Drosophila Insulin Pathway Mutants Affect Visual Physiology and Brain Function Besides Growth, Lipid, and Carbohydrate Metabolism

Abstract

OBJECTIVEType 2 diabetes is the most common form of diabetes worldwide. Some of its complications, such as retinopathy and neuropathy, are long-term and protracted, with an unclear etiology. Given this problem, genetic model systems, such as in flies where type 2 diabetes can be modeled and studied, offer distinct advantages.RESEARCH DESIGN AND METHODSWe used individual flies in experiments: control and mutant individuals with partial loss-of-function insulin pathway genes. We measured wing size and tested body weight for growth phenotypes, the latter by means of a microbalance. We studied total lipid and carbohydrate content, lipids by a reaction in single fly homogenates with vanillin-phosphoric acid, and carbohydrates with an anthrone-sulfuric acid reaction. Cholinesterase activity was measured using the Ellman method in head homogenates from pooled fly heads, and electroretinograms with glass capillary microelectrodes to assess performance of central brain activity and retinal function.RESULTSFlies with partial loss-of-function of insulin pathway genes have significantly reduced body weight, higher total lipid content, and sometimes elevated carbohydrate levels. Brain function is impaired, as is retinal function, but no clear correlation can be drawn from nervous system function and metabolic state.CONCLUSIONSThese studies show that flies can be models of type 2 diabetes. They weigh less but have significant lipid gains (obese); some also have carbohydrate gains and compromised brain and retinal functions. This is significant because flies have an open circulatory system without microvasculature and can be studied without the complications of vascular defects.

Subpopulation of Macrophage-Like Plasmatocytes Attenuates Systemic Growth via JAK/STAT in the Drosophila Fat Body

“…Given that both proximal and distal components of insulin signaling-PI3K and InR respectively-are altered when JAK/STAT pathway is activated, convergence of the two pathways could occur at the direct downstream of InR activity or InR transcription level. It will be intriguing to uncover the exact confluence between the two pathways despite the dichotomy that exists between them: while insulin signaling is growth and proliferation-biased, JAK/STAT is immunological (71)(72)(73)(74). More so, this may provide insights into how immunity and metabolism differentially interact in normal development and pathologies.…”

Hobbit regulates intracellular trafficking to drive insulin-dependent growth duringDrosophiladevelopment

“…Disruption of the insulin signaling pathway has a profound effect on Drosophila body size. Ablation of the IPCs (Rulifson et al, 2002), genetic deletion of Dilps (Grönke et al, 2010), or mutation of targets downstream of InR (Böhni et al, 1999;Brogiolo et al, 2001;Murillo-Maldonado et al, 2011) all result in a dramatic reduction in body size. However, despite the importance of the insulin signaling pathway for systemic growth in flies and for disease in humans, the factors regulating insulin secretion remain largely unknown.…”

Carbohydrate Metabolism in Drosophila: Reliance on the Disaccharide Trehalose

“…In this regard, fly mutant growth phenotypes are similar to IRS1 loss-of-function mice models [30,31] and other murine diabetic models [32] where growth phenotypes also exist; besides, in flies, the insulin and IGF (insulin growth factor) pathways are mediated by a common route. In addition, fly mutants also have nervous system abnormalities [29].…”

“…Perhaps the clearest demonstration of the insulin pathway's role in carbohydrate and lipid metabolism comes from studies of Drosophila insulin pathway mutants: From the pioneering studies on Chico, a Drosophila insulin-receptor-substrate (IRS) homolog [10], it has now been demonstrated that practically all viable mutant combinations, that create partial loss-of-function or hypomorphic conditions for the insulin pathway, course with altered lipid and carbohydrate levels [29]. This is also akin to having congenital diabetes mellitus type 2, as these flies are born with a dysfunctional insulin pathway.…”