Although the developing pancreas is exquisitely sensitive to nutrient supply in utero, it is not entirely clear how nutrient-driven posttranslational modification of proteins impacts the pancreas during development. We hypothesized that the nutrient-sensing enzyme O-GlcNAc transferase (Ogt), which catalyzes an O-GlcNAc-modification onto key target proteins, integrates nutrient-signaling networks to regulate cell survival and development. In this study, we investigated the heretofore unknown role of Ogt in exocrine and endocrine islet development. By genetic manipulation in vivo and by using morphometric and molecular analyses, such as immunofluorescence imaging and single cell RNA sequencing, we show the first evidence that Ogt regulates pancreas development. Genetic deletion of Ogt in the pancreatic epithelium (OgtKO Panc) causes pancreatic hypoplasia, in part by increased apoptosis and reduced levels of of Pdx1 protein. Transcriptomic analysis of single cell and bulk RNA sequencing uncovered cell-type heterogeneity and predicted upstream regulator proteins that mediate cell survival, including Pdx1, Ptf1a and p53, which are putative Ogt targets. In conclusion, these findings underscore the requirement of O-GlcNAcylation during pancreas development and show that Ogt is essential for pancreatic progenitor survival, providing a novel mechanistic link between nutrients and pancreas development.

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NMDA receptors (NMDARs) have recently been discovered as functional regulators of pancreatic β-cell insulin secretion. While these excitatory receptor channels have been extensively studied in the brain for their role in synaptic plasticity and development, little is known about how they work in β-cells. In neuronal cells, NMDAR activation requires the simultaneous binding of glutamate and a rate-limiting co-agonist, such as D-serine. D-serine levels and availability in most of the brain rely on endogenous synthesis by the enzyme serine racemase (Srr). Srr transcripts have been reported in human and mouse islets but it is not clear whether Srr is functionally expressed in β-cells or what its role in the pancreas might be. In this investigation, we reveal that Srr protein is highly expressed in primary human and mouse β-cells. Mice with whole body deletion of Srr (Srr KO) show improved glucose tolerance through enhanced insulin secretory capacity, possibly through Srr-mediated alterations in islet NMDAR expression and function. We observed elevated insulin sensitivity in some animals, suggesting Srr metabolic regulation in other peripheral organs as well. Srr expression in neonatal and embryonic islets, and adult deficits in Srr KO pancreas weight and islet insulin content, point toward a potential role for Srr in pancreatic development. These data reveal the first evidence that Srr may regulate glucose homeostasis in peripheral tissues and provide circumstantial evidence that D-serine may be an endogenous islet NMDAR co-agonist in β-cells.

Fetal growth restriction, or low birthweight is a strong determinant for eventual obesity and Type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulate fetal birthweight and the metabolic health trajectory of the offspring. In the current study, we used genetic model with loss of placental mTOR function (mTORKO Placenta ) to test the direct role of mTOR signaling on birthweight and the metabolic health in the adult offspring. mTORKO Placenta animals displayed reduced placental area and total weight, as well as fetal bodyweight at embryonic day (e) 17.5. Birthweight and serum insulin levels were reduced; however, β-cell mass was normal in mTORKO Placenta newborns. Adult mTORKO Placenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared to littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from a diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.

The prevalence of obesity and type 2 (T2D) diabetes is a major health concern in the United States and around the world. T2D is a complex disease characterized by pancreatic β-cell failure in association with obesity and insulin resistance in peripheral tissues. Although several genes associated with T2D have been identified, it is speculated that genetic variants account for only less than 10% of the risk for this disease. A strong body of data from both human epidemiological and animal studies shows that fetal nutrient factors in utero confer significant susceptibility to T2D. Numerous studies done in animals have shown that sub-optimal maternal environment or placental insufficiency causes intrauterine growth restriction (IUGR) in the fetus, a critical factor known to predispose offspring to obesity and T2D, in part by causing permanent consequences in total functional β-cell mass. This mini-review will focus on the contribution of the placenta in fetal programming of obesity and T2D, and its likely impact on pancreatic β-cell development and growth.