2016-11-02T18:49:00

It has been suggested that pancreatic acinar cells can serve as progenitors for pancreatic islets, a concept with substantial implications for therapeutic efforts to increase insulin-producing β cell mass in patients with diabetes. We report what we believe to be the first in vivo lineage tracing approach to determine the plasticity potential of pancreatic acinar cells. We developed an acinar cell-specific inducible Cre recombinase transgenic mouse, which, when mated with a reporter strain and pulsed with tamoxifen, resulted in permanent and specific labeling of acinar cells and their progeny. During various time periods of observation and using several models to provoke injury, we failed to observe any chase of the labeled cells into the endocrine compartment, indicating that acinar cells do not normally transdifferentiate into islet β cells in vivo in adult mice. In contrast, we observed a substantial role for replication of preexisting acinar cells in the regeneration of new acinar cells after partial pancreatectomy. These results indicate that mature acinar cells harbor a facultative acinar but not endocrine progenitor capacity.

Uteroplacental insufficiency resulting in fetal growth retardation is a common complication of pregnancy and a significant cause of perinatal morbidity and mortality. Epidemiological studies show an increased incidence of type 2 diabetes in humans who were growth retarded at birth. The mechanisms by which an abnormal intrauterine milieu leads to the development of diabetes in adulthood are not known. Therefore, a rat model of uteroplacental insufficiency was developed; intrauterine growth-retarded (IUGR) rats develop diabetes with a phenotype similar to that observed in the human with type 2 diabetes. We show here that administration of a pancreatic ␤-cell trophic factor, exendin-4 (Ex-4), during the prediabetic neonatal period dramatically prevents the development of diabetes in this model. This occurs because neonatal Ex-4 prevents the progressive reduction in insulin-producing ␤-cell mass that is observed in IUGR rats over time. Expression of PDX, a critical regulator of pancreas development and islet differentiation, is restored to normal levels, and islet ␤-cell proliferation rates are normalized by the neonatal Ex-4 treatment. These results indicate that exposure to Ex-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of diabetes in adulthood. Diabetes 52: 734 -740, 2003

2016-11-02T18:49:00

Hyperinsulinism is the single most common mechanism of hypoglycemia in neonates. Dysregulated insulin secretion is responsible for the transient and prolonged forms of neonatal hypoglycemia, and congenital genetic disorders of insulin regulation represent the most common of the permanent disorders of hypoglycemia. Mutations in at least five genes have been associated with congenital hyperinsulinism: they encode glucokinase, glutamate dehydrogenase, the mitochondrial enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase, and the two components (sulfonylurea receptor 1 and potassium inward rectifying channel, subfamily J, member 11) of the ATP-sensitive potassium channels (K(ATP) channels). K(ATP) hyperinsulinism is the most common and severe form of congenital hyperinsulinism. Infants suffering from K(ATP) hyperinsulinism present shortly after birth with severe and persistent hypoglycemia, and the majority are unresponsive to medical therapy, thus requiring pancreatectomy. In up to 40-60% of the children with K(ATP) hyperinsulinism, the defect is limited to a focal lesion in the pancreas. In these children, local resection results in cure with avoidance of the complications inherent to a near-total pancreatectomy. Hyperinsulinism can also be part of other disorders such as Beckwith-Wiedemann syndrome and congenital disorders of glycosylation. The diagnosis and management of children with congenital hyperinsulinism requires a multidisciplinary approach to achieve the goal of therapy: prevention of permanent brain damage due to recurrent hypoglycemia.

