The β2-adrenergic receptor in the apical membrane of intestinal enterocytes senses sugars to stimulate glucose uptake from the gut.

The presence of sugar in the gut causes induction of SGLT1, the sodium/glucose cotransporter in intestinal epithelial cells (enterocytes), and this is accompanied by stimulation of sugar absorption. Sugar sensing was suggested to involve a G-protein coupled receptor and cAMP - protein kinase A signalling, but the sugar receptor has remained unknown. We show strong expression and co-localization with SGLT1 of the β2-adrenergic receptor ( -AR) at the enterocyte apical membrane and reveal its role in stimulating glucose uptake from the gut by the sodium/glucose-linked transporter, SGLT1.

Normal Pregnancy-Induced Islet Beta Cell Proliferation in Mouse Models That Are Deficient in Serotonin-Signaling.

During mouse pregnancy placental lactogens stimulate prolactin receptors on pancreatic islet beta cells to induce expression of the tryptophan hydroxylase , resulting in the synthesis and secretion of serotonin. Presently, the functional relevance of this phenomenon is unclear. One hypothesis is that serotonin-induced activation of 5-HT receptors on beta cells stimulates beta cell proliferation during pregnancy.

Discovery and 3D imaging of a novel ΔNp63-expressing basal cell type in human pancreatic ducts with implications in disease.

Objective: The aggressive basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) harbours a ΔNp63 (p40) gene expression signature reminiscent of a basal cell type. Distinct from other epithelia with basal tumours, ΔNp63 basal cells reportedly do not exist in the normal pancreas.

Design: We evaluated ΔNp63 expression in human pancreas, chronic pancreatitis (CP) and PDAC.

Insulitis in the pancreas of non-diabetic organ donors under age 25 years with multiple circulating autoantibodies against islet cell antigens.

Autoantibodies against islet cell antigens are routinely used to identify subjects at increased risk of symptomatic type 1 diabetes, but their relation to the intra-islet pathogenetic process that leads to positivity for these markers is poorly understood. We screened 556 non-diabetic organ donors (3 months to 24 years) for five different autoantibodies and found positivity in 27 subjects, 25 single- and two double autoantibody-positive donors. Histopathological screening of pancreatic tissue samples showed lesion characteristic for recent-onset type 1 diabetes in the two organ donors with a high-risk profile, due to their positivity for multiple autoantibodies and HLA-inferred risk.

Insulitis and lymphoid structures in the islets of Langerhans of a 66-year-old patient with long-standing type 1 diabetes.

Insulitis is a characteristic inflammatory lesion consisting of immune cell infiltrates around and within the pancreatic islets of patients with recent-onset type 1 diabetes (T1D). The infiltration is typically mild, both in terms of the number of infiltrating cells and the number of islets affected. Here, we present an unusual histopathological case study of a 66-year-old female patient with long-standing T1D, insulitis, and islet-associated lymphoid tissue.

Evidence of Tissue Repair in Human Donor Pancreas After Prolonged Duration of Stay in Intensive Care.

M2 macrophages play an important role in tissue repair and regeneration. They have also been found to modulate β-cell replication in mouse models of pancreatic injury and disease. We previously reported that β-cell replication is strongly increased in a subgroup of human organ donors characterized by prolonged duration of stay in an intensive care unit (ICU) and increased number of leukocytes in the pancreatic tissue.

Efficient CRISPR/Cas9-mediated editing of trinucleotide repeat expansion in myotonic dystrophy patient-derived iPS and myogenic cells.

CRISPR/Cas9 is an attractive platform to potentially correct dominant genetic diseases by gene editing with unprecedented precision. In the current proof-of-principle study, we explored the use of CRISPR/Cas9 for gene-editing in myotonic dystrophy type-1 (DM1), an autosomal-dominant muscle disorder, by excising the CTG-repeat expansion in the 3'-untranslated-region (UTR) of the human myotonic dystrophy protein kinase (DMPK) gene in DM1 patient-specific induced pluripotent stem cells (DM1-iPSC), DM1-iPSC-derived myogenic cells and DM1 patient-specific myoblasts. To eliminate the pathogenic gain-of-function mutant DMPK transcript, we designed a dual guide RNA based strategy that excises the CTG-repeat expansion with high efficiency, as confirmed by Southern blot and single molecule real-time (SMRT) sequencing.

