Using <i>Drosophila</i> to discover mechanisms underlying type 2 diabetes

Alfa, Ronald W.; Kim, Seung K.

doi:10.1242/dmm.023887

Cited by 97 publications

(88 citation statements)

References 134 publications

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“…Hence, similar to mammals, Drosophila displays reciprocal humoral interactions between adipocytes/liver and brain neuroendocrine cells. The adult fat body can release hormonal factors to modulate IPCs and systemic insulin signalling, which in turn signals to the fat body [17,60,63,86]. In mammals, systemic insulin signalling is influenced by adipocyte-derived hormonal factors, such as leptin and adiponectin [87,88].…”

Section: Discussionmentioning

confidence: 99%

Systemic corazonin signalling modulates stress responses and metabolism inDrosophila

Kubrak¹,

Lushchak²,

Zandawala³

et al. 2016

Open Biol.

103

127

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Stress triggers cellular and systemic reactions in organisms to restore homeostasis. For instance, metabolic stress, experienced during starvation, elicits a hormonal response that reallocates resources to enable food search and readjustment of physiology. Mammalian gonadotropin-releasing hormone (GnRH) and its insect orthologue, adipokinetic hormone (AKH), are known for their roles in modulating stress-related behaviour. Here we show that corazonin (Crz), a peptide homologous to AKH/GnRH, also alters stress physiology in Drosophila. The Crz receptor (CrzR) is expressed in salivary glands and adipocytes of the liver-like fat body, and CrzR knockdown targeted simultaneously to both these tissues increases the fly's resistance to starvation, desiccation and oxidative stress, reduces feeding, alters expression of transcripts of Drosophila insulin-like peptides (DILPs), and affects gene expression in the fat body. Furthermore, in starved flies, CrzR-knockdown increases circulating and stored carbohydrates. Thus, our findings indicate that elevated systemic Crz signalling during stress coordinates increased food intake and diminished energy stores to regain metabolic homeostasis. Our study suggests that an ancient stress-peptide in Urbilateria evolved to give rise to present-day GnRH, AKH and Crz signalling systems.

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Section: Discussionmentioning

confidence: 99%

Systemic corazonin signalling modulates stress responses and metabolism inDrosophila

Kubrak¹,

Lushchak²,

Zandawala³

et al. 2016

Open Biol.

103

127

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“…Thus, overall, while it is clear that modeling T2D in flies is possible, such modeling requires extreme caution in controlling for genetic differences, rearing conditions and extrapolating to the human condition. To learn more about modeling T2D in Drosophila , we suggest a recent review on this topic, published while this chapter was in press (Alfa & Kim, 2016). …”

Section: Drosophila As a Model For Insulin Resistance And Type 2 Dmentioning

confidence: 99%

Drosophila as a Model for Diabetes and Diseases of Insulin Resistance

Graham

Pick

2017

Current Topics in Developmental Biology

114

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Despite the importance of insulin signaling pathways in human disease, initial concerns that insect physiology and sugar metabolism differ enough from humans that flies would not model human disease hampered research in this area. However, during the past 10–15 years, evidence has accumulated that flies can indeed model various aspects of diabetes and related human disorders. This cluster of diseases impact insulin and insulin signaling pathways, fields which have been discussed in many excellent review articles in recent years. In this chapter, we restrict our focus to specific examples of diabetes-related disease models in Drosophila, discussing the advantages and limitations of these models in light of physiological similarities and differences between insects and mammals. We discuss features of metabolism and sugar regulation that are shared between flies and mammals, and specific Drosophila models for Type 1 and Type 2 diabetes, Metabolic syndrome, and related abnormalities including insulin resistance and heart disease. We conclude that fly models for diabetes and related disorders enhance our ability to identify genes and discern functional interactions that can be exploited for disease intervention.

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“…The insulin/TOR signaling pathway regulates development in response to nutrients, and disruptions of this pathway are known to affect body size and developmental duration [19,44,46,47]. Genetic defects in the insulin signaling pathway (including dILPs, Drosophila insulin-like proteins), reduced insulin receptor activity, the inhibition of DREF (DNA replication-related element-binding factor), or disruptions in TOR activation, can cause long development times and smaller-bodied flies, similar to the adverse mannitol developmental effects we observed in larvae [9,19,48–53]. High-sugar diet fed larvae experience reduced growth due to insulin signaling resistance, even when dILP levels are increased, while reductions in nutrition can simply prevent the release of dILPs, thereby reducing growth [10,44].…”

Section: Discussionmentioning

confidence: 75%

“…High-carbohydrate diets, specifically sucrose and glucose, affect insect growth and development. High-sugar diets disrupt the insulin/TOR signaling pathway through increased circulating trehalose levels [9,10]. High-sugar fed D. melanogaster adults are a model system for studying metabolic phenotypes associated with insulin resistance and diabetes [9–15].…”

Section: Introductionmentioning

confidence: 99%

“…High-sugar diets disrupt the insulin/TOR signaling pathway through increased circulating trehalose levels [9,10]. High-sugar fed D. melanogaster adults are a model system for studying metabolic phenotypes associated with insulin resistance and diabetes [9–15]. At the larval stage, high-sugar diets lead to delays in adult eclosion (due to delayed onset of pupation, but not prolonged pupation periods), reduced survival, and smaller pupal case volumes and lower adult dry mass [10,16–19].…”

Section: Introductionmentioning

confidence: 99%

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Larval mannitol diets increase mortality, prolong development, and decrease adult body sizes in fruit flies (Drosophila melanogaster)

Barrett

Fiocca

Waddell

et al. 2019

Preprint

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Ingestion of the polyol mannitol caused sex-biased mortality in adult Drosophila melanogaster, but larval mortality was not sex-biased. High-sugar diets prolong development and generate smaller adult body sizes in D. melanogaster. We hypothesized that mannitol ingestion would generate similar developmental phenotypes as other high-carbohydrate diets. We predicted concentration-dependent effects on development similar to high-sugar diets when D. melanogaster larvae are fed mannitol, as well as a concentration-dependent amelioration of developmental effects if introduction to mannitol media is delayed past the third instar. Both male and female larvae had prolonged development and smaller adult body sizes when fed increasing concentrations of mannitol. Mannitol-induced increases in mortality were concentration dependent in 0 M to 0.8 M treatments beginning as early as 48 hours post-hatching. Larval survival, and pupation and eclosion times, were normal in 0.4 M mannitol treatments when larvae were first introduced to mannitol 72 hours post-hatching (the beginning of the third-instar); the adverse mannitol effects occurred in 0.8 M mannitol treatments, but at a lower magnitude. Female D. melanogaster adults prefer laying eggs on diets with high sugar concentrations, despite the negative effects on offspring performance. However, when given a choice, female D. melanogaster avoided laying eggs on mannitol-containing media that was otherwise identical to the control media, suggesting females perceived and avoided mannitol. In conclusion, the developmental effects of a larval mannitol diet closely resemble those of high-sugar diets, but adult female oviposition responses to mannitol in laying substrates are distinct from responses to other carbohydrates.

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Using Drosophila to discover mechanisms underlying type 2 diabetes

Cited by 97 publications

References 134 publications

Systemic corazonin signalling modulates stress responses and metabolism inDrosophila

Systemic corazonin signalling modulates stress responses and metabolism inDrosophila

Drosophila as a Model for Diabetes and Diseases of Insulin Resistance

Larval mannitol diets increase mortality, prolong development, and decrease adult body sizes in fruit flies (Drosophila melanogaster)

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