwent endoscopic (duodenal) infusion of glucose, followed by duodenal biopsy collection. Ex vivo studies then used a series of agonists and antagonists to uncover the glucose-sensing pathway in duodenum, ileum, and colon tissues. According to the authors, the outcomes largely fit with the knowledge derived from previous “seminal” studies in rodents, but key differences emerged. Approximately half of all duodenal L cells were activated by glucose infusion, which potently triggered GLP-1 release. Ex vivo studies then showed that the Na+ glucose cotransporter sodium–glucose cotransporter 1 was likely to be central to the L-cell glucose response, but in certain circumstances, there were differences from what was uncovered in prior animal- and cell-based studies on this hormone. One difference was the finding that GLP-1 release was effectively triggered only at intestinal glucose concentrations compatible with meal-related glucose and that responses are not seen in the colon, contrary to prior findings in mice. Authors Damien J. Keating and Richard L. Young commented: “We know surprisingly little about the basic mechanisms controlling gut hormone release, so we are very pleased that our unique access to human intestinal tissues has provided the outcomes in this study. It builds on influential rodent studies by key groups at Cambridge and Copenhagen. While many of our findings reflect their findings, some key differences emerged, highlighting the value of such studies in human tissue.”

Sun et al. Mechanisms controlling glucose-induced GLP-1 secretion in human small intestine. Diabetes 2017;66:2144–2149

Functional activation of duodenal cells after intraduodenal glucose infusion in healthy subjects. A and D: GLP-1–immunopositive cells in the duodenal mucosa. B and E: pCaMKII-immunopositive cells in the duodenum after 30 min of intraduodenal glucose infusion, highlighted by blue arrows. Composite images of a pCaMKII-immunopositive L cell (C) and separate pCaMKII and L cells (F). Scale bar = 20 µm.

Functional activation of duodenal cells after intraduodenal glucose infusion in healthy subjects. A and D: GLP-1–immunopositive cells in the duodenal mucosa. B and E: pCaMKII-immunopositive cells in the duodenum after 30 min of intraduodenal glucose infusion, highlighted by blue arrows. Composite images of a pCaMKII-immunopositive L cell (C) and separate pCaMKII and L cells (F). Scale bar = 20 µm.

A common missense variant in the gene that encodes a subunit of the sulfonylurea receptor (p.A1369S in ABCC8) is associated with a reduced risk of type 2 diabetes and an increased BMI, mimicking the effects of pharmacological sulfonylurea therapy. But, according to Emdin et al. (p. 2310), the variant also associates with a reduced risk of coronary heart disease, which they suggest might mean long-term sulfonylurea therapy for the treatment of type 2 diabetes may provide coronary heart disease protection. Using data from ∼120,000 individuals in UK Biobank and ∼190,000 individuals from genome-wide association studies, they report that the risk of coronary heart disease was significantly reduced among carriers of this variant. Although the variant associated with an increase in BMI (consistent with the weight gain observed with pharmacological sulfonylurea therapy), it also associated with improved abdominal fat distribution. Although they discuss a number of limitations of the study, the authors say that the approach used does have a history in correctly predicting risk outcomes of various therapies, giving the example of statin therapy where it was predicted that it would lower LDL cholesterol and cardiovascular risk while increasing risk of type 2 diabetes—an effect that subsequently came to pass in large clinical trials. Author Amit V. Khera said: “Genetic studies allow for the study of lifelong consequences of a given perturbation in a drug target. This can prove useful for drugs in which randomized trials were never conducted or to help anticipate clinical efficacy for preclinical compounds. Here, we find that individuals with a genetic exposure that mimics sulfonylurea therapy are protected from both type 2 diabetes and cardiovascular disease. Moving forward, large biobanks that link genotype and phenotype are likely to inform ongoing drug development efforts for chronic disease.”

Emdin et al. Genetic variation at the sulfonylurea receptor, type 2 diabetes, and coronary heart disease. Diabetes 2017;66:2310–2315

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