How stable is repression of disallowed genes in pancreatic islets in response to metabolic stress?

The specific phenotype of mature differentiated beta cells not only depends on the specific presence of genes that allow beta cell function but also on the selective absence of housekeeping genes ("disallowed genes") that would interfere with this function. Recent studies have shown that both histone modifications and DNA methylation via the de novo methyltransferase DNMT3A are involved in repression of disallowed genes in neonatal beta cells when these cells acquire their mature phenotype. It is unknown, however, if the environmental influence of advanced age, pregnancy and the metabolic stress of high fat diet or diabetes could alter the repression of disallowed genes in beta cells.

Pancreas and gallbladder agenesis in a newborn with semilobar holoprosencephaly, a case report.

Background: Pancreatic agenesis is an extremely rare cause of neonatal diabetes mellitus and has enabled the discovery of several key transcription factors essential for normal pancreas and beta cell development.

Case Presentation: We report a case of a Caucasian female with complete pancreatic agenesis occurring together with semilobar holoprosencephaly (HPE), a more common brain developmental disorder. Clinical findings were later confirmed by autopsy, which also identified agenesis of the gallbladder.

Pancreatic β-Cells Express the Fetal Islet Hormone Gastrin in Rodent and Human Diabetes.

β-Cell failure in type 2 diabetes (T2D) was recently proposed to involve dedifferentiation of β-cells and ectopic expression of other islet hormones, including somatostatin and glucagon. Here we show that gastrin, a stomach hormone typically expressed in the pancreas only during embryogenesis, is expressed in islets of diabetic rodents and humans with T2D. Although gastrin in mice is expressed in insulin cells, gastrin expression in humans with T2D occurs in both insulin and somatostatin cells.

Identification of Donor Origin and Condition of Transplanted Islets In Situ in the Liver of a Type 1 Diabetic Recipient.

Transplantation of islet allografts into type 1 diabetic recipients usually requires multiple pancreas donors to achieve insulin independence. This adds to the challenges of immunological monitoring of islet transplantation currently relying on surrogate immune markers in peripheral blood. We investigated donor origin and infiltration of islets transplanted in the liver of a T1D patient who died of hemorrhagic stroke 4 months after successful transplantation with two intraportal islet grafts combining six donors.

Prolactin receptors and placental lactogen drive male mouse pancreatic islets to pregnancy-related mRNA changes.

Pregnancy requires a higher functional beta cell mass and this is associated with profound changes in the gene expression profile of pancreatic islets. Taking Tph1 as a sensitive marker for pregnancy-related islet mRNA expression in female mice, we previously identified prolactin receptors and placental lactogen as key signalling molecules. Since beta cells from male mice also express prolactin receptors, the question arose whether male and female islets have the same phenotypic resilience at the mRNA level during pregnancy.

Plasma GAD65, a Marker for Early β-Cell Loss After Intraportal Islet Cell Transplantation in Diabetic Patients.

Context And Objective: Intraportal islet transplantation can restore insulin production in type 1 diabetes patients, but its effect is subject to several interfering processes. To assess the influence of β-cell loss before and during engraftment, we searched for a real-time marker of β-cell destruction. Previous studies showed that 65-kDa isoform of glutamate decarboxylase (GAD65) is discharged by chemically damaged rat β-cells.

Detection of EGFR-TK domain-activating mutations in NSCLC with generic PCR-based methods.

Somatic mutations in the epidermal growth factor receptor-tyrosine kinase (EGFR-TK) domain of non-small cell lung cancer (NSCLC) influence the responsiveness of these tumors to EGFR-TK inhibitors, indicating their usefulness as a predictive molecular marker. However, for mutation analysis, the amount of clinical material available from NSCLC patients is often very limited, suboptimally preserved, and composed of both normal and tumor cells. As a consequence, the total amount of recovered DNA is frequently very limited, with mutant alleles being often strongly underrepresented, and thus requiring highly sensitive methods for the detection of mutations.

Rodent versus human insulitis: why the huge disconnect?

Purpose Of Review: The purpose of this article is to summarize recent developments in the histopathology of recent-onset type 1 diabetes.

