Insulin resistance and impaired insulin secretion due to phosphofructo-1-kinase-deficiency in humans

The etiology of non-insulin-dependent diabetes mellitus (NIDDM) is usually explained