Aims/hypothesis The aim of this study was to investigate the evidence of an increased risk of childhood-onset type 1 diabetes in children born by Caesarean section by systematically reviewing the published literature and performing a meta-analysis with adjustment for recognised confounders. Methods After MEDLINE, Web of Science and EMBASE searches, crude ORs and 95% CIs for type 1 diabetes in children born by Caesarean section were calculated from the data reported in each study. Authors were contacted to Diabetologia (2008) 51:726-735

Aims/hypothesis Increasing evidence suggests that environ-

channel blocker isradipine evoked a paradoxical stimulation of glucagon secretion. This effect was not observed in the presence of SR95531, and we therefore conclude that isradipine stimulates glucagon secretion by inhibition of GABA release. Diabetes 53

We have monitored electrical activity, voltage-gated Ca2+ currents, and exocytosis in single rat glucagon-secreting pancreatic A-cells. The A-cells were electrically excitable and generated spontaneous Na+- and Ca2+-dependent action potentials. Under basal conditions, exocytosis was tightly linked to Ca2+ influx through ω-conotoxin-GVIA–sensitive (N-type) Ca2+ channels. Stimulation of the A-cells with adrenaline (via β-adrenergic receptors) or forskolin produced a greater than fourfold PKA-dependent potentiation of depolarization-evoked exocytosis. This enhancement of exocytosis was due to a 50% enhancement of Ca2+ influx through L-type Ca2+ channels, an effect that accounted for <30% of the total stimulatory action. The remaining 70% of the stimulation was attributable to an acceleration of granule mobilization resulting in a fivefold increase in the number of readily releasable granules near the L-type Ca2+ channels.

It is important for our understanding of the pancreatic islets to study whether new islets are able to form in the intact pancreas. We developed a new method to determine the total number and the mean volume of the pancreatic islets, and we used this method to study the expansion of the islet mass in ob/ob mice (n ‫؍‬ 8), using ob/؉ mice (n ‫؍‬ 8) as controls. The total islet volume was increased by a factor of 3.6 in ob/ob mice compared with ob/؉ mice, whereas, importantly, the total number of islets did not differ among ob/ob mice and ob/؉ mice (3,193 ؎ 160 islets in ob/ob mice vs. 3,184 ؎ 142 islets in ob/؉ mice, P ‫؍‬ 0.97). The coefficient of variation in the volume distribution of islets was equal in the two groups, showing that in ob/ob mice, the existing islets expand their volume by the same proportion, without a net formation of new islets. We suggest that the pancreatic islets should be considered as anatomically such complex structures that islet neogenesis does not spontaneously occur in an intact pancreas. Cells within the existing islets are presumably the most important sources for islet cell hyperplasia during expansion of the total islet mass. Diabetes 52:1716 -1722, 2003 Afundamental and yet unanswered question in the understanding of the pathogenesis of type 2 diabetes is the limitation in the formation of enough additional ␤-cells to maintain normoglycemia during an increased demand for insulin; even individuals with significant insulin resistance do not develop diabetes if they have an appropriate number of functioning ␤-cells, emphasizing the pathophysiological importance of the total ␤-cell mass.The ob/ob mouse has been extensively studied as a model of type 2 diabetes (1). These mice are obese and develop insulin resistance and diabetes because of an inherited inability to produce leptin (2), despite a marked expansion of the total mass of the pancreatic islets. It has been stated in the literature that both islet hyperplasia and islet hypertrophia are responsible for the increase in the total islet mass in ob/ob mice (3,4), but among the few studies that actually addressed this question by applying methods that, in theory, could measure the total number of islets (5,6), the results are in fact diverging. Previously, we found a linear correlation between the total islet volume and the volume-weighted mean volume in rats (7), a result that suggested-but, because of the nature of the method, could not prove-that the expansion of the islet mass during physiological growth in rats is caused by the growth of existing islets without the formation of new islets. We therefore developed a method relying on recent stereological methods to determine the total number and mean volume of the pancreatic islets, and we used this method to investigate the expansion of the islet mass in ob/ob mice. An understanding of whether new islets are able to form in the intact pancreas is important for understanding the islets as an anatomical structure, and, in addition, it could be important for understanding whi...

In isolated rat pancreatic alpha-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated glucagon release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P<0.05; n=5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker omega-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced glucagon release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon release increased monotonically with increasing K+ concentrations. omega-Conotoxin suppressed glucagon release to 15 mM K+, whereas a combination of omega-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mM K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response evoked by membrane depolarization 3-fold. This correlated with a doubling of glucagon secretion by glucose in intact rat islets exposed to diazoxide and high K+. In whole-cell experiments, exocytosis was stimulated by reducing the cytoplasmic ADP concentration, whereas changes of the ATP concentration in the physiological range had little effect. We conclude that glucose stimulates glucagon release from isolated rat alpha-cells by KATP-channel closure and stimulation of Ca2+ influx through N-type Ca2+ channels. Glucose also stimulated exocytosis by an amplifying mechanism, probably involving changes in adenine nucleotides. The stimulatory action of glucose in isolated alpha-cells contrasts with the suppressive effect of the sugar in intact islets and highlights the primary importance of islet paracrine signaling in the regulation of glucagon release.

Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.

Background Epidemiological as well as animal studies have shown that environmental factors such as nutrition contribute to the development of diabetes. In this study we investigated whether the early introduction of a gluten‐free diet can influence the onset and/or incidence of diabetes, as well as insulitis and the number of gut mucosal lymphocytes, in non‐obese diabetic (NOD) mice. Methods Gluten‐free and standard Altromin diets (with the same milk protein and vitamin content) were given to breeding pairs of NOD mice as well as to the first generation of NOD female mice, which were then observed for 320 days. Results A substantially lower diabetes incidence (χ2=15.8, p=0.00007) was observed in NOD mice on the gluten‐free diet (15%, n=27) compared to mice on the standard diet (64%, n=28). In addition, mice on the gluten‐free diet developed diabetes significantly later (244±24 days SEM) compared to those on the standard diet (197±8 days, p=0.03). No differences in the number of CD3+, TCR‐γδ+, IgA+, and IgM+ cells in the small intestine were observed. Conclusion We showed that gluten‐free diet both delayed and to a large extent prevented diabetes in NOD mice that have never been exposed to gluten. Copyright © 1999 John Wiley & Sons, Ltd.