A reduction in ␤-cell mass is an important causative factor in type 1 and type 2 diabetes. Glucagon-like peptide-1 (GLP-1) and the long-acting agonist exendin 4 (Ex-4) expand ␤-cell mass by stimulating neogenesis and proliferation. In the partial pancreatectomy (Ppx) model, exogenous Ex-4 promotes islet regeneration, leading to sustained improvement in glucose tolerance. In this study, we investigate the potential role of endogenous GLP-1 in islet growth. We examined ␤-cell mass regeneration after 70% Ppx in mice receiving the GLP-1 antagonist Ex9-39 and in GLP-1R ؊/؊ mice. In Ex9-39 -treated sham-operated mice, persistent fasting hyperglycemia was observed, but ␤-cell mass was not diminished. In pancreatectomized mice, persistent glucose intolerance was noted, but this was not further exacerbated by Ex9-39. Accordingly, ␤-cell mass recovery of Ppx mice was not impaired by Ex9-39. In contrast, GLP-1R؊/؊ CD1 mice showed worse glucose intolerance after Ppx compared with wild-type CD1 Ppx mice, and this correlated with a significant defect in ␤-cell mass regeneration. The recovery of ␤-cell mass differed markedly in the BALB/c and CD1 control mice, indicating a significant role of genetic background in the regulation of ␤-cell mass. These studies point to a role for endogenous GLP-1 in ␤-cell regeneration after Ppx in mice.

The calcium-regulated phosphatase calcineurin intersects with both calcium and cAMP-mediated signaling pathways in the pancreatic ␤-cell. Pharmacologic calcineurin inhibition, necessary to prevent rejection in the setting of organ transplantation, is associated with post-transplant ␤-cell failure. We sought to determine the effect of calcineurin inhibition on ␤-cell replication and survival in rodents and in isolated human islets. Further, we assessed whether the GLP-1 receptor agonist and cAMP stimulus, exendin-4 (Ex-4), could rescue ␤-cell replication and survival following calcineurin inhibition. Following treatment with the calcineurin inhibitor tacrolimus, human ␤-cell apoptosis was significantly increased. Although we detected no human ␤-cell replication, tacrolimus significantly decreased rodent ␤-cell replication. Ex-4 nearly normalized both human ␤-cell survival and rodent ␤-cell replication when co-administered with tacrolimus. We found that tacrolimus decreased Akt phosphorylation, suggesting that calcineurin could regulate replication and survival via the PI3K/ Akt pathway. We identify insulin receptor substrate-2 (Irs2), a known cAMP-responsive element-binding protein target and upstream regulator of the PI3K/Akt pathway, as a novel calcineurin target in ␤-cells. Irs2 mRNA and protein are decreased by calcineurin inhibition in both rodent and human islets. The effect of calcineurin on Irs2 expression is mediated at least in part through the nuclear factor of activated T-cells (NFAT), as NFAT occupied the Irs2 promoter in a calcineurinsensitive manner. Ex-4 restored Irs2 expression in tacrolimustreated rodent and human islets nearly to baseline. These findings reveal calcineurin as a regulator of human ␤-cell survival in part through regulation of Irs2, with implications for the pathogenesis and treatment of diabetes following organ transplantation.New onset diabetes mellitus is a major complication following solid organ transplantation, often leading to decreased graft survival and increased mortality (1-3). As with other forms of diabetes, hyperglycemia ensues when there is inadequate pancreatic ␤-cell mass to meet insulin demand (4). Post-transplant diabetes is strongly associated with the use of calcineurin inhibitors, antirejection medications that are widely used in clinical solid organ transplantation (5). This association has prompted long-standing speculation that the calcineurin inhibitors are ␤-cell toxic and pathogenic in transplant-related ␤-cell failure.Calcineurin is a calcium-activated cytosolic phosphatase that is critical for antigen-stimulated T lymphocyte activation (6). Therefore, pharmacologic calcineurin inhibition is highly effective in preventing allograft rejection. However, calcineurin is also expressed in ␤-cells where it has two well described molecular targets, the nuclear factor of activated T cell (NFAT) 2 family of transcription factors (7), and the cAMP-responsive element-binding protein (CREB) transcriptional co-activator, transducer of regulated CREB activity-2 (TO...

The first two cases demonstrate that mutations in HNF1A (MODY3) can cause hyperinsulinism early in life and diabetes later, similar to the phenotype recently reported for HNF4A (MODY1) mutations. Case 3 indicates that the effects of HNF4A mutations in infancy may extend beyond pancreatic β-cells to produce a disorder similar to glucose transporter 2 deficiency involving both liver glycogen metabolism and renal tubular transport.