Distinct cell clusters touching islet cells induce islet cell replication in association with over-expression of Regenerating Gene (REG) protein in fulminant type 1 diabetes.

Background: Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear.

Procedures: The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans.

Result: Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters.

Concurrent overexpression of RET/PTC1 and TTF1 confers tumorigenicity to thyrocytes.

A variant located on 14q13.3 nearest to thyroid transcription factor-1 (TTF1) predisposes individuals to thyroid cancer, but whether this variant is related to the RET/PTC rearrangement associated with human papillary thyroid carcinomas (PTCs) is unknown. The aims of this study were to investigate the effects of RET/PTC1 on the expression of thyroid-specific genes in thyrocytes and their relationship with malignant transformation of the thyrocytes.

Excess TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

Hypothyroidism in the young leads to irreversible growth failure. hyt/hyt Mice have a nonfunctional TSH receptor (TSHR) and are severely hypothyroid, but growth retardation was not observed in adult mice. We found that epiphysial cartilage as well as cultured chondrocytes expressed functional TSHR at levels comparable to that seen in the thyroid, and that addition of TSH to cultured chondrocytes suppressed expression of chondrocyte differentiation marker genes such as Sox-9 and type IIa collagen.

Ligand-bound thyroid hormone receptor contributes to reprogramming of pancreatic acinar cells into insulin-producing cells.

One goal of diabetic regenerative medicine is to instructively convert mature pancreatic exocrine cells into insulin-producing cells. We recently reported that ligand-bound thyroid hormone receptor α (TRα) plays a critical role in expansion of the β-cell mass during postnatal development. Here, we used an adenovirus vector that expresses TRα driven by the amylase 2 promoter (AdAmy2TRα) to induce the reprogramming of pancreatic acinar cells into insulin-producing cells.

Immunization of mice with a newly identified thyroid-stimulating hormone receptor splice variant induces Graves'-like disease.

We have cloned a thyroid-stimulating hormone receptor (TSHR) cDNA from mouse thyroid glands. The sequence of this cDNA indicated that it encoded a 739 amino acid TSHR splice variant that lacked exon 5 (TSHR739). In thyroid gland samples from adult mice, the amount of TSHR739 mRNA was about 10% of the amount of full-length TSHR (TSHR764) mRNA.

Dominant negative effect of mutated thyroid stimulating hormone receptor (P556L) causes hypothyroidism in C.RF-Tshr(hyt/wild) mice.

C.RF-Tshr(hyt/hyt) mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.

Expression of functional TSH receptor in white adipose tissues of hyt/hyt mice induces lipolysis in vivo.

To determine the relative importance of TSH in white adipose tissue, we compared the adipose phenotypes of two distinct mouse models of hypothyroidism. These models differed in that the normal reciprocal relationship between thyroid hormone and TSH was intact in one and disrupted in the other. One model, thyroidectomized (THYx) mice, had a 100-fold increase in TSH and a normal TSH receptor (TSHR); in contrast, the other model, hyt/hyt mice, had a 120-fold elevation of TSH but a nonfunctional TSHR.

Thyroid-specific gene expression in chondrocytes.

Previously, we demonstrated that Runx2 (Cbfa1/AML3), a chondrocyte-specific transcription factor, is expressed in thyroid glands of mice, where it stimulates expression of the thyroglobulin (Tg) gene. Here, we reverse transcribed thyroid transcription factor-1 (TTF-1), Pax-8, Tg, thyroid peroxidase (TPO) and Na(+)/I(-) symporter (NIS) cDNAs from mouse trachea and bronchus RNA samples, but were unable to recover these cDNAs from mouse liver RNA samples. Tg mRNA levels in trachea and bronchus were about 5.

RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates beta-cell death in fulminant type 1 diabetes.

Objective: The contribution of innate immunity responsible for aggressive β-cell destruction in human fulminant type 1 diabetes is unclear.

Research Design And Methods: Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes.

Results: RIG-I was strongly expressed in β-cells in all three pancreata infected with enterovirus.

Liganded thyroid hormone receptor-alpha enhances proliferation of pancreatic beta-cells.

Failure of the functional pancreatic beta-cell mass to expand in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing beta-cells is important for beta-cell proliferation in adult animals. In rat pancreatic beta-cell lines (RIN5F), treatment with 100 nM thyroid hormone (triiodothyronine, T(3)) enhances cell proliferation.

Runx2 deficiency in mice causes decreased thyroglobulin expression and hypothyroidism.

We recently reported on the overexpression of Runx2 (Cbfa1/AML3), an osteoblast-specific transcription factor, in human papillary thyroid cancer tissues. We report here that normal thyrocytes also express Runx2 and that Runx2(+/-) mice are in a hypothyroid state. To clarify the mechanism, we studied the effects of small interfering RNA-mediated silencing of Runx2 on thyroid-specific gene expression in FRTL-5 cells.

Diabetes associated with autoimmune pancreatitis: new insights into the mechanism of β-cell dysfunction.