Recent Findings: Insulitis is considered to be the defining lesion in young type 1 diabetic patients, and insight into its pathogenic mechanism is crucial for the development of effective new therapies. The present overview highlights some recent developments including an international consensus guideline for the diagnosis of insulitis in type 1 diabetic patients, immunophenotyping of the insulitic lesions, evidence for a heterogeneity of the disease process and a discussion on the differences and similarities between insulitis in patients and in rodent models of the disease.

Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression.

The human growth hormone (hGH) minigene is frequently used in the derivation of transgenic mouse lines to enhance transgene expression. Although this minigene is present in the transgenes as a secondcistron, and thus not thought to be expressed, we found that three commonly used lines, Pdx1-Cre(Late), RIP-Cre, and MIP-GFP, each expressed significant amounts of hGH in pancreatic islets. Locally secreted hGH binds to prolactin receptors on β cells, activates STAT5 signaling, and induces pregnancy-like changes in gene expression, thereby augmenting pancreatic β cell mass and insulin content.

Insulitis in human type 1 diabetes: a comparison between patients and animal models.

Human type 1 diabetes (T1D) is considered to be an autoimmune disease, with CD8+ T-cell-mediated cytotoxicity being directed against the insulin-producing beta cells, leading to a gradual decrease in beta cell mass and the development of chronic hyperglycemia. The histopathologically defining lesion in recent-onset T1D patients is insulitis, a relatively subtle leucocytic infiltration present in approximately 10% of the islets of Langerhans from children with recent-onset (<1 year) disease. Due to the transient nature of the infiltrate, its heterogeneous distribution in the pancreas and the nature of the patient population, material for research is extremely rare and limited to a cumulative total of approximately 150 cases collected over the past century.

Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells.

β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53.

Omentum is better site than kidney capsule for growth, differentiation, and vascularization of immature porcine β-cell implants in immunodeficient rats.

Background: Rapid revascularization of islet cell implants is important for engraftment and subsequent survival and function. Development of an adequate vascular network is expected to allow adaptive growth of the β-cell mass. The present study compares omentum and kidney capsule as sites for growth and differentiation of immature β-cell grafts.

Beta cell count instead of beta cell mass to assess and localize growth in beta cell population following pancreatic duct ligation in mice.

Background: Pancreatic-tail duct ligation (PDL) in adult rodents has been reported to induce beta cell generation and increase beta cell mass but increases in beta cell number have not been demonstrated. This study examines whether PDL increases beta cell number and whether this is caused by neogenesis of small clusters and/or their growth to larger aggregates.

Methodology: Total beta cell number and its distribution over small (<50 µm), medium, large (>100 µm) clusters was determined in pancreatic tails of 10-week-old mice, 2 weeks after PDL or sham.

Orthotopic grafting of cryopreserved prepubertal testicular tissue: in search of a simple yet effective cryopreservation protocol.

Objective: To investigate whether solid-surface vitrification (SSV) is an effective cryopreservation strategy regarding the integrity and function of prepubertal mouse testicular tissue.

Design: Prospective experimental study.

Setting: Academic research unit.

Insulitis in human type 1 diabetes: The quest for an elusive lesion.

The histopathology of type 1 diabetes is defined by a decreased β-cell mass in association with insulitis, a characteristic lymphocytic infiltration limited to the islets of Langerhans and prominent in early stage disease in children. A cytotoxic T-cell mediated destruction of insulin-producing β-cells is thought to be initiated by an unknown (auto)antigen, leading to the destruction > 75% of β-cell mass at clinical diagnosis. Although considered to be pathognomonic for recent onset disease, insulitis has only been described in approximately 150 cases over the past century.

Cyclooxygenase-2 network as predictive molecular marker for clinical pregnancy in in vitro fertilization.

The gene expression of human endometrium on the day of oocyte retrieval of pregnant and nonpregnant patients in a stimulated IVF cycle was compared in two independent groups with different GnRH-antagonist ovarian stimulation protocols. The present data suggest that increased gene expression of cyclooxygenase-2, together with the expression of other molecules in the cyclooxygenase-2 network, on the day of oocyte retrieval in GnRH-antagonist cycles coincides with a lower probability of achieving a clinical pregnancy in this cycle.