Pancreas deficiency modifies bone development in the ovine fetus near term.

Hormones have an important role in the regulation of fetal growth and development, especially in response to nutrient availability in utero. Using micro-CT and an electromagnetic three-point bend test, this study examined the effect of pancreas removal at 0.8 fraction of gestation on the developing bone structure and mechanical strength in fetal sheep. When fetuses were studied at 10 and 25 days after surgery, pancreatectomy caused hypoinsulinaemia, hyperglycaemia and growth retardation which was associated with low plasma concentrations of leptin and a marker of osteoclast activity and collagen degradation. In pancreatectomized fetuses compared to control fetuses, limb lengths were shorter, and trabecular (Tb) bone in the metatarsi showed greater bone volume fraction, Tb thickness, degree of anisotropy and porosity, and lower fractional bone surface area and Tb spacing. Mechanical strength testing showed that pancreas deficiency was associated with increased stiffness and a greater maximal weight load at fracture in a subset of fetuses studied near term. Overall, pancreas deficiency in utero slowed the growth of the fetal skeleton and adapted the developing bone to generate a more compact and connected structure. Maintenance of bone strength in growth-retarded limbs is especially important in a precocial species in preparation for skeletal loading and locomotion at birth.

Annular Pancreas in Adults: Case Report and Literature Review.

Annular pancreas is an uncommon congenital cause of gastric outlet obstruction. The incidence is usually referenced at between five and 15 per 100,000 based on autopsy series. When present, this rare condition surfaces with symptoms in the pediatric population during the first few months of life. An adult presenting with symptoms of gastric outlet obstruction due to annular pancreas is an unusual incident. This case describes gastric outlet obstruction due to a partial annular pancreatic band in an otherwise healthy 32-year-old male. Given the scarcity of this pathological process in adults; no specific guidelines exist about the management of this condition. Continued reporting of this pathology is essential for development of such guidelines. Literature review, embryology and treatment options will be discussed.

Gene expression profiling of a mouse model of pancreatic islet dysmorphogenesis.

BACKGROUND: In the past decade, several transcription factors critical for pancreas organogenesis have been identified. Despite this success, many of the factors necessary for proper islet morphogenesis and function remain uncharacterized. Previous studies have shown that transgenic over-expression of the transcription factor Hnf6 specifically in the pancreatic endocrine cell lineage resulted in disruptions in islet morphogenesis, including dysfunctional endocrine cell sorting, increased individual islet size, increased number of peripheral endocrine cell types, and failure of islets to migrate away from the ductal epithelium. The mechanisms whereby maintained Hnf6 causes defects in islet morphogenesis have yet to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: We exploited the dysmorphic islets in Hnf6 transgenic animals as a tool to identify factors important for islet morphogenesis. Genome-wide microarray analysis was used to identify differences in the gene expression profiles of late gestation and early postnatal total pancreas tissue from wild type and Hnf6 transgenic animals. Here we report the identification of genes with an altered expression in Hnf6 transgenic animals and highlight factors with potential importance in islet morphogenesis. Importantly, gene products involved in cell adhesion, cell migration, ECM remodeling and proliferation were found to be altered in Hnf6 transgenic pancreata, revealing specific candidates that can now be analyzed directly for their role in these processes during islet development. CONCLUSIONS/SIGNIFICANCE: This study provides a unique dataset that can act as a starting point for other investigators to explore the role of the identified genes in pancreatogenesis, islet morphogenesis and mature beta cell function.

Intrauterine programming of the endocrine pancreas.

Epidemiological studies have revealed strong relationships between poor foetal growth and subsequent development of the metabolic syndrome. Persisting effects of early malnutrition become translated into pathology, thereby determine chronic risk for developing glucose intolerance and diabetes. These epidemiological observations identify the phenomena of foetal programming without explaining the underlying mechanisms that establish the causal link. Animal models have been established and studies have demonstrated that reduction in the availability of nutrients during foetal development programs the endocrine pancreas and insulin-sensitive tissues. Whatever the type of foetal malnutrition, whether there are not enough calories or protein in food or after placental deficiency, malnourished pups are born with a defect in their beta-cell population that will never completely recover, and insulin-sensitive tissues will be definitively altered. Despite the similar endpoint, different cellular and physiological mechanisms are proposed. Hormones operative during foetal life like insulin itself, insulin-like growth factors and glucocorticoids, as well as specific molecules like taurine, or islet vascularization were implicated as possible factors amplifying the defect. The molecular mechanisms responsible for intrauterine programming of the beta cells are still elusive, but two hypotheses recently emerged: the first one implies programming of mitochondria and the second, epigenetic regulation.

Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development.