A high proportion of patients with autoimmune pancreatitis (AIP) have diabetes. The decreased β-cell function in active AIP, which leads to diabetes, can sometimes be reversed by corticosteroid treatment. However, the immunological mechanisms causing this β-cell dysfunction are largely unclear.

Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes.

Objective: Fulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated beta-cell failure are unclear.

Research Design And Methods: Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2-5 days after onset of fulminant type 1 diabetes.

HSP 10 is a new autoantigen in both autoimmune pancreatitis and fulminant type 1 diabetes.

To search autoantigens in autoimmune pancreatitis (AIP), we have screened the human pancreas cDNA library with a patient's serum and obtained 10 positive clones. Seven out of 10 clones were amylase alpha-2A, the autoantibody to which was specifically detected in sera from patients with AIP and fulminant type 1 diabetes (FT1DM) [T. Endo, S.

Immunization with thyroglobulin induces Graves'-like disease in mice.

We immunized AKR/N mice with bovine thyroglobulin (Tg) once every 2 weeks and monitored their time-dependent changes in (125)I uptake activity in the thyroid glands. After 3 months, anti-Tg antibody was positive in all sera from the immunized mice. Serum free tri-iodothyronine (T(3)) and free thyroxine (T(4)) levels in the immunized mice (n=6) were significantly higher than those in the saline injected (control) mice (n=6).

Amylase alpha-2A autoantibodies: novel marker of autoimmune pancreatitis and fulminant type 1 diabetes.

Objective: The pathogenesis of autoimmune pancreatitis (AIP) and fulminant type 1 diabetes remains unclear, although it is known that immune-mediated processes severely compromise the endocrine and exocrine functions in both diseases.

Research Design And Methods: We have screened a lambdaTriplEx2 human pancreas cDNA library with serum from a patient with AIP and obtained positive clones. Sequence analysis revealed that 7 of 10 clones were identical to human amylase alpha-2A.

Distinct autoantibodies against exocrine pancreatic antigens in European patients with type 1 diabetes mellitus and non-alcoholic chronic pancreatitis.

Context: Histopathological analysis has demonstrated lymphocytic infiltration in both the endocrine and the exocrine pancreas in some patients with type 1 diabetes and non-alcoholic chronic pancreatitis, suggesting an immune-mediated mechanism which affects both diabetes mellitus and chronic pancreatitis.

Objective: The examination of exocrine pancreatic humoral markers in Caucasian patients with respect to the interactions between exocrine and endocrine pancreatic diseases.

Patients: One hundred and thirty-six European Caucasian subjects subdivided into three groups: type 1 diabetes (n=48); non-alcoholic chronic pancreatitis (n=48); controls (n=40).

Thyroid-stimulating hormone receptor in brown adipose tissue is involved in the regulation of thermogenesis.

C.RF- Tshr(hyt/hyt) mice have a mutated thyroid-stimulating hormone receptor (TSHR), and, without thyroid hormone supplementation, these mice develop severe hypothyroidism. When hypothyroid Tshr(hyt/hyt) mice were exposed to cold (4 degrees C), rectal temperature rapidly dropped to 23.

Expression and function of Cbfa-1/Runx2 in thyroid papillary carcinoma cells.

Context: Development of calcifying foci is a common finding in human thyroid papillary carcinoma, but its mechanisms remain unknown.

Objective: We therefore investigated whether osteocalcin and/or Cbfa-1 genes are expressed in malignant thyroid epithelial cells. We also studied the effects of Cbfa-1 on the expression of osteoblast-specific and thyrotropin receptor genes in thyrocytes.

New insulin sensitivity index from the oral glucose tolerance test.

A new insulin sensitivity index was devised on the basis of an autoregressive model and its validity was investigated. Using data from the 75-g oral glucose tolerance test (OGTT), 115 subjects were divided into 3 groups: 40 with normal glucose tolerance, 34 with impaired glucose tolerance, and 41 with type 2 diabetes mellitus. The new insulin sensitivity index: oral glucose insulin sensitivity index (GSI) was calculated from five sets of plasma glucose and insulin levels obtained at 0, 30, 60, 90 and 120 min during OGTT using a formula based on an autoregressive model.

Involvement of cAMP response element-binding protein in the regulation of cell proliferation and the prolactin promoter of lactotrophs in primary culture.

Hypothalamic hormones, including dopamine, regulate critical functions of pituitary cells via the cAMP-protein kinase A (PKA) pathway. The PKA-downstream transcription factor cAMP response element (CRE)-binding protein (CREB) is an integrating molecule that is also activated by many other protein kinase pathways. We investigated the involvement of CREB in the regulation of cell proliferation and the PRL promoter of rat lactotrophs in primary cell culture.

[Thyrotropin receptor--structure, autoantibody and signal transduction].

Thyrotropin receptor (TSHR) belongs to type A G protein-coupled receptor family, which possesses a large entracellular domain (ED). Recent studies have revealed the importance of leucine rich repeats domain in the ED and the formation of oligomer in its TSH binding and its signal transduction. TSHR binds to Gs and Gq.