Regulation of Macronutrients in Insulin Resistance and Glucose Homeostasis during Type 2 Diabetes Mellitus

Abstract

Insulin resistance is an important feature of metabolic syndrome and a precursor of type 2 diabetes mellitus (T2DM). Overnutrition-induced obesity is a major risk factor for the development of insulin resistance and T2DM. The intake of macronutrients plays a key role in maintaining energy balance. The components of macronutrients distinctly regulate insulin sensitivity and glucose homeostasis. Precisely adjusting the beneficial food compound intake is important for the prevention of insulin resistance and T2DM. Here, we reviewed the effects of different components of macronutrients on insulin sensitivity and their underlying mechanisms, including fructose, dietary fiber, saturated and unsaturated fatty acids, and amino acids. Understanding the diet-gene interaction will help us to better uncover the molecular mechanisms of T2DM and promote the application of precision nutrition in practice by integrating multi-omics analysis.

Keywords: glucose homeostasis; insulin resistance; macronutrients; type 2 diabetes mellitus.

Figure 1

FoxO1 plays a pivotal role as a metabolic regulator in hormonal regulation, metformin function, and the influence of bioactive functional foods in both health and disease. Insulin and estrogen stimulate FoxO1 phosphorylation at T24, S253, and S316 through PI3K → AKT signaling, thereby inhibiting FoxO1 activity. Glucagon stimulates FoxO1 phosphorylation at S273 through cAMP → PKA and cAMP → EPAC2 → p38 signaling, thereby increasing FoxO1 activity. Activation of FoxO1 promotes hepatic glucose production, increases hepatokine secretion, impairs cardiac and hepatic mitochondrial function, and induces inflammation during metabolic stress and aging. AC, adenylyl cyclase; AKT, protein kinase B; cAMP, cyclic adenosine monophosphate; EPAC2, exchange protein directly activated by cAMP 2; ERα, estrogen receptor α; FoxO1, forkhead/winged helix transcription factor O-class member 1; Gcgr, glucagon receptor; G6Pase, glucose-6-phosphatase; IRS, insulin receptor substrate; P, phosphorylation; PDK, phosphoinositide-dependent protein kinase; PKA, protein kinase A; PI3K, phosphatidylinositol 3-kinase. →: Activation; : Inhibition [50,51,61,62,63,64,65,66,67,68,69,70,73,76,77].

Figure 2

Macronutrients regulate insulin resistance and glucose homeostasis through distinct molecular mechanisms. Fructose leads to insulin resistance by increasing hepatic lipogenesis and impairing gut immunity. Dietary fiber improves insulin sensitivity through gut microbiome-derived SCFAs. Increased dietary fat intake elevates free fatty acid levels, especially unsaturated fatty acids, thereby attenuating insulin sensitivity by inducing pro-inflammatory activity and activating DAG-PKC signaling. Increased BCAA levels induce insulin resistance through activation of mTOR-IRS signaling and BCAA metabolite-induced oxidative stress. Glycine improves insulin sensitivity potentially through the generation of glutathione, and arginine contributes to insulin sensitivity by inhibiting FoxO1. BCAA, branched-chain amino acid; DAG, diglyceride; ER stress, endoplasmic reticulum stress; FA, fatty acid; FFAR, free fatty acid receptor; FoxO1, forkhead/winged helix transcription factor O-class member 1; GPR120, G-protein coupled receptor 120; GLP-1, glucagon-like peptide-1; IR, insulin receptor; IRS, insulin receptor substrate; mTOR, mammalian target of rapamycin; PYY, peptide tyrosine tyrosine; PKC, protein kinase C; PPAR, peroxisome proliferator-activated receptor; PUFA, polyunsaturated fatty acid; SCFA, short-chain fatty acid; TLR, toll-like receptor; TNF, tumor necrosis factor. →: Activation; : Inhibition.