Insulinresistenz und Krebs: Wie belastbar ist der Zusammenhang?

Insulin resistance (IR) is traditionally viewed within the context of type 2 diabetes. However, it increasingly appears to represent a broader systemic metabolic risk state with potential relevance for carcinogenesis. Chronic hyperinsulinemia can activate insulin-like growth factor-1-dependent pathways, including phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin and mitogen-activated protein kinase signaling, promoting cellular proliferation while limiting apoptosis. At the same time, IR is closely linked to oxidative stress, chronic low-grade inflammation, and epigenetic alterations, together shaping a tumor-promoting microenvironment. Epidemiological studies report consistent associations between IR and increased cancer risk, particularly for endometrial, liver, and colorectal cancers. Yet causality remains uncertain and likely varies by tumor type. Notably, metabolic dysfunction may also occur in individuals with normal body mass index (BMI), underscoring the limitations of BMI-based risk assessment. Unlike previous reviews that primarily focused on individual mechanisms or epidemiological associations, this review examines IR as a systemic metabolic risk state by integrating molecular, epidemiological, biomarker-based, and prevention-oriented perspectives. Particular emphasis is placed on strategies for earlier risk identification using integrated biomarker approaches, including fasting glucose, homeostatic model assessment of insulin resistance,

Insulin resistance (IR) describes impaired hormone signaling that triggers compensatory homeostatic responses resulting in hyperinsulinemia, increased accumulation of fatty substrates, lipotoxicity, oxidative stress, inflammation, cell death and fibrosis in target tissues. These processes ultimately lead to organ dysfunction and predispose certain individuals to various types of cancer. In this context, we will review the molecular pathogenesis and clinical significance of IR, its role in 'metaflammation', and the damage caused by IR in the pancreas, cardiovascular system, liver, and kidneys. Additionally, we will discuss principles of drug treatment for IR and outline a research agenda in this field.

<h4>Background</h4>Insulin resistance has been considered a metabolic disorder related to obesity, metabolic syndrome, and type 2 diabetes mellitus. Growing evidence points to possible interactions between insulin resistance and hyperinsulinemia and the biological aging process and age-related non-communicable diseases, like cardiovascular disease, neurodegenerative disorders, sarcopenia, frailty, adipose tissue dysfunction, chronic kidney disease, and liver disease. Most published associations lack causality, and some biological aging mechanisms may also independently increase the risk for both insulin resistance and chronic disease.<h4>Aim</h4>In this narrative review, we summarize bidirectional connections between insulin resistance, compensatory hyperinsulinemia, aging biology, and age-related non-communicable diseases and the quality of existing data.<h4>Methods</h4>We performed a structured narrative literature review for mechanistic, translational, omics, epidemiologic, and intervention studies on the connection between insulin resistance and biological mechanisms of aging and chronic disease.<h4>Results</h4>Mechanisms of age-related disease that may be affected by insulin resistance include insulin/IGF-1 signaling disruption, hyperinsulinemia, mitochondria dysfunction, oxidative stress, endothelial dysfunction, adipokine imbalance, chronic low-grade inflammation, cell senescence, ectopic lipids accumulation, AGE-RAGE signaling, and autophagy impairment. Aging mechanis