Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues — prominently in muscle, fat and liver — is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia and hyperlipidaemia. Insulin resistance is caused by a combination of genetic and environmental factors. Recent genetic and biochemical studies suggest a key role for adipose tissue in the development of insulin resistance, potentially by releasing lipids and other circulating factors that promote insulin resistance in other organs. These extracellular factors perturb the intracellular concentration of a range of intermediates, including ceramide and other lipids, leading to defects in responsiveness of cells to insulin. Such intermediates may cause insulin resistance by inhibiting one or more of the proximal components in the signalling cascade downstream of insulin (insulin receptor, insulin receptor substrate (IRS) proteins or AKT). However, there is now evidence to support the view that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway that is more closely linked to the terminal biological response. Identifying these targets is of major importance, as it will reveal potential new targets for treatments of diseases associated with insulin resistance. Insulin resistance is one of the earliest manifestations of several human diseases, including type 2 diabetes and cardiovascular disease. This Review discusses the causes of insulin resistance and recent insights into the underlying mechanisms, providing directions for the development of novel therapeutic strategies

The aetiology and molecular landscape of insulin resistance.

The fruit fly Drosophila melanogaster has been a valuable model to investigate the genetic mechanisms of innate immunity. Initially focused on the resistance to bacteria and fungi, these studies have been extended to include antiviral immunity over the last decade. Like all living organisms, insects are continually exposed to viruses and have developed efficient defense mechanisms. We review here our current understanding on antiviral host defense in fruit flies. A major antiviral defense in Drosophila is RNA interference, in particular the small interfering (si) RNA pathway. In addition, complex inducible responses and restriction factors contribute to the control of infections. Some of the genes involved in these pathways have been conserved through evolution, highlighting loci that may account for susceptibility to viral infections in humans. Other genes are not conserved and represent species-specific innovations.

/pdf/innate-and-intrinsic-antiviral-immunity-in-drosophila-4io6lzbfmb.pdf

Innate and intrinsic antiviral immunity in Drosophila.

In animals, systemic control of metabolism is conducted by metabolic tissues and relies on the regulated circulation of a plethora of molecules, such as hormones and lipoprotein complexes. MicroRNAs (miRNAs) are a family of post-transcriptional gene repressors that are present throughout the animal kingdom and have been widely associated with the regulation of gene expression in various contexts, including virtually all aspects of systemic control of metabolism. Here we focus on glucose and lipid metabolism and review current knowledge of the role of miRNAs in their systemic regulation. We survey miRNA-mediated regulation of healthy metabolism as well as the contribution of miRNAs to metabolic dysfunction in disease, particularly diabetes, obesity and liver disease. Although most miRNAs act on the tissue they are produced in, it is now well established that miRNAs can also circulate in bodily fluids, including their intercellular transport by extracellular vesicles, and we discuss the role of such extracellular miRNAs in systemic metabolic control and as potential biomarkers of metabolic status and metabolic disease.

MicroRNA-mediated regulation of glucose and lipid metabolism.

The control of body and organ growth is essential for the development of adults with proper size and proportions, which is important for survival and reproduction. In animals, adult body size is determined by the rate and duration of juvenile growth, which are influenced by the environment. In nutrient-scarce environments in which more time is needed for growth, the juvenile growth period can be extended by delaying maturation, whereas juvenile development is rapidly completed in nutrient-rich conditions. This flexibility requires the integration of environmental cues with developmental signals that govern internal checkpoints to ensure that maturation does not begin until sufficient tissue growth has occurred to reach a proper adult size. The Target of Rapamycin (TOR) pathway is the primary cell-autonomous nutrient sensor, while circulating hormones such as steroids and insulin-like growth factors are the main systemic regulators of growth and maturation in animals. We discuss recent findings in Drosophila melanogaster showing that cell-autonomous environment and growth-sensing mechanisms, involving TOR and other growth-regulatory pathways, that converge on insulin and steroid relay centers are responsible for adjusting systemic growth, and development, in response to external and internal conditions. In addition to this, proper organ growth is also monitored and coordinated with whole-body growth and the timing of maturation through modulation of steroid signaling. This coordination involves interorgan communication mediated by Drosophila insulin-like peptide 8 in response to tissue growth status. Together, these multiple nutritional and developmental cues feed into neuroendocrine hubs controlling insulin and steroid signaling, serving as checkpoints at which developmental progression toward maturation can be delayed. This review focuses on these mechanisms by which external and internal conditions can modulate developmental growth and ensure proper adult body size, and highlights the conserved architecture of this system, which has made Drosophila a prime model for understanding the coordination of growth and maturation in animals.

