Defining the underlying defect in insulin action in type 2 diabetes

Abstract

Insulin resistance is one of the earliest defects in the pathogenesis of type 2 diabetes. Over the past 50 years, elucidation of the insulin signalling network has provided important mechanistic insights into the abnormalities of glucose, lipid and protein metabolism that underlie insulin resistance. In classical target tissues (liver, muscle and adipose tissue), insulin binding to its receptor initiates a broad signalling cascade mediated by changes in phosphorylation, gene expression and vesicular trafficking that result in increased nutrient utilisation and storage, and suppression of catabolic processes. Insulin receptors are also expressed in non-classical targets, such as the brain and endothelial cells, where it helps regulate appetite, energy expenditure, reproductive hormones, mood/behaviour and vascular function. Recent progress in cell biology and unbiased molecular profiling by mass spectrometry and DNA/RNA-sequencing has provided a unique opportunity to dissect the determinants of insulin resistance in type 2 diabetes and the metabolic syndrome; best studied are extrinsic factors, such as circulating lipids, amino acids and other metabolites and exosomal microRNAs. More challenging has been defining the cell-intrinsic factors programmed by genetics and epigenetics that underlie insulin resistance. In this regard, studies using human induced pluripotent stem cells and tissues point to cell-autonomous alterations in signalling super-networks, involving changes in phosphorylation and gene expression both inside and outside the canonical insulin signalling pathway. Understanding how these multi-layered molecular networks modulate insulin action and metabolism in different tissues will open new avenues for therapy and prevention of type 2 diabetes and its associated pathologies.

Dietary Flavonoids and Insulin Signaling in Diabetes and Obesity

“…On the contrary, the flavonoid myricetin up-regulated p-IR, p-IRS1 and p-AKT in the liver of HFD-fed and STZ-induced type 2 diabetic rats by inhibiting the activity and expression of PTP1B, the tyrosine phosphatase that negatively regulates the insulin signal transduction [38]. Notably, the impaired insulin signaling in the liver promotes gluconeogenesis and suppresses glycogen synthesis [32]. In this sense, it has been shown that flavonoids can modulate several genes related to the glucose metabolism through the IRS/PI3K/AKT pathway [39][40][41].…”

“…It is a complex metabolic disorder characterized by persistent elevated blood glucose due to the progressive insulin deficiency (beta-cell dysfunction) on the background of insulin resistance [31]. In diabetes, intrinsic genetic and epigenetic factors, as well as extrinsic factors, including circulating levels of lipids, glucose, or amino acids, can disrupt the insulin signaling network in insulinsensitive tissues, leading to insulin resistance [32]. Numerous scientific evidences have revealed that flavonoids may contribute to prevent or ameliorate the insulin resistance in diabetes by their ability to modulate the insulin signaling pathway in classical target tissues such as liver, muscle, and adipose tissue.…”

“…These effects have widely been reported from both in vitro and in vivo animal models (Table 2). Liver plays a major role in maintaining the balance of glucose homeostasis; however, in diabetes, the ability of insulin to trigger downstream metabolic actions is impaired, leading to alterations in the hepatic metabolism [32]. In this regard, dietary flavonoids may enhance insulin sensitivity in diabetes by acting as insulin sensitizers.…”

Glucosamine Ameliorates Symptoms of High-Fat Diet-Fed Mice by Reversing Imbalanced Gut Microbiota

“…By using PICRUSt analysis to predict the functional changes of gut microbiota due to their altered compositions and abundances, we observed that GlcN mainly interfered with the glucolipid metabolism and biosynthesis pathways of intestinal floral in HFD-fed mice ( Figures 6A,B ). Among these pathways, glycolysis/gluconeogenesis, lipid biosynthesis protein, and energy metabolism are closely associated with the development of diabetes mellitus ( Kosanam et al, 2014 ; Batista et al, 2021 ; Wang et al, 2021 ). As an effective arthritis inhibitor, GlcN has been proved to suppress the activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome in mouse and human macrophages.…”

Celebrating 100 years of insulin

“…Meanwhile, Kahn and colleagues [8] discuss how most people with disordered glucose metabolism exhibit insulin resistance, rather than insulin deficiency. The authors outline current and evolving concepts of insulin action and insulin resistance, specifically in type 2 diabetes.…”