Kim SK, Rulifson E J. Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells. Nature

Department of Developmental Biology, Stanford University School of Medicine, Beckman Center B300, Stanford, California 94305-5329, USA.
Nature (Impact Factor: 41.46). 10/2004; 431(7006):316-20. DOI: 10.1038/nature02897
Source: PubMed


Antagonistic activities of glucagon and insulin control metabolism in mammals, and disruption of this balance underlies diabetes pathogenesis. Insulin-producing cells (IPCs) in the brain of insects such as Drosophila also regulate serum glucose, but it remains unclear whether insulin is the sole hormonal regulator of glucose homeostasis and whether mechanisms of glucose-sensing and response in IPCs resemble those in pancreatic islets. Here we show, by targeted cell ablation, that Drosophila corpora cardiaca (CC) cells of the ring gland are also essential for larval glucose homeostasis. Unlike IPCs, CC cells express Drosophila cognates of sulphonylurea receptor (Sur) and potassium channel (Ir), proteins that comprise ATP-sensitive potassium channels regulating hormone secretion by islets and other mammalian glucose-sensing cells. They also produce adipokinetic hormone, a polypeptide with glucagon-like functions. Glucose regulation by CC cells is impaired by exposure to sulphonylureas, drugs that target the Sur subunit. Furthermore, ubiquitous expression of an akh transgene reverses the effect of CC ablation on serum glucose. Thus, Drosophila CC cells are crucial regulators of glucose homeostasis and they use glucose-sensing and response mechanisms similar to islet cells.

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    • "Here we used Drosophila to identify a hormonal regulator of insulin output, glucose, and lipid metabolism without an identified antecedent mammalian ortholog—emphasizing the possibility for work on flies to presage endocrine hormone discovery in mammals . Gain of Lst function in our studies led to reduced insulin signaling, and hyperglycemia, consistent with prior work by our group and others (Broughton et al., 2005;Kim and Rulifson, 2004). By contrast, loss of Lst function led to excessive insulin production and secretion, hypoglycemia, and elevated triglycerides , phenotypes consistent with the recognized anabolic functions of insulin signaling in metazoans, and with the few prior metabolic studies of flies with insulin excess (Erion et al., 2012;Rajan and Perrimon, 2012). "
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    ABSTRACT: Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Cell Metabolism
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    • "The ion channel involved in the action of Phote-HrTH on the crop muscle contractions is probably the potassium channel. The K ATP channel has also been shown to govern the release of AKH in the CC, thus regulating concentrations of circulating glucose in the hemolymph of D. melanogaster (Kim and Rulifson, 2004). It has been shown, but not published that tetraethylammonium, a known potassium channel blocker, applied to the in vitro crop bioassay of P. regina and, several other known channel blockers significantly reduced crop lobe (P5) contractions (Stoffolano et al., 2013). "
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    ABSTRACT: Phote-HrTH (Phormia terraenovae hypertrehalosemic hormone) has been demonstrated in the Diptera to be involved in flight metabolism, reproduction, and diapause. Each of these events needs the hormone’s action and requirement for carbohydrates is the common denominator. In Diptera, carbohydrates are taken up during feeding by action of the cibarial pump and are then stored in the crop. Using adult Phormia regina, both a bioassay and electrophysiological recordings show that Phote-HrTH slows down or inhibits the crop lobe muscles (P5) and, at the same time, stimulates the muscles of the pump 4 (P4) involved in pushing fluids out of the crop and up into the midgut for digestion. The EC50 for P4 was in the nanomolar range while the IC50 for P5 was 1.4-75.1 pM. The effect of Phote-HrTH on P4/5 suggests that the peptide is important in coordinating the two pumps, which are involved in moving carbohydrates up into the midgut for digestion. The adult crop organ is an essential storage organ for carbohydrates and now should be considered an important structure capable of delivering nutrients to the midgut for digestion.
    Full-text · Article · Oct 2014 · Journal of Insect Physiology
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    • "In Drosophila, sugar homeostasis is often associated with the AKH and insulin signaling, whereas insulin signaling is also modulated by proteins and amino acids in the diet (Brogiolo et al., 2001; Buch et al., 2008; Kim and Rulifson, 2004; Lee and Park, 2004; Rulifson et al., 2002). Recently, Bai and colleagues have showed that Daw expression is modulated by insulin signaling and identified Daw as a target of dFOXO (Bai et al., 2013), raising the possibility that glucose repression may be similarly affected by insulin signaling. "
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    ABSTRACT: Organisms need to assess their nutritional state and adapt their digestive capacity to the demands for various nutrients. Modulation of digestive enzyme production represents a rational step to regulate nutriment uptake. However, the role of digestion in nutrient homeostasis has been largely neglected. In this study, we analyzed the mechanism underlying glucose repression of digestive enzymes in the adult Drosophila midgut. We demonstrate that glucose represses the expression of many carbohydrases and lipases. Our data reveal that the consumption of nutritious sugars stimulates the secretion of the transforming growth factor β (TGF-β) ligand, Dawdle, from the fat body. Dawdle then acts via circulation to activate TGF-β/Activin signaling in the midgut, culminating in the repression of digestive enzymes that are highly expressed during starvation. Thus, our study not only identifies a mechanism that couples sugar sensing with digestive enzyme expression but points to an important role of TGF-β/Activin signaling in sugar metabolism.
    Full-text · Article · Oct 2014 · Cell Reports
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