Background: Type 2 diabetes (T2D) represents a growing global health challenge, with its prevalence and associated metabolic complications rising sharply over the past two decades. Although the pathogenesis of T2D is complex and influenced by lifestyle and (micro)environmental factors, genetic constituents have been considered major predisposing factors. Recent literature shows significant individual variations in both the progression of T2D and the efficacy of antidiabetic drugs. These individual variations are expected to emanate from the inherent genetic make-up and potential epigenetic modifications by environmental factors.

Hypothesis: It has been proposed that altered metabolism (including cellular bioenergetic mechanisms) provides protection from T2D. Moreover, several researchers have proposed that proteins regulating cellular bioenergetics, for example, involved in adaptive thermogenesis, represent good targets to counter T2D. Therefore, we thoroughly searched the literature on genetic variability associated with T2D in this review.

Results: We could only find genes involved in (1) insulin secretion (INS, PDX1, ABCC8, KCNJ11, KCNQ1, CDKAL1, IGFBP2) and (2) cellular bioenergetics in insulin-responsive tissues (INSR, IRS, AKT, SLC2A4, TBC1D4, PPP1R3A, LEP, LEPR, ADIPOQ, TCF7L2, PPAR-γ, SLC30A8). Specific attention is given to diverse ethnic populations, in particular Indian subgroups where these genetic factors may display clearer association to T2D.

Conclusion: By emphasizing genetic predispositions, this review highlights the lack of studies on the genetic association of cellular bioenergetics proteins in T2D pathogenesis. It also underscores the potential for early detection, personalized management, and the development of targeted therapies for individuals with T2D across different genetic profiles.