PKN2 and Type 2 Diabetes Mellitus

Recent genetic studies evaluating the association of PKN2 with type 2 diabetes mellitus (MONDO_0005148) have yielded conflicting results. Three independent investigations in European, African American, and East Asian cohorts failed to demonstrate significant associations with PKN2 variants, with several analyses explicitly noting no support for an association (PMID:18437351, PMID:18443202, PMID:19892838).

The genetic evidence has been derived from large-scale case‑control studies where thousands of participants were evaluated, yet no segregation or consistent variant signal was observed. As such, no Mendelian inheritance pattern could be determined, and the complex genetic architecture of type 2 diabetes has further obscured any clear role for PKN2. There were no specific familial segregation data or valid HGVS variant strings available for PKN2 from the studies.

In contrast, functional studies provide moderate support for a role of PKN2 in cellular pathways that are potentially relevant to diabetes pathogenesis. Experimental models using gene knockout and replacement strategies have demonstrated that full‑length PKN2 is critical for embryonic viability and proper cell survival, with caspase‑related modifications affecting apoptotic responses (PMID:21499899). Additionally, investigations into endothelial cell signaling pathways implicate PKN2 in processes such as cell migration and stress fiber formation (PMID:16966330).

However, despite these functional insights, the lack of robust genetic association weakens the overall evidence linking PKN2 to type 2 diabetes mellitus. The experimental data support a plausible biological mechanism, but they do not compensate for the failure to demonstrate a genetic correlation in multiple well‑powered studies. Further research might uncover additional insights, though current evidence does not favor a diagnostic role for PKN2 in type 2 diabetes.

Key take‑home: While PKN2 plays important roles in cellular survival and signaling, its genetic involvement in type 2 diabetes remains disputed, limiting its immediate clinical utility in diagnostic decision‑making.

References

• Diabetologia • 2008 • Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT study). PMID:18437351
• Diabetes • 2008 • Association analysis in african americans of European-derived type 2 diabetes single nucleotide polymorphisms from whole-genome association studies. PMID:18443202
• The Journal of clinical endocrinology and metabolism • 2010 • Polymorphisms identified through genome-wide association studies and their associations with type 2 diabetes in Chinese, Malays, and Asian-Indians in Singapore. PMID:19892838
• Mammalian genome : official journal of the International Mammalian Genome Society • 2011 • Functional PAK-2 knockout and replacement with a caspase cleavage-deficient mutant in mice reveals differential requirements of full-length PAK-2 and caspase-activated PAK-2p34. PMID:21499899
• The Journal of biological chemistry • 2006 • Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of Nck and activation of Fyn leading to SAPK2/p38 activation and endothelial cell migration in response to VEGF. PMID:16966330

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