The Interplay Between Obesity and Type 2 Diabetes: Common Pathophysiological Mechanisms Contributing to Telomere Shortening

Abstract

The worldwide prevalence of obesity continues to increase, representing a serious public health issue due to associated comorbidities. Obesity is associated with type 2 diabetes mellitus (T2D), which shares similar pathophysiological mechanisms. In both conditions, oxidative stress, inflammation, mitochondrial dysfunction, abnormal adipose tissue function, and senescence are observed, ultimately leading to insulin resistance. In both cases, hypertrophic adipose tissue is associated with telomere shortening. Elucidating the mechanisms underlying telomere shortening in obesity and diabetes may be crucial for deepening our understanding of these pathologies, with the ultimate aim of its translational implications. Several studies have shown that telomere shortening is present in patients with metabolic disorders, emphasizing its prognostic value for the onset and progression of these diseases. From this perspective, this article highlights the importance of telomere biology, which can aid in developing new therapeutic options for metabolic disorders.

Keywords: age-related diseases; aging biomarkers; chronic inflammation; insulin resistance; obesity; oxidative stress; senescence; telomere shortening; telomeres; type 2 diabetes mellitus.

Figure 1

Pathophysiological alterations in type 2 diabetes (T2D). Insulin resistance results from β-cell dysfunction, impaired insulin secretion, and reduced glucose uptake due to desensitized insulin receptors. In healthy conditions, insulin binds to its receptor, facilitating glucose entry into cells via glucose transporter type 4 (GLUT4). In T2D, this signaling is impaired. Contributing vascular factors include atherosclerosis (triggered by hyperlipidemia, activation of the polyol pathway, and increased growth factors) and endothelial dysfunction (characterized by reduced nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) activity, as well as activation of angiotensin-converting enzyme (ACE) and protein kinase C (PKC)). Metabolic factors involve chronic inflammation (mediated by nuclear factor kappa B (NF-κB) and inflammatory cytokines) and oxidative stress (driven by superoxide radicals, polyol pathway activity, non-enzymatic glycation, elevated protein kinase C (PKC), and excess oxidant molecules) (created with Biorender.com).

Figure 2

Hyperglycemia-activated signaling pathways. In conditions of high blood glucose, glycolysis intermediates such as glucose-6-phosphate, fructose-6-phosphate, and glyceraldehyde 3-phosphate divert into alternative metabolic routes. These include the polyol pathway (producing sorbitol and fructose, leading to osmotic pressure and cellular damage), the hexosamine pathway (producing uridine 5-diphosphate-N-acetylglucosamine (UDP-GlcNAc), which promotes abnormal phosphorylation of cellular proteins), and the protein kinase C (PKC) pathway, which disrupts cellular signaling. Additionally, methylglyoxal formation leads to the accumulation of advanced glycosylation end-products (AGEPs), contributing to oxidative stress. All pathways increase reactive oxygen species (ROS), which are also generated in mitochondria through the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) after conversion of pyruvate to acetyl coenzyme A (acetyl-CoA), further amplifying oxidative stress and cellular dysfunction (created with Biorender.com).

Figure 3

The molecular mechanisms that link obesity and type 2 diabetes (T2D). Enlarged fat cells in obesity contribute to hypertrophic growth of adipose tissue, promoting inflammation and impairing adipogenesis. Inflammatory responses in adipose tissue arise as preadipocytes adopt pro-inflammatory phenotypes, reducing insulin sensitivity. Impaired differentiation of progenitor cells results in dysfunctional adipogenesis, contributing to insulin resistance. Immune cell infiltration and cytokine release occur as hypertrophic adipocytes attract macrophages and lymphocytes, releasing pro-inflammatory cytokines that disrupt glucose and lipid metabolism. The dysregulation of adipose-derived hormones, or adipokine imbalance [e.g., leptin, resistin, visfatin, angiotensin II, plasminogen activator inhibitor-1 (PAI-1)], promotes insulin resistance in the liver and muscle. Senescence-associated secretory phenotype (SASP) factors amplify inflammation through paracrine signaling. Increased lipolytic activity raises free fatty acids, impairing pancreatic β-cell function. Hypoxia-induced adipocyte dysfunction drives inflammation, fibrosis, and cell death. Exosome secretion from macrophages enhances systemic inflammation, exacerbating insulin resistance and contributing to the pathophysiology of diabesity (created with Biorender.com).

Figure 4

Molecular mechanisms underlying telomere shortening in obesity. Obesity disrupts mitochondrial function in adipocytes, leading to impaired mitochondrial respiratory capacity, reduced adenosine triphosphate (ATP) production, and elevated reactive oxygen species (ROS). Activation of mechanistic target of rapamycin complex 1 (mTORC1) inhibits mitophagy by phosphorylating unc-51-like kinase 1 and 2 (ULK-1, ULK-2). Excess oxidative damage surpasses the antioxidant response, promoting chronic inflammation as adipocytes and preadipocytes release cytokines. Elevated free fatty acids impair insulin receptor signaling and promote insulin resistance. Endothelial dysfunction, marked by reduced nitric oxide (NO), fosters a pro-inflammatory and pro-coagulant environment. Obesity also impairs stem cell function and increases expression of negative regulators of the shelterin complex, destabilizing telomeres. Altered telomerase activity and aberrant lipid peroxidation (e.g., the production of 8-epi-prostaglandin F2α (8-epi-PGF2α)) further accelerate telomere shortening and cellular aging (created with Biorender.com).

Figure 5

Molecular interplay between T2D and telomere dynamics. Legend: Diabetes contributes to telomere shortening through multiple interconnected mechanisms. Elevated oxidative stress, common in T2D, induces DNA damage and promotes cellular senescence. Mitochondrial dysfunction further exacerbates ROS production, while chronic inflammation, mediated by nuclear factor kappa B (NF-κB), amplifies cellular stress. Insulin resistance driven by high blood glucose and fatty acids activates the protein kinase C (PKC) pathway, contributing to endothelial dysfunction and telomerase inhibition. Hyperglycemia causes an imbalance between oxidants and antioxidants, leading to β-cell death and impaired insulin production. Collectively, these alterations trigger progressive telomere shortening, impairing genomic stability and accelerating biological aging in individuals with T2D (created with Biorender.com).

Figure 6

Hyperglycemia-activated metabolic pathways and their by-products contribute to telomere attrition. In type 2 diabetes (T2D), elevated glucose levels activate several harmful metabolic routes. The polyol pathway converts glucose to sorbitol and fructose, causing osmotic stress and cellular dysfunction, while depleting nicotinamide adenine dinucleotide phosphate (NADPH) and reducing glutathione regeneration, weakening antioxidant defenses. The advanced glycation end-product (AGEP) pathway leads to AGE accumulation, which binds to receptors for advanced glycation end-products (RAGE), triggering nuclear factor kappa B (NF-κB) signaling and the release of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These cytokines drive DNA damage and activate senescence markers (p53, p21, p16). The hexosamine pathway, via uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), alters transcription factor activity and insulin signaling, contributing to inflammation and genomic instability. The protein kinase C (PKC) pathway, activated by diacylglycerol from glyceraldehyde-3-phosphate, upregulates pro-inflammatory cytokines and causes endothelial dysfunction through nitric oxide (NO) suppression. All these pathways increase reactive oxygen species (ROS) and promote inflammation, accelerating telomere shortening and cellular aging (created with Biorender.com).