AIM: The transcription factor hepatocyte nuclear factor-1beta (HNF-1beta) is expressed in rodent pancreatic progenitor cells, where it is an important member of the genetic hierarchy that regulates the generation of pancreatic endocrine and exocrine cells. The recent description of an HNF-1beta mutation in a patient with neonatal diabetes suggests that HNF-1beta may also play a key role in human pancreatic B-cell development. We aimed to investigate the role of HNF-1beta mutations in neonatal diabetes and also the impact of HNF-1beta mutations on fetal growth. METHODS: We sequenced the HNF-1beta gene in 27 patients with neonatal diabetes in whom other known genetic aetiologies had been excluded. Birth weight was investigated in 21 patients with HNF-1beta mutations. RESULTS: A heterozygous HNF-1beta mutation, S148L, was identified in one patient with neonatal diabetes diagnosed at 17 days, which rapidly resolved only to relapse at 8 years. This patient had pancreatic atrophy, mild exocrine insufficiency and low birth weight (1.83 kg at 40 weeks' gestation). Intrauterine growth was markedly reduced in patients born to unaffected mothers with a median birth weight of 2.4 kg (range 1.8-3.3) (P = 0.006), median centile weight 3 (0.008-38), and 69% were small for gestational age. CONCLUSION: HNF-1beta mutations are a rare cause of neonatal diabetes as well as pancreatic exocrine and endocrine dysfunction. Low birth weight is a common feature of patients with HNF-1beta mutations and is consistent with reduced insulin secretion in utero. These findings support a key role for HNF-1beta in early pancreatic progenitor cells in man.

[Human "pancreatic" bladder. Two case reports]. / Vésicule "pancréatique" chez l'homme. A propos de deux observations.

The aim of this study is to report two similar cases with an "accessory biliary duct" confluent to the main pancreatic duct. There was pancreatic juice inside the "gallbladder". There was no connection between "accessory biliary duct" and intra or extrahepatic biliary ducts. This anomalous junction of the "cystic duct" and the main pancreatic duct may be explained by embryology. These two cases could be the first human "pancreatic" bladders reported.

Detection of embryologic ventral pancreatic parenchyma with endoscopic ultrasound.

BACKGROUND: The prevalence of detecting the embryologic ventral pancreas (ventral anlage) with endoscopic ultrasound (EUS) is unknown. PURPOSE: To determine the frequency of, and factors associated with, EUS findings consistent with the ventral anlage. METHODS: One hundred patients undergoing upper gastrointestinal EUS for any indication were prospectively evaluated for the presence of a focal, hypoechoic area in the pancreatic head using a radial scanning echoendoscope. Multiple clinical and EUS variables were tested against the ability to detect the ventral anlage. RESULTS: The overall detection rate of the ventral anlage was 59%. The ventral anlage was detected in 75% of patients undergoing EUS for nonpancreatic indications, compared to 40% of patients undergoing EUS to evaluate suspected pancreatic disease (p< 0.001). EUS detected the ventral anlage in 72% of patients with a normal EUS-appearing pancreatic head, compared to 29% of patients who had abnormal pancreatic head parenchyma (mass or chronic pancreatitis) on EUS (p < 0.001). Multivariate analysis revealed the only variable associated with detecting the ventral anlage was abnormal pancreatic head parenchyma on EUS. CONCLUSION: The ventral anlage is frequently detected during pancreatic EUS, with a significantly lower rate of detection in patients with EUS findings of a pancreatic head mass or diffuse chronic pancreatitis.

Nesidioblastosis and endocrine hyperplasia of the pancreas: a secondary phenomenon.

Diffuse endocrine cell proliferation (nesidioblastosis) and islet cell hyperplasia are considered causes of organic hyperinsulinism but have not been distinguished (by histometric or immunohistologic methods) from the normally variable pancreatic islet cell population during development and in adults. Therefore, in this study morphologic, immunohistologic (to detect insulin, glucagon, somatostatin, and pancreatic polypeptide), and morphometric features were evaluated in 1) normal pancreases (from fetal to adult; n = 49); 2) pancreases from patients with nesidioblastosis (n = 5); and 3) tumor-associated pancreases (TAP) from patients with insulin-producing islet cell tumors (n = 8). The study of normal postnatal development revealed that all features of fetal development remain present after birth and that the diagnosis of any diffuse endocrine disorder should therefore be based essentially on quantitative histometric parameters (total endocrine area, islet size distribution, distribution of each endocrine cell type). With these parameters endocrine cell hyperplasia was demonstrated in TAP from adults due to increased numbers of A and D cells. However, in the cases previously diagnosed as pathologic nesidioblastosis, all parameters were within the normal range. Thus, nesidioblastosis does not appear to be a pathologic entity. Careful re-examination of the pancreases, prompted by these data, revealed small islet cell tumors in three of these five cases. It is concluded that the endocrine pancreas can react rapidly, both morphologically and functionally, to changes in hormonal feedback, e.g., islet cell tumors. Therefore, the observation of a diffuse islet cell disorder in a patient with hyperinsulinism should not be considered an indication that an islet cell tumor is not present.

[The sectorisation of pancreatic pathology (author's transl)]. / Sectorisation de la pathologie du pancréas.

The existence of dilatation of the Wirsung duct distal to an isthmic calculus, the marked dilatation of the cephalic portion of the duct contrasting with the sub-normal calibre of the corporeo-caudal duct in a case of pancreatic lithiasis, are all against the pathogenic hypothesis of a retrodilatation proximal to an obstruction, a supposition which is apparently satisfactory but not always confirmed by the facts. Thus duct distension would not seem to be a purely mechanical phenomenon. The confusing topography of sectorial dilatation of the Wirsung duct in chronic pancreatitis may be explained by a process affecting in isolation or predominantly one or another embryonic sector. The paradox of the association of cephalic dilatation of the duct with stenosis of the intrapancreatic common bile duct offers further support for this hypothesis.