Aharon Helman

At birth, blood glucose levels drop sharply before rising to normoglycemic adult levels. This is accompanied by functional maturation of pancreatic β-cells and the acquisition of glucose-responsive insulin secretion. Although transcriptional programs have been well characterized, the metabolic adjustments that enhance insulin secretion in neonatal β-cells remain poorly understood. Neonatal islets exhibit a high rate of basal insulin secretion, and elevating glucose to high concentrations produces little additional stimulation (unlike adult islets). This study aimed to elucidate how neonatal pancreatic β-cells become glucose-responsive, using an in vitro protocol involving culture of neonatal islets at low glucose to emulate systemic hypoglycemia. Low-glucose exposure markedly improved glucose responsiveness of neonatal islets by selectively lowering insulin secretion at low glucose concentrations. Unlike adult β-cells, neonatal β-cells were depolarized and generated spontaneous action potentials at low glucose, resulting in elevated [Ca2+]i and a blunted response to high glucose. These changes were reversed by brief (1-2 hours) low-glucose culture, which was accompanied by increased KATP channel surface expression and activity. The effects of low-glucose incubation were mimicked by the AMPK agonist AICAR. These insights may inform strategies to restore glucose-regulated insulin secretion in type 2 diabetes.

Aims/hypothesis: Maternal diabetes confers two opposing risks to fetal growth, resulting in macrosomia in mild cases and intrauterine growth restriction (IUGR) in severe cases. The mechanisms governing these divergent responses are poorly understood, given the intimate regulation of insulin by glucose and insulin’s fetal growth-promoting effects. We hypothesised that the degree of maternal hyperglycaemia dictates a bimodal pattern of fetal insulin secretion that determines fetal growth, and that use of a ketogenic diet (KD) as a nutritional intervention could modify this outcome. Methods: We used the Insulin-rtTA;TET-DTA mouse model to induce preconception diabetes. Dams were stratified based on maternal blood glucose, namely non-diabetes (glucose 16.7 mmol/l), and maintained on either a normal diet or a KD. We assessed fetal growth and plasma C-peptide, performed islet functional assays ex vivo, and characterised changes in plasma metabolites. Fetal pancreases were analysed by immunohistochemistry for beta cell area, proliferation, maturation and mechanistic target of rapamycin complex 1 (mTORC1) activity. Results: Mild maternal diabetes induced fetal macrosomia, driven by beta cell hyperplasia, hyperinsulinaemia and premature beta cell functional maturation, as reflected by glucose-stimulated insulin secretion and upregulated MafA expression. This was associated with strong activation of the mTORC1 pathway. In contrast, severe diabetes caused IUGR associated with reduced beta cell mass and profound functional impairment. The KD had divergent effects: it normalised fetal growth in the mild diabetes group by preventing beta cell proliferation and premature maturation, thereby reducing insulin secretion, but failed to rescue IUGR in the severe diabetes group, despite partially restoring beta cell function. Notably, the KD uncoupled the positive correlation between fetal insulin and body weight, revealing a primary, insulin-independent, growth-restrictive effect. Conclusions/interpretation: Fetal growth in a mouse model of diabetes in pregnancy is governed by a bimodal beta cell response to the maternal glycaemic environment, orchestrated at the molecular level by the mTORC1 pathway. A KD can prevent diabetes-derived macrosomia by reducing beta cell stimulation and through insulin-independent mechanisms, but cannot reverse IUGR, warranting further studies of its role in diabetes during pregnancy.

Supplementary Table from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination

Supplementary Table from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination

Supplementary Table from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination

Supplementary Table from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination

Supplementary Data from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination

Supplementary Data from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination