AKT2 – Type 2 Diabetes Mellitus

AKT2 pathogenic variants cause autosomal dominant insulin resistance and early-onset diabetes mellitus. A heterozygous missense mutation, c.821G>A (p.Arg274His), segregates with severe insulin resistance and diabetes in a multi‐generation family (3 affected relatives) (PMID:15166380).

Subsequent population studies identified a low-frequency inactivating variant, c.148C>A (p.Pro50Thr), enriched in Finnish individuals (1.1% frequency) that associates with increased fasting insulin, reduced insulin sensitivity and elevated type 2 diabetes risk in up to 39 339 normoglycemic subjects and exome‐array cohorts (PMID:28341696; 20 carriers) and causes a 39.4% reduction in whole-body glucose uptake on PET imaging (PMID:29141982).

Variant spectrum is dominated by rare heterozygous missense alleles in the pleckstrin homology domain that impair kinase activity and insulin signaling. Biochemical analyses demonstrate dominant-negative disruption of wild-type AKT2 signaling in cultured cells and reduced phosphorylation of downstream substrates AS160 and GSK3β in variant carriers.

Genetic association studies of common AKT2 SNPs in large case–control series (n = 2 200; n = 742 vs 743) found no significant relationships with diabetes or metabolic traits (PMID:17327441; PMID:21518566).

Mechanism of pathogenicity is haploinsufficiency/partial loss of function leading to impaired insulin signaling and glucose uptake across multiple tissues. Rescue of metabolic phenotypes in cellular and animal models by PI3K/AKT activation highlights functional concordance.

AKT2 variants underlie rare monogenic diabetes forms and contribute modestly to population risk; genetic testing is recommended in early-onset insulin resistance.

References

• Science (New York, N.Y.) • 2004 • A family with severe insulin resistance and diabetes due to a mutation in AKT2. PMID:15166380
• Diabetes • 2017 • A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. PMID:28341696
• Diabetes • 2018 • A Partial Loss-of-Function Variant in AKT2 Is Associated With Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A Genotype-Based Callback Positron Emission Tomography Study. PMID:29141982
• Diabetes • 2007 • Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes. PMID:17327441
• Chinese medical journal • 2011 • Contribution of the Akt2 gene to type 2 diabetes in the Chinese Han population. PMID:21518566

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