Diabetes is a major public issue due to its high prevalence and long-term complications (1). The molecular pathogenesis of diabetes, however, remains largely unknown. The common forms of diabetes are syndromes with heterogeneous etiologies, each of which is influenced by polygenic and multiple environmental factors. Therefore, genetic and pathophysiologic analysis of diabetes remains a major challenge. On the other hand, recent progress in the identification of genetic alterations in monogenic disorders has provided clues for understanding the molecular pathogenesis of the common forms with similar phenotypes. There are several rare monogenic forms of diabetic syndromes, both in humans and in rodent models. In humans, there is a syndrome called maturity-onset diabetes of the young (MODY), which is inherited in an autosomal dominant mode (2). The primary lesions in these diseases are in the pancreatic β cells, resulting in decreased insulin secretion. The causal genes of some types of MODY were recently identified (3).In contrast, most of the monogenic diabetic syndromes in rodent models such as ob, db, agouti, tubby, and fat mice accompany obesity (4). The responsible genes are involved in the regulation of body weight, and their alterations result in increased insulin resistance in peripheral tissues, except in fat mice. Very recently, Yoshioka and colleagues established a monogenic diabetic model, called the Akita mouse (5). This model does not accompany either obesity or insulitis, but is accompanied by a notable pancreatic β-cell dysfunction, which distinguishes this mouse from the other well-characterized animal models. Diabetes in this mouse resembles that of human MODY in terms of early onset, an autosomal dominant mode of inheritance, and primary dysfunction of the β cells. The gene locus is named murine Mody and has been determined to be located on a distal end of Chromosome 7 by linkage analysis (5) and quantitative trait locus analysis (6).In this study, we demonstrate that the Mody mouse has a missense mutation of the insulin 2 gene (Ins2), which lies on a corresponding area of the Mody locus identified by the genetic analysis. This mutation completely cosegregates with the qualitative phenotype of diabetes in the Mody congenic lines, and it is therefore concluded to be responsible for diabetes in this mouse. The Mody mutation codes insulin 2, whose cysteine residue at the seventh amino acid of the A chain is replaced with tyrosine. This cysteine is involved in the formation of one of the Received for publication June 30, 1998, and accepted in revised form November 10, 1998.The mouse autosomal dominant mutation Mody develops hyperglycemia with notable pancreatic β-cell dysfunction. This study demonstrates that one of the alleles of the gene for insulin 2 in Mody mice encodes a protein product that substitutes tyrosine for cysteine at the seventh amino acid of the A chain in its mature form. This mutation disrupts a disulfide bond between the A and B chains and can induce a drastic conformational chan...

The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the secretory vesicles of PVN neurons, and immunoneutralization against endogenous nesfatin-1 suppresses oxytocin release in the PVN, suggesting paracrine/autocrine actions of nesfatin-1. Nesfatin-1-induced anorexia is abolished by an oxytocin receptor antagonist. Moreover, oxytocin terminals are closely associated with and oxytocin activates pro-opiomelanocortin neurons in the NTS. Oxytocin induces melanocortin-dependent anorexia in leptin-resistant Zucker-fatty rats. The present results reveal the nesfatin-1-operative oxytocinergic signaling in the PVN that triggers leptin-independent melanocortin-mediated anorexia.

Aquaporin-5 (AQP5) is a water channel protein and is considered to play an important role in water movement across the plasma membrane. We raised anti-AQP5 antibody and examined the localization of AQP5 protein in rat salivary and lacrimal glands by immunofluorescence microscopy. AQP5 was found in secretory acinar cells of submandibular, parotid, and sublingual glands, where it was restricted to apical membranes including intercellular secretory canaliculi. In the submandibular gland, abundant AQP5 was also found additionally at the apical membrane of intercalated duct cells. Upon stimulation by isoproterenol, apical staining for AQP5 in parotid acinar cells tended to appear as clusters of dots. These results suggest that AQP5 is one of the candidate molecules responsible for the water movement in the salivary glands.

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