Carol Huang

Tissue-specific roles of IRS proteins in insulin signaling and glucose transport

In type 2-diabetes and impaired glucose tolerance, the muscle, fat and liver become resistant to insulin, and recent developments place dysregulation of insulin receptor substrate (IRS) expression and activation at the center of such defects. IRS1 and IRS2 are the major insulin receptor substrates leading to glucose homeostasis, and have distinct and overlapping roles in diverse organs. The majority of the published literature in this field suggests that IRS1 is the major substrate leading to stimulation of glucose transport in muscle and adipose tissues, whereas in liver, IRS1 and IRS2 have complementary roles in insulin signaling and metabolism.

Cellular location of insulin-triggered signals and implications for glucose uptake

Insulin stimulation of glucose uptake into muscle and fat cells requires movement of GLUT4-containing vesicles from intracellular compartments to the plasma membrane. Accordingly, insulin-derived signals must arrive at and be recognized by the appropriate intracellular GLUT4 pools. We describe the insulin signals participating in GLUT4 translocation, and review evidence that they are recruited to intracellular membranes in conjunction with cytoskeletal elements. Such segregation may facilitate the encounter between signals and target vesicles. In most animal and cellular models of insulin resistance, insulin-stimulated GLUT4 translocation to the plasma membrane is reduced. Insulin resistance caused by oxidative stress does not affect early insulin signals, rather their intracellular localization is altered. In this and several other insulin-resistant states, insulin-induced actin remodelling is concomitantly diminished. We summarize evidence suggesting that spatial localization of signals is critical for efficient insulin action, and that the cytoskeleton may act as a scaffold to promote efficient translocation of GLUT4 to the cell surface.

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

Development of strategies capable of specifically curbing pathogenic autoimmune responses in a disease- and organ-specific manner without impairing foreign or tumor antigen-specific immune responses represents a long sought-after goal in autoimmune disease research. Unfortunately, our current understanding of the intricate details of the different autoimmune diseases that affect mankind, including type 1 diabetes, is rudimentary. As a result, progress in the development of the so-called antigen-specific therapies for autoimmunity has been slow and fraught with limitations that interfere with bench-to-bedside translation. Absent or incomplete understanding of mechanisms of action and lack of adequate immunological biomarkers, for example, preclude the rational design of effective drug development programs. Here, we provide an overview of antigen-specific approaches that have been tested in preclinical models of T1D and, in some cases, human subjects. The evidence suggests that effective translation of these approaches through clinical trials and into patients will continue to meet with failure unless detailed mechanisms of action at the level of the organism are defined.

Proneural bHLH Genes in Development and Disease

Proneural genes encode evolutionarily conserved basic-helix-loop-helix transcription factors. In Drosophila, proneural genes are required and sufficient to confer a neural identity onto naïve ectodermal cells, inducing delamination and subsequent neuronal differentiation. In vertebrates, proneural genes are expressed in cells that already have a neural identity, but they are still required and sufficient to initiate neurogenesis. In all organisms, proneural genes control neurogenesis by regulating Notch-mediated lateral inhibition and initiating the expression of downstream differentiation genes. The general mode of proneural gene function has thus been elucidated. However, the regulatory mechanisms that spatially and temporally control proneural gene function are only beginning to be deciphered. Understanding how proneural gene function is regulated is essential, as aberrant proneural gene expression has recently been linked to a variety of human diseases-ranging from cancer to neuropsychiatric illnesses and diabetes. Recent insights into proneural gene function in development and disease are highlighted herein.

Contribution of a Non-β-Cell Source to β-Cell Mass during Pregnancy

β-cell mass in the pancreas increases significantly during pregnancy as an adaptation to maternal insulin resistance. Lineage tracing studies in rodents have presented conflicting evidence on the role of cell duplication in the formation of new β-cells during gestation, while recent human data suggest that new islets are a major contributor to increased β-cell mass in pregnancy. Here, we aim to: 1) determine whether a non-β-cell source contributes to the appearance of new β-cells during pregnancy and 2) investigate whether recapitulation of the embryonic developmental pathway involving high expression of neurogenin 3 (Ngn3) plays a role in the up-regulation of β-cell mass during pregnancy. Using a mouse β-cell lineage-tracing model, which labels insulin-producing β-cells with red fluorescent protein (RFP), we found that the percentage of labeled β-cells dropped from 97% prior to pregnancy to 87% at mid-pregnancy. This suggests contribution of a non-β-cell source to the increase in total β-cell numbers during pregnancy. In addition, we observed a population of hormone-negative, Ngn3-positive cells in islets of both non-pregnant and pregnant mice, and this population dropped from 12% of all islets cells in the non-pregnant mice to 5% by day 8 of pregnancy. Concomitantly, a decrease in expression of Ngn3 and changes in its upstream regulatory network (Sox9 and Hes-1) as well as downstream targets (NeuroD, Nkx2.2, Rfx6 and IA1) were also observed during pregnancy. Our results show that duplication of pre-existing β-cells is not the sole source of new β-cells during pregnancy and that Ngn3 may be involved in this process.

