Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments

Abstract

The prevalence of obesity and diabetes mellitus (DM) has been consistently increasing worldwide. Sharing powerful genetic and environmental features in their pathogenesis, obesity amplifies the impact of genetic susceptibility and environmental factors on DM. The ectopic expansion of adipose tissue and excessive accumulation of certain nutrients and metabolites sabotage the metabolic balance via insulin resistance, dysfunctional autophagy, and microbiome-gut-brain axis, further exacerbating the dysregulation of immunometabolism through low-grade systemic inflammation, leading to an accelerated loss of functional β-cells and gradual elevation of blood glucose. Given these intricate connections, most available treatments of obesity and type 2 DM (T2DM) have a mutual effect on each other. For example, anti-obesity drugs can be anti-diabetic to some extent, and some anti-diabetic medicines, in contrast, have been shown to increase body weight, such as insulin. Meanwhile, surgical procedures, especially bariatric surgery, are more effective for both obesity and T2DM. Besides guaranteeing the availability and accessibility of all the available diagnostic and therapeutic tools, more clinical and experimental investigations on the pathogenesis of these two diseases are warranted to improve the efficacy and safety of the available and newly developed treatments.

Keywords: bariatric surgery; diabetes mellitus; islet function; microenvironment; obesity; pathogenesis; β-cell failure.

Figure 1

Genetic and environmental factors affecting islet function and connecting obesity and T2DM. Genetic factors mainly alter the energy balance in obesity while regulating the development and function of β-cells in T2DM. Being further promoted by various environmental factors, obesity accelerates the β-cell loss and blunts insulin signaling in T2DM. Meanwhile, insulin prescribed to patients with T2DM can have a weight-increasing effect. Arrows in color indicate the interactions between obesity and T2DM. T2DM, type 2 diabetes mellitus; ECM, extracellular matrix.

Figure 2

The critical roles of obesity-induced insulin resistance in the consequent pathogenesis of T2DM. (A) The aberrant accumulation and expansion of adipose tissue in obesity create a microenvironment characterized by hypoactive fatty acid metabolism and fuel cellular stress and pro-inflammatory perturbations, which results in an increased lipolysis, oxidative stress, and hypoxia due to fibrosis and insufficient angiogenesis. (B) In the liver, the excessive infusion resulting from enhanced lipolysis within adipose tissue causes a transient increase in DAG, which occurs once the rates of DAG synthesis exceed rates of mitochondrial long-chain CoA oxidation under mitochondrial dysfunction, and then the DAG is synthesized into TAG and stored as lipid droplets. Meanwhile, DAG activates PKCϵ and blunts the insulin receptor tyrosine kinase, damaging insulin signaling and decreasing insulin-stimulated glycogen synthesis owing to reduced phosphorylation of GSK3. At the same time, it also dampens the activity of glycogen synthase and indulges hepatic gluconeogenesis through decreased phosphorylation of FoxO, where the increased FoxO translocates to the nucleus and enhances the gene transcription of gluconeogenic enzymes, such as PEP-CK and G6P (39). Similarly, the cytokines and adipocytokines released in systemic inflammation increase hepatic gluconeogenic enzyme transcription by activating NF-κB and JNK. (C) In the skeletal muscle, the increased lipid fusion results in the accumulation of intracellular long-chain CoA and elevates the level of DAG, which is also caused by the decline in fat oxidation owing to mitochondrial dysfunction and subsequent reduction in glucose uptake. Apart from increasing the synthesis of TAG as cellular lipid storage, DAG also activates the theta isoform of protein kinase C (PKCθ), which leads to increased phosphorylation of IRS-1 and hinders insulin signaling and subsequent activation of the PI3K/AKT pathway, dampening glucose transport and glycogen synthesis. (D) While obesity-induced insulin resistance exacerbates inflammation and glucose transport in adipose tissue, the volume of β-cell mass is increased to meet the growing demand for insulin secretion. However, the increased insulin secretion results in hyperinsulinemia afterward and exasperates both hepatic and systemic lipid accumulation. Moreover, hyperinsulinemia increases the level of lactate in muscles, which is released into circulation and used as a substrate for hepatic lipogenesis. Finally, β-cells collapse, and the deficiency of insulin secretion leads to hyperglycemia. AKT, protein kinase B; ATM, adipose tissue macrophage; CoA, acetyl coenzyme A; DAG, diacylglycerol; FoxO, forkhead box subgroup O; G6P, glucose 6-phosphate; GLUT4, glucose transporter type 4; GSK3, glycogen synthase kinase 3; IRS-1, insulin receptor substrate 1; JNK, Jun N-terminal kinase; NF-κB, nuclear factor κB; NK, natural killer (cell); P, phosphorylation; PEP-CK, phosphoenolpyruvate carboxykinase; PI3K, phosphatidylinositol-3-kinase; PKCϵ (θ), epsilon (theta) isoform of protein kinase C; ROS, reactive oxygen species; TAG, triglyceride.

Figure 3

Mechanisms of fatty acids affecting insulin signaling and fueling hyperglycemia. Contradictory to the anti-inflammatory and insulin-sensitizing effect of PUFAs, MUFAs, and FAHFAs, SFAs sabotage insulin sensitivity by promoting pro-inflammatory signaling via TLR4 and its adaptor proteins TRIP and MYD88, which jointly enhance the activity of pro-inflammatory pathway and transcription factors, such as IRF3, NF-κB, and AP1 to augment the expression of chemocytokines. Mutually, these pro-inflammatory chemocytokines can also activate these pro-inflammatory transcription factors as a positive feedback loop to maintain an inflammatory environment detrimental to insulin signaling. Meanwhile, the accumulation of TAG, ceramides, and increased ER stress due to activated NF-κB signaling and inflammatory cascade can also exacerbate insulin resistance and fuel hyperglycemia. AP1, activator protein 1; ER, endoplasmic reticulum; FAHFA, branched fatty acid esters of hydroxy fatty acid; IKKβ, inhibitor of nuclear factor-κB (NF-κB) kinase subunit-β; Ikβ, inhibitor of NF-κB subunit-β; IRF3, interferon regulatory factor 3; JNK, Jun N-terminal kinase; MUFA, monounsaturated fatty acid; MYD88, myeloid differentiation primary response protein MYD88; NF-κB, nuclear factor-κB; P, phosphorylation; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; TAG, triglyceride; TLR4, Toll-like receptor 4; TRIF, TIR-domain-containing adaptor-inducing interferon-β.

