Fatty acids and physical activity are critical for β-cell mass and insulin sensitivity: Pathways to T2D and prevention

Existing mathematical models investigating the progression of type 2 diabetes (T2D) over time primarily focus on glucose, insulin, $\beta$-cell mass, and other related factors, while often omitting fatty acids (FA) as an explicit variable—despite FA being a major energy source for the body. There exists a complex network of dynamical interactions among glucose, insulin, FA, and $\beta$-cell mass. To gain deeper insights into the metabolic dynamics and pathophysiology of T2D, it is essential to incorporate FA into such models.

In this paper, we extend the classic Topp’s $GI\beta$ model by explicitly incorporating FA and exploring its interactions with glucose, insulin, and $\beta$-cell mass. A new formula for insulin sensitivity ($S_I$) is proposed to better capture the impaired effect of FA on $S_I$, enabling the exploration of diabetes development pathways and strategies for prevention or delay. Model simulations align well with clinical data and successfully replicate key characteristics of T2D progression, including declining $S_I$, reduced $\beta$-cell mass, a sedentary lifestyle, and excessive dietary intake. Our results demonstrate a strong positive correlation between glucose and FA levels, indicating that elevated FA is associated with increased glucose concentrations. Model analysis shows that FA levels in diabetic subjects rise significantly as a result of T2D development. Numerical analyses indicate that maintaining adequate physical activity or reducing dietary excess effectively preserves $S_I$ and $\beta$-cell mass, thereby reducing the risk of developing T2D.

Most notably, our detailed simulations reveal a striking pattern: in healthy and non-diabetic individuals, FA levels consistently remain below glucose levels across their lifespan. In contrast, in individuals with T2D, FA levels initially remain lower but begin to increase sharply and tangle with glucose levels, and then surpass glucose concentrations near the time of $\beta$-cell failure. These patterns suggest that elevated FA may play a contributory role in increasing glucose levels, reducing insulin sensitivity, and ultimately leading to hyperglycemia. Our findings support the notion that glucotoxicity and lipotoxicity accelerate $\beta$-cell decline, impair insulin secretion, and drive T2D progression. Elevated FA thus emerges not only as a contributing pathway but also as a potential biomarker for monitoring disease development. Furthermore, the observed relationship between glucose and FA levels seems suggesting a quantitative marker that could be used to track progression toward T2D.