Effect of prebiotic intake on gut microbiota, intestinal permeability and glycemic control in children with type 1 diabetes: study protocol for a randomized controlled trial

BackgroundThe gut microbiome is increasingly recognized as a contributor to disease states. Patients with type 1 diabetes (DM1) have distinct gut microbiota in comparison to non-diabetic individuals, and it has been linked to changes in intestinal permeability, inflammation and insulin resistance. Prebiotics are non-digestible carbohydrates that alter gut microbiota and could potentially improve glycemic control in children with DM1. This pilot study aims to determine the feasibility of a 12-week dietary intervention with prebiotics in children with DM1.Methods/designThis pilot study is a single-centre, randomized, double-blind, placebo-controlled trial in children aged 8 to 17xa0years with DM1 for at least one year. Participants will be randomized to receive either placebo (maltodextrin 3.3xa0g orally/day) or prebiotics (oligofructose-enriched inulin 8xa0g orally/day; Synergy1, Beneo, Mannheim, Germany). Measures to be assessed at baseline, 3xa0months and 6xa0months include: anthropometric measures, insulin doses/regimens, frequency of diabetic ketoacidosis, frequency of severe hypoglycemia, average number of episodes of hypoglycemia per week, serum C-peptide, HbA1c, serum inflammatory markers (IL-6, IFN-gamma, TNF-alpha, and IL-10), GLP-1 and GLP-2, intestinal permeability using urine assessment after ingestion of lactulose, mannitol and 3-O-methylglucose, and stool sample collection for gut microbiota profiling.DiscussionThis is a novel pilot study designed to test feasibility for a fully powered study. We hypothesize that consumption of prebiotics will alter gut microbiota and intestinal permeability, leading to improved glycemic control. Prebiotics are a potentially novel, inexpensive, low-risk treatment addition for DM1 that may improve glycemic control by changes in gut microbiota, gut permeability and inflammation.Trial registrationClinicalTrials.gov: NCT02442544. Registered on 10 March 2015.

Oligofructose as an adjunct in treatment of diabetes in NOD mice

In type 1 diabetes, restoration of normoglycemia can be achieved if the autoimmune attack on beta cells ceases and insulin requirement is met by the residual beta cells. We hypothesize that an adjunctive therapy that reduces insulin demand by increasing insulin sensitivity will improve the efficacy of an immunotherapy in reversing diabetes. We tested the gut microbiota-modulating prebiotic, oligofructose (OFS), as the adjunctive therapy. We treated non-obese diabetic mice with an immunotherapy, monoclonal anti-CD3 antibody (aCD3), with or without concurrent dietary supplement of OFS. After 8 weeks of OFS supplement, the group that received both aCD3 and OFS (aCD3u2009+u2009OFS) had a higher diabetes remission rate than the group that received aCD3 alone. The aCD3u2009+u2009OFS group had higher insulin sensitivity accompanied by reduced lymphocytic infiltrate into the pancreatic islets, higher beta-cell proliferation rate, higher pancreatic insulin content, and secreted more insulin in response to glucose. The addition of OFS also caused a change in gut microbiota, with a higher level of Bifidobacterium and lower Clostridium leptum. Hence, our results suggest that OFS can potentially be an effective therapeutic adjunct in the treatment of type 1 diabetes by improving insulin sensitivity and beta-cell function, leading to improved glycemic control.

Corrigendum: Oligofructose as an adjunct in treatment of diabetes in NOD mice

Scientific Reports 6: Article number: 37627; published online: 22 November 2016; updated: 05 April 2017 This Article contains an error in the labelling of Figure 4D, where the panel labels ‘αCD3’ and ‘αCD3u2009+u2009OFS’ are inverted. The correct Figure 4 appears below as Figure 1.