Figure 4

Alterations of autophagy in different metabolic organs during the transition from overnutrition and obesity to T2DM. The excessive intake of nutrients such as lipids, glucose, and amino acids results in the suppression of autophagy via different signaling pathways and contributes to obesogenesis by increasing the accumulation of lipids, and proteins, enhancing low-grade systemic inflammation and exacerbating insulin signaling. In obesity, distinct dissimilarities can be observed in the changes in autophagy among different sites. In adipose tissue, the elevations in the levels of lipids and FAs and the upregulation of autophagy genes can enhance autophagy, whereas cellular stress can suppress autophagy. While the hepatic can also be enhanced or blunted by different signaling pathways and lead to the promotion of lipogenesis, glucogenesis, inflammation, and apoptosis. Insulin and metabolites, such as lipids, amino acids, glucagon, and FAs can also induce a dual impact on pancreatic autophagy and result in hyperinsulinemia as an initial protective mechanism against hyperglycemia but eventually favors the onset of insulin resistance and DM following the concurrent dysfunction of β-cells. Pancreatic autophagy might also be enhanced by elevated levels of free fatty acids (FFAs) and glucagon in obesity. Jointly, all these disruptions in autophagy of different sites contribute to the aberrant accumulation of protein aggregates, lipids, and other detrimental components in the microenvironment that fuels cellular stress and causes insulin resistance and subsequent transition from obesity to DM. BCAAs, branched-chain amino acids; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. AKT, protein kinase B; AMPK, AMP-activated protein kinase; BCAA, branched-chain amino acid; DM, diabetes mellitus; ER, endoplasmic reticulum; FAs, fatty acids; IGF-1, insulin-like growth factor 1; JNK, Jun N-terminal kinase; mTORC1, mechanistic target of rapamycin (mTOR) complex 1; PI3K, phosphatidylinositol-3-kinase; PLIN2, perilipin 2; STAT3, signal transducer and activator of transcription 3.

Figure 5

Obesity-induced acceleration of β-cell loss in the pancreatic islets of T2DM. The accumulation of lipid and glucose induces glucolipotoxicity, which jointly exacerbates insulin resistance and exhausts β-cells with enhanced low-grade inflammation owing to the increased secretion of pro-inflammatory cytokines to the microenvironment. In the islets of T2DM with a similarity to the inflammatory microenvironment as in adipose tissue, the deposition of amyloid worsens oxidative stress, resulting in increased apoptosis of β-cells, while the dedifferentiation of β-cells to progenitor-like cells or transdifferentiation to other identities (e.g., α-cells) further jeopardize the β-cell population. Collaboratively, the constant pro-apoptotic and pro-inflammatory signals promoting ER stress lead to β-cell loss. ER, endoplasmic reticulum; T2DM, type 2 diabetes mellitus.

Figure 6

Regulators of the microbiome-gut-brain axis. The crucial function of the microbiome-gut-brain axis is regulated by various factors, such as diet, sexual differences, genetics/epigenetics, exercise, environment, medication, and maternal environment.

Figure 7

Dysfunction of the microbiome-gut-brain axis in obesity and T2DM. The composition and diversity of the gut microbiome are significantly altered in obesity. Apart from the consequent aberrances in the metabolism and metabolites of the microbiomes, such as the decrease in the production of BAs and SCFAs and the increase in LPS, the protective function of the gut is compromised by the increased permeability resulting from the inflammatory stimulations of nitric oxide, ammonia, carbon oxide, indole, and hydrogen sulfide, allowing the drastic elevation in the flux of LPS, which can not only activate the TLR4 on enterocytes to promote the secretion of inflammatory cytokine and recruit inflammatory dendritic cells, B cells, and macrophages, but also directly inducing the production of inflammatory cytokines from these cells. Meanwhile, the profound reduction in the production of SCFAs and BAs leads to the subsequent drop in the activation of GPCR and FXR in enteroendocrine cells to sustain the production of GI hormones vital for energy homeostasis, which include GLP-1, GIP, PYY, and CCK. All these peptides have both peripheral and central effects on modifying the host metabolism and regulation of appetite directly through the vagus nerve or indirectly via immunoneuroendocrine mechanisms. Centrally, the aberrant hormonal signals transmitted from the gut to the hypothalamus in the brain result in aberrant eating behavior and metabolic control. While peripherally, the influx of LPS, pro-inflammatory cytokines, and bacterial DNA, along with inadequate SCFAs, Bas, and GI peptides in the circulation further exacerbates insulin signaling and metabolic imbalance. Altogether, these central and peripheral abnormalities in metabolic control eventually lead to hyperglycemia. 5-HT, 5-hydroxytryptamine; BA, BA; CCK, cholecystokinin; FXR, Farnesoid X receptor; GABA, γ-aminobutyric acid; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; GPCR, G-protein coupled receptor; LPS, lipopolysaccharide; PYY, peptide YY; SCFA, short-chain fatty acid; TLR4, Toll-like receptor 4.