Demonstrating cerebellar hypoplasia/aplasia in one of the original cases caused by PTFA1 mutation and described by the author. Taken from Hoveyda et al. [30] .

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... of neonatal diabetes associated with cerebellar hypoplasia [30] . The 3 children of consanguineous, Paki- stani origin had dysmorphic features (low-set ears, triangular facies, talipes equin- ovarus and joint stiffness), associated with neonatal diabetes, microcephaly, recur- rent apnoeic attacks and absent cerebellar tissue on brain imaging ( fig. 1). A further child of North European descent was later identified with an identical phenotype in whom an autopsy demonstrated complete pancreatic agenesis. Further studies on this child and the original family led to the identification of the gene responsible, PTF1A. This gene encodes the pancreas transcription factor 1 which is ...

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... transcription factors, the genes Pdx1 and Ptf1a/p48, regulate the very early steps of pancreas development. The homeobox gene Pdx1/IPF1 is already expressed in the prepancreatic endoderm (E8.5-9) before any evidence of bud formation and persists in proliferating pancreatic epithelial cells at the bud stage ( fig. 1 a, b) and during sub- sequent branching of the epithelium [4,5] . During -cell development Pdx1 is later reexpressed in the mature -cell where it controls the transcription of the insulin gene in the adult pancreas [6] . Knocking out Pdx1 results in pancreas agenesis [5] . Pancreatic buds form but then stop their development and ...

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... Ptf1a-expressing cells and their progeny permanently express the -galactosidase gene and can thus be identified. This experiment revealed that Ptf1a is, like Pdx1, largely expressed at the early bud stage in uncommitted pancreatic progenitors ( fig. 1 c). Accordingly, fate mapping of these Ptf1a-expressing cells demonstrated that Ptf1a-positive cells give rise to endocrine, ductal and acinar cells. ...

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... although expression of dominant negative HNF1 in -cells results in a severe reduc- tion of -cell mass, overexpression of the wild-type version of HNF1 unexpectedly also results in a comparably severe phenotype [50,51] . We have measured the proportion of -cells relative to other pancreatic cells in very young (2-week-old) mice to circumvent possible confounding consequences of prolonged diabetes and metabolic abnormalities, and noted no major differences rel- ative to wild-type mice ( fig. 1 a). However, a clear reduction in the size of pancreatic islets was noted that is compensated by a larger number of extra-insular -cells or small clusters ( fig. 1 b, c). ...

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... have measured the proportion of -cells relative to other pancreatic cells in very young (2-week-old) mice to circumvent possible confounding consequences of prolonged diabetes and metabolic abnormalities, and noted no major differences rel- ative to wild-type mice ( fig. 1 a). However, a clear reduction in the size of pancreatic islets was noted that is compensated by a larger number of extra-insular -cells or small clusters ( fig. 1 b, c). We also measured proliferation rates in embryonic day 18.5 embryos, where blood glucose is normal in all genotypes, and in 3-month-old mice ( fig. 1 d-f). ...

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... a clear reduction in the size of pancreatic islets was noted that is compensated by a larger number of extra-insular -cells or small clusters ( fig. 1 b, c). We also measured proliferation rates in embryonic day 18.5 embryos, where blood glucose is normal in all genotypes, and in 3-month-old mice ( fig. 1 d-f). Although lower than average values were noted in Hnf1 -/--cells, this did not reach statistical significance ( fig. 1 d-f). ...

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... also measured proliferation rates in embryonic day 18.5 embryos, where blood glucose is normal in all genotypes, and in 3-month-old mice ( fig. 1 d-f). Although lower than average values were noted in Hnf1 -/--cells, this did not reach statistical significance ( fig. 1 d-f). ...

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... T antigen oncogene selectively in pancreatic -cells under the control of the rat insulin II promoter (Rip2- TAg) on either Hnf1 +/+ , Hnf1 +/-, or Hnf1 -/-backgrounds. As expected [52,53] , the Rip2-TAg transgene invariably caused insulinomas after 3 months of age on both Hnf1 +/+ and Hnf1 +/-backgrounds, and this led to hypoglycaemia and death ( fig. 1 d, e). However, on an Hnf1 -/-background the development of tumours was exceptional, it was observed only after 9 months, and tumour size at this time was more than 2-fold smaller than in Hnf1 +/+ or Hnf1 +/-littermates at 12 weeks ( fig. 1 d, e). Although sev- eral factors could theoretically account for such reduced tumourgenicity, ...

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... expected [52,53] , the Rip2-TAg transgene invariably caused insulinomas after 3 months of age on both Hnf1 +/+ and Hnf1 +/-backgrounds, and this led to hypoglycaemia and death ( fig. 1 d, e). However, on an Hnf1 -/-background the development of tumours was exceptional, it was observed only after 9 months, and tumour size at this time was more than 2-fold smaller than in Hnf1 +/+ or Hnf1 +/-littermates at 12 weeks ( fig. 1 d, e). Although sev- eral factors could theoretically account for such reduced tumourgenicity, it was found to be in part due to reduced proliferation. ...

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... sev- eral factors could theoretically account for such reduced tumourgenicity, it was found to be in part due to reduced proliferation. Thus, in situ analysis of pancreatic tissues revealed that Ki67 labelling was reduced by 3-fold in T-antigen-expressing -cells from Hnf1 -/-Rip2-TAg versus Hnf1 +/+ Rip2-TAg mice ( fig. 1 f). Furthermore, where- as explanted Hnf1 +/+ Rip2-TAg -cell lines exhibited a robust expansion in culture, dissected Hnf1 -/-Rip2-TAg tumour cells placed in culture showed a complete failure to grow ( fig. 1 g). ...

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... in situ analysis of pancreatic tissues revealed that Ki67 labelling was reduced by 3-fold in T-antigen-expressing -cells from Hnf1 -/-Rip2-TAg versus Hnf1 +/+ Rip2-TAg mice ( fig. 1 f). Furthermore, where- as explanted Hnf1 +/+ Rip2-TAg -cell lines exhibited a robust expansion in culture, dissected Hnf1 -/-Rip2-TAg tumour cells placed in culture showed a complete failure to grow ( fig. 1 g). These results thus show that HNF1 is essential for the proliferative response that is induced by the T antigen oncogene in -cells, and more generally they indicate that HNF1 controls cellular processes required for oncogenesis in -cells. ...

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... order to determine the exact mechanism of FGF10 effect, we next used culture experiments. The pancreases from E13.5 rat embryos were dissected as described previously [12,13,17] and as presented in figure 1 . The pancreases were cultured on filters at the air-liquid interface ( fig. 2 ). ...

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... MRI studies were non-informative concerning the differentiation between focal and diffuse HI but confirmed the localization of the [ 18 F]fluoro-L -DOPA in the pancreas. PET images showed that most of the radioactivity accumulated in the kid- neys and urinary bladder, the main elimination route of the radiotracer ( fig. 1 ). Con- sequently, the high radioactivity in these organs, particularly in the left kidney, might increase the difficulty in identifying focal forms localized in the tail of the pancreas when the PET images alone are interpreted. ...

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... 15 patients, a focal uptake of [ 18 F]fluoro-L -DOPA was observed in the pancre- atic area ( fig. 1 a). In these patients, the area of the suspected pancreatic abnormality, based on imaging diagnosis, was biopsied. ...

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... 39 children, a diffuse accumulation of [ 18 F]fluoro-L -DOPA ( fig. 1 b) was ob- served, and diffuse HI was suspected. Nine children were resistant to the medical treatment and were submitted to surgery. ...

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... heart cells and SUR2B in smooth muscle [6] . Kir6.2 subunit forms the channel pore in the majority of tissues such as pancreatic -cell, brain, heart and skeletal muscle [3] , while Kir6.1 can be found in smooth vas- cular muscle and astrocytes. These different channel forms have different pore prop- erties and adenine nucleotide sensitivity [3] ( fig. 1 ). The KCNJ11 and ABCC8 genes, encoding Kir6.2 and SUR1, are located at 11p15 [7] , close to the large IDDM2 linkage peak. The K ATP channels play multiple physiological roles in the regulation of glucose metabolism: insulin secretion by the pancreatic -cells, glucagon release by the pan- creatic -cells [8] , somatostatin secretion ...

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... The open- ing of K ATP channels exerts a strong suppressive effect on neuronal activity during hypoxia by shifting membrane potentials in the hyperpolarized direction [22] . Mice lacking Kir6.2 are extremely susceptible to generalized seizure after brief hypoxia and K ATP channels might therefore participate in a preconditioning-induced neuronal Fig. 1. Different K ATP channel forms and metabolic regulation. Several isoforms of either Kir and SUR subunits are found in the different organs and confer to the channels their specificity but all inter- fere with the glucose metabolism. The Kir6.2/SUR1 channels are found in neurons and the pancreas, whereas the Kir6.2/SUR2 channels are ...

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... marks then have to survive periods of extensive epigenetic repro- gramming of the genome during pre-implantation and post-implantation develop- ment [38] , as these marks normally accompany the parental alleles throughout the lifetime of the organism. DNA methylation, either directly or acting in concert with histone modifications and other chromosomal proteins [39] , has the capacity to determine gene activity of imprinted genes in a number of ways ( fig. 1 ). The most direct occurs where the DNA methylation mark sits on the promoter of an imprinted gene, leading to silencing of that allele. ...

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... term 'epigenetics' is used to describe this phenomenon whereby gene expression is reversibly silenced/activated independent of change to gene structure. One of the simplest models is where the DMR lies within the promoter of a gene and the methylated copy is silenced ( fig. 1 ). This is the case at the TND locus. ...

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... 6q24 there are two known imprinted genes, ZAC and HYMAI ( fig. 1 ). ZAC codes for a zinc finger protein that localises to the nucleus and is a transcription factor. ...

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... sensors were well tolerated by these small infants with no appar- ent discomfort or problems of infection or oedema at the sensor site. Using this device it was possible to demonstrate that these infants had prolonged periods of hypergly- caemia and periods of undetected hypoglycaemia ( fig. 1 ) Clinical Importance of Hyperglycaemia Recent retrospective studies have shown hyperglycaemia to be a risk factor for short- term mortality [55][56][57] and morbidities such as retinopathy of prematurity in the premature infant [58,59] . Hyperglycaemia as a marker of relative insulin deficiency may also have a significant impact on growth and metabolism in the newborn. ...