Pathohistological changes were investigated in the pancreas of a recently inbred 'non-obese diabetic (NOD) mouse' which becomes diabetic due to severe insulitis which resembles that in human juvenile onset or Type I diabetes. In 4 and 5 week old mice, pancreatic islets are infiltrated by lymphocytes. This lymphocytic insulitis selectively and progressively destroy the B cells of islets. The diabetic symptoms appear when most of the B cells have been lost. The circulation route and the nature of the infiltrating lymphocytes as well as the cytological changes in the B and other islet cells were studied by light and electron microscopy. Immunohistochemistry for insulin, glucagon, somatostatin and pancreatic polypeptide (PP) added information on the process leading to the disappearance of insulin and the attitude of the islet cells containing other hormones.

The endocrine cells and nerves in the islet and the gut of the arctic lamprey Lampetra japonica were examined immunocytochemically by using antisera against brain-gut peptides and amine. The cellular composition of the islets as reported by previous researchers in European species of the lamprey was confirmed in the present study. The islet consisted exclusively of insulin immunoreactive cells in the larvae (ammocoetes), whereas in the adult somatostatin immunoreactive cells were added to the insulin immunoreactive cells; the gut epithelium in the adult was now devoid of somatostatin cells. In the gut of the lamprey, the endocrine cells--which were flask-shaped with a cytoplasmic process extended to the lumen--were classified into three types in the larvae, but were represented by a single type in the adult. In the larval lamprey, the first type was immunoreactive for somatostatin, the second one for gastrin/cholecystokinin (CCK) and the third cell type was immunoreactive for glucagon, pancreatic polypeptide and FMRFamide, simultaneously. In the gut of the adult lamprey, the single type of endocrine cell reacted simultaneously to C-terminal specific anti-glucagon serum, N-terminal specific anti-glucagon serum, anti-bovine PP serum, anti-neuropeptide Y serum and anti-FMRFamide serum. These cells occurred most frequently in the upper intestine, their distribution decreasing from the middle to the lower intestine. Two types of peptide containing nerves were identified in the islet and the gut of the larval and adult lamprey. The first type of neurons (perikarya and fibers) was immunoreactive for serotonin and calcitonin gene-related peptide (CGRP), and was located in the mucous and muscular layer of the intestine and in the islet. The second type of neurons contained both serotonin- and gastrin releasing peptide (GRP)-like immunoreactivities and was scattered exclusively in the muscular layer of the gut. In larval and adult lampreys, a few serotonin/CGRP immunoreactive nerve cell bodies and beaded fibers were found in the connective tissue around the islet cell cords. These nerve fibers were sometimes closely apposed to the blood capillaries and to the islet cells. These findings indicate that a neuroendocrine correlation comparable with that in mammals may have been established in the islet of this most primitive vertebrate.

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All-trans retinoic acid and bone morphogenetic protein 2 (BMP2) synergistically induced an alkaline phosphatase (ALP) activity, one of the osteoblastic differentiation markers, and promoted the extracellular matrix calcification in a myoblastic C2C12 cell culture system. The induced ALP mRNA was not suppressed in the presence of a protein synthesis inhibitor, suggesting that the de novo protein synthesis does not influence this induction. There are three isotypes for the retinoic acid receptor (RARα, RARβ, RARγ). Both the ALP activity and the extracellular matrix calcification were inhibited by the addition of the specific siRNA for RARγ, but not by that for RARα or RARβ. When the effects of the RAR subtype-specific agonists on the ALP activity in the presence of BMP2 were examined, the RARγ-specific agonist was the most effective. The ALP activity induced by any RAR subtype-specific agonist was inhibited by the addition of the specific siRNA for RARγ, but not by that for RARα or RARβ. These results suggest that a RARγ-dependent functional crosstalk is present between the retinoic acid and BMP2 signaling to induce osteogenic transdifferentiation in myoblastic C2C12 cells.

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