All major cell types in pancreatic islets express the transforming growth factor (TGF)-␤ superfamily receptor ALK7, but the physiological function of this receptor has been unknown. Mutant mice lacking ALK7 showed normal pancreas organogenesis but developed an age-dependent syndrome involving progressive hyperinsulinemia, reduced insulin sensitivity, liver steatosis, impaired glucose tolerance, and islet enlargement. Hyperinsulinemia preceded the development of any other defect, indicating that this may be one primary consequence of the lack of ALK7. In agreement with this, mutant islets showed enhanced insulin secretion under sustained glucose stimulation, indicating that ALK7 negatively regulates glucose-stimulated insulin release in ␤-cells. Glucose increased expression of ALK7 and its ligand activin B in islets, but decreased that of activin A, which does not signal through ALK7. The two activins had opposite effects on Ca 2؉ signaling in islet cells, with activin A increasing, but activin B decreasing, glucosestimulated Ca 2؉ influx. On its own, activin B had no effect on WT cells, but stimulated Ca 2؉ influx in cells lacking ALK7. In accordance with this, mutant mice lacking activin B showed hyperinsulinemia comparable with that of Alk7 ؊/؊ mice, but double mutants showed no additive effects, suggesting that ALK7 and activin B function in a common pathway to regulate insulin secretion. These findings uncover an unexpected antagonism between activins A and B in the control of Ca 2؉ signaling in ␤-cells. We propose that ALK7 plays an important role in regulating the functional plasticity of pancreatic islets, negatively affecting ␤-cell function by mediating the effects of activin B on Ca 2؉ signaling.T he signaling networks controlling metabolic processes are highly regulated and integrate the actions of both positively and negatively acting components from many different signaling pathways. Members of the transforming growth factor (TGF)-␤ superfamily, including TGF-␤s, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs) and activins, have been implicated in the regulation of several metabolic processes. These ligands signal via distinct complexes of type I and type II receptor serine-threonine kinases, each binding to different classes of TGF-␤ ligands (1, 2). The main and most widely studied signaling pathway downstream of these receptors involves activation and nuclear translocation of Smad proteins, which in turn regulate gene transcription through multiple interactions with distinct sets of transcription factors in a cell type-specific manner (1, 2). Although less well understood, Smad-independent pathways have also been described in a variety of cell systems and involve the activation of MAP kinases, small GTPases, and Ca 2ϩ mobilization (3).Identification of cell-intrinsic factors controlling the specification and function of pancreatic endocrine cells is of major importance for understanding the regulation of blood-glucose homeostasis. The characterization of signals regul...

Serum levels of apolipoprotein CIII (apoCIII) are increased in type 1 diabetic patients, and when β cells are exposed to these diabetic sera, apoptosis occurs, an effect abolished by an antibody against apoCIII. We have investigated the BB rat, an animal model that develops a human-like type 1 diabetes, and found that apoCIII was also increased in sera from prediabetic rats. This increase in apoCIII promoted β-cell death. The endogenous levels of apoCIII were reduced by treating prediabetic animals with an antisense against this apolipoprotein, resulting in a significantly delayed onset of diabetes. ApoCIII thus serves as a diabetogenic factor, and intervention with this apolipoprotein in the prediabetic state can arrest disease progression. These findings suggest apoCIII as a target for the treatment of type 1 diabetes.W e have previously shown that there is a group of patients with type 1 diabetes (T1D) whose sera induce an increased activity of voltage-gated Ca 2+ channels in pancreatic β cells, resulting in increased cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) and apoptosis (1). T1D serum was found to contain increased concentrations of apolipoprotein CIII (apoCIII), and we could later demonstrate that this serum factor was responsible for the [Ca 2+ ] i increase and β-cell death in vitro (2). Consequently, the effects of both T1D serum and apoCIII on [Ca 2+ ] i and β-cell death are abolished when β cells are coincubated with an antibody against apoCIII (2).To clarify the extent to which apoCIII is also involved in β-cell death in vivo, we have used the animal model diabetes-prone BB rat (DPBB), which spontaneously, at around the age of 60 d, develops T1D that resembles the human form of the disease (3, 4). Diabetes-resistant BB rats (DRBB) were developed from selective breeding from diabetes-prone (DP) forebears and were used as controls (5).This model gives an opportunity to study the impact of prediabetic interventions to prevent or delay onset of the disease. In this study, three prediabetic age groups (40, 50, and 60 d) were investigated both in vitro and in vivo, and we could demonstrate that lowering the endogenous levels of apoCIII by antisense treatment markedly delayed onset of diabetes. ResultsMorphological and Immunohistochemical Characterization. Qualitative morphological analysis showed that pancreas taken from prediabetic rats at the age of 40 d had a lower number of insulincontaining cells than the age-matched controls. The shape of the islets was round to oval with an intact thin layer of collagen around the islets. No inflammation was seen (Fig. 1A). At the age of 50 d, the number of insulin-containing cells did not differ compared with islets from control rats. Islet shape and border did not differ from control rats. No inflammation was seen (Fig. 1B). At 60 d of age, there was a clear decrease in the number of insulin-positive cells. The shape of the islet was irregular, and in some islets, exocrine cells were found. There was no distinct border between the islets and the surroun...

Transthyretin (TTR) is a functional protein in the pancreatic β-cell. It promotes insulin release and protects against β-cell death. We now demonstrate by ligand blotting, adsorption to specific magnetic beads, and surface plasmon resonance that TTR binds to glucose-regulated proteins (Grps)78, 94, and 170, which are members of the endoplasmic reticulum chaperone family, but Grps78 and 94 have also been found at the plasma membrane. The effect of TTR on changes in cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) was abolished if the cells were treated with either dynasore, a specific inhibitor of dynamin GTPase that blocks clathrin-mediated endocytosis, or an antibody against Grp78, that prevents TTR from binding to Grp78. The conclusion is that TTR binds to Grp78 at the plasma membrane, is internalized into the β-cell via a clathrin-dependent pathway, and that this internalization is necessary for the effects of TTR on β-cell function.

The effects of LV in two different species, CD-1 mice, without a genetic disposition for diabetes, and BB rats prone to T1D were examined. Male CD-1 mice that had been exposed to LV in utero developed a type 2-like diabetes with increased blood glucose, insulin levels and epididymal fat at the age of 10-15 weeks. Combination therapy including LV-antiserum and an antiviral drug, Pleconaril, significantly reduced the levels of blood glucose and insulin and the amount of abdominal fat. In BB rats, LV has been found in both prediabetic-and diabetic diabetes-prone rats, as well as in diabetes-resistant rats. To evaluate whether the presence of LV has any influence on the onset of T1D, prediabetic BB rats were treated with an antiserum against LV or a combination of the antiviral drugs Pleconaril and Ribavirin. In the group treated with antiviral drugs, the onset was significantly delayed. These results indicate that the presence of LV can be involved in the pathogenesis of diabetes in these animal models.