https://www.genetics.org/content/genetics/216/2/269.full.pdf

Regulation of Body Size and Growth Control

The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into a medically manageable chronic condition. Insulin is a key peptide hormone and mediates the systemic glucose metabolism in different tissues. Insulin resistance (IR) is a disordered biological response for insulin stimulation through the disruption of different molecular pathways in target tissues. Acquired conditions and genetic factors have been implicated in IR. Recent genetic and biochemical studies suggest that the dysregulated metabolic mediators released by adipose tissue including adipokines, cytokines, chemokines, excess lipids and toxic lipid metabolites promote IR in other tissues. IR is associated with several groups of abnormal syndromes that include obesity, diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and other abnormalities. Although no medication is specifically approved to treat IR, we summarized the lifestyle changes and pharmacological medications that have been used as efficient intervention to improve insulin sensitivity. Ultimately, the systematic discussion of complex mechanism will help to identify potential new targets and treat the closely associated metabolic syndrome of IR. 

/pdf/trends-in-insulin-resistance-insights-into-mechanisms-and-4t4a9d8e.pdf

Trends in insulin resistance: insights into mechanisms and therapeutic strategy

MicroRNA function in Drosophila melanogaster.

The insulin/insulin-like growth factor (IGF) pathway is essential for linking nutritional status to growth and metabolism. MicroRNAs (miRNAs) are short RNAs that are players in the regulation of this process. The miRNA miR-7 shows highly conserved expression in insulin-producing cells across the animal kingdom. However, its conserved functions in regulation of insulin-like peptides (ILPs) remain unknown. Using Drosophila as a model, we demonstrate that miR-7 limits ILP availability by inhibiting its production and secretion. Increasing miR-7 alters body growth and metabolism in an ILP-dependent manner, elevating circulating sugars and total body triglycerides, while decreasing animal growth. These effects are not due to direct targeting of ILP mRNA, but instead arise through alternate targets that affect the function of ILP-producing cells. The Drosophila F-actin capping protein alpha (CPA) is a direct target of miR-7, and knockdown of CPA in insulin-producing cells phenocopies the effects of miR-7 on ILP secretion. This regulation of CPA is conserved in mammals, with the mouse ortholog Capza1 also targeted by miR-7 in β-islet cells. Taken together, these results support a role for miR-7 regulation of an actin capping protein in insulin regulation, and highlight a conserved mechanism of action for an evolutionarily ancient microRNA.

MicroRNA miR-7 Regulates Secretion of Insulin-Like Peptides.

The insulin/IGF pathway is essential for linking nutritional status to growth and metabolism. MicroRNAs (miRNAs) are short RNAs that are players in the regulation of this process. The miRNA miR-7 shows highly conserved expression in insulin-producing cells across the animal kingdom, however, its conserved functions in regulation of insulin-like peptides (ILPs) remains unknown. Using Drosophila as a model, we demonstrate that miR-7 limits ILP availability by inhibiting its production and secretion. Increasing miR-7 alters body growth and metabolism in an ILP-dependent manner, elevating circulating sugars and total body triglycerides, while decreasing animal growth. These effects are not due to direct targeting of ILP mRNA, but instead arise through alternate targets that affect the function of ILP-producing cells. The Drosophila F-actin capping protein, CPA, is a direct target of miR-7, and knockdown of CPA in IPCs phenocopies the effects of miR-7 on ILP secretion. This regulation of CPA is conserved in mammals, with the mouse ortholog Capza1 also targeted by miR-7 in β-islet cells. Taken together, these results support a role for miR-7 regulation of an actin capping protein in insulin regulation, and highlight a conserved mechanism of action for an evolutionarily ancient microRNA. Disclosure Statement PA, JB, AJ and RWC have nothing to declare. JJC is an employee of Sg2, LLC, a healthcare consulting company.

https://biorxiv.org/content/biorxiv/early/2019/10/03/791640.full-text.pdf

Pamela Agbu

Papers

MicroRNA-mediated regulation of glucose and lipid metabolism.

MicroRNA function in Drosophila melanogaster.

MicroRNA miR-7 Regulates Secretion of Insulin-Like Peptides.

MicroRNA miR-7 regulates synthesis and secretion of insulin-like peptides