The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia.

Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.

Fetal nutrient and growth restriction is associated with development of type 2 diabetes. Although the exact mechanisms responsible for this association remain debated, intrauterine and/or postnatal maldevelopment of β-cell mass has been proposed as a potential mechanism. To address this hypothesis, β-cell mass development and turnover was assessed in rats exposed to either intrauterine and/or postnatal caloric/growth restriction. In total, four groups of male and female Sprague Dawley rats (n = 69) were developed and studied: 1) control rats, i.e. control mothers rearing control pups; 2) intrauterine calorically and growth-restricted rats, i.e. 50% prenatal calorically restricted pups cross-fostered to control mothers; 3) postnatal calorically and growth-restricted rats, i.e. 50% calorically restricted mothers rearing pups born to control mothers; and 4) prenatal and postnatal calorically and growth restricted rats, i.e. 50% calorically restricted mothers rearing intrauterine 50% calorically restricted pups. Intrauterine growth restriction resulted in approximately 45% reduction of postnatal β-cell fractional area and mass characterized by reduced rate of β-cell replication and decreased evidence of neogenesis. In contrast, β-cell fractional area and weight-adjusted β-cell mass in postnatal growth restriction was approximately 30% higher than in control rats. Rats exposed to both intrauterine and postnatal caloric and growth restriction demonstrated approximately 80% decrease in β-cell mass, reduction in β-cell replication, and decreased evidence of neogenesis compared with control. Neither intrauterine nor postnatal caloric restriction significantly affected the rate of β-cell apoptosis. These data support the hypothesis that intrauterine maldevelopment of β-cell mass may predict the increased risk of type 2 diabetes in adult life.

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