ABSTRACT
Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.
Subject(s)
Bile Acids and Salts/metabolism , Epichlorohydrin/pharmacology , Gene Expression/drug effects , Glucagon-Like Peptide 1/drug effects , Imidazoles/pharmacology , Intestines/drug effects , Proprotein Convertase 1/drug effects , RNA, Messenger/drug effects , Receptors, G-Protein-Coupled/drug effects , Resins, Synthetic/pharmacology , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Blotting, Western , Diet, High-Fat , Fluorescent Antibody Technique , Glucagon-Like Peptide 1/metabolism , Insulin/metabolism , Intestinal Mucosa/metabolism , Male , Mice , Proprotein Convertase 1/genetics , RNA, Messenger/genetics , Receptors, G-Protein-Coupled/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Weight Gain/drug effectsABSTRACT
A numerical and functional deficit of natural killer T (NKT) cells has been reported to be associated with the pathogenesis of Caucasian patients with type 1 diabetes. However, a conflicting finding of a higher frequency of NKT cells (Valpha24+ Vbeta11+ T cells) was observed in islet-associated Ab+ and Ab- Japanese "classic" type 1 diabetes. Here, we combined the data of NKT cell frequency in Ab+ and Ab- "classic" type 1 diabetic patients and then analyzed the relationship between NKT cell frequency and disease activity.
Subject(s)
Diabetes Mellitus, Type 1/immunology , Killer Cells, Natural/immunology , Adolescent , Female , Glycated Hemoglobin/analysis , Humans , Japan , Male , Middle AgedABSTRACT
Recently, a novel subtype of type 1 diabetes, so-called fulminant type 1 diabetes, has been proposed. One of the characteristics of this subtype is the absence of detectable "islet-associated" autoantibody, so it was originally proposed as being "nonautoimmune-mediated"; however, it has not yet been concluded whether autoimmunity is involved. We have previously shown that serum interferon-inducible protein-10 and glutamic acid decarboxylase-reactive CD4(+) interferon-gamma-producing cells in the peripheral blood are good markers for T cell-mediated autoimmunity in type 1 diabetes. Here, we report two cases of fulminant type 1 diabetes in which these markers were detected and in which the involvement of islet-associated autoimmunity is suggested.
Subject(s)
Autoimmunity , Diabetes Mellitus, Type 1/immunology , Adult , Autoantibodies/blood , Chemokine CXCL10/blood , Diabetes Mellitus, Type 1/physiopathology , Glutamate Decarboxylase/immunology , Humans , Isoenzymes/immunology , Male , Middle Aged , T-Lymphocytes/immunologyABSTRACT
OBJECTIVE: Natural killer T-cells (NKT cells) are believed to play an important role in the regulation of immune response, and a numerical and functional deficit of NKT cells has been reported to be associated with the pathogenesis of autoimmune diseases. Thus far, it has been shown that subjects with type 1 diabetes have a lower frequency of NKT cells than nondiabetic subjects. In this study, we measured the frequency of peripheral Valpha24(+) Vbeta11(+) T-cells, which include human NKT cells, in Japanese diabetic patients. RESEARCH DESIGN AND METHODS: Peripheral blood samples were obtained from 164 Japanese diabetic patients and 67 healthy subjects. The diabetic patients were classified into four categories as follows: islet-associated autoantibody-positive (Ab(+)) and -negative (Ab(-)) classic type 1 diabetes, latent autoimmune diabetes in adults (LADA), and type 2 diabetes. We measured the frequency of peripheral Valpha24(+) Vbeta11(+) CD3(+) triple-positive cells. RESULTS: Unexpectedly, a higher frequency of Valpha24(+) Vbeta11(+) T-cells was observed in Ab(+) and Ab(-) patients compared with LADA patients (P = 0.0294 and P = 0.0021), type 2 diabetic patients (P < 0.0001 and P < 0.0001), and healthy subjects (P = 0.0046 and P = 0.0001). Moreover, an inverse correlation between Valpha24(+) Vbeta11(+) T-cell frequency and disease duration was observed in Ab(+) (rho = -0.455; P = 0.0023) and Ab(-) (rho = -0.432; P = 0.0162) patients. CONCLUSIONS: Our findings indicate that a high frequency of Valpha24(+) Vbeta11(+) T-cells is a unique finding in recent-onset classic type 1 diabetes, and measurement of Valpha24(+) Vbeta11(+) T-cell frequency may be useful to assess the disease activity of classic type 1 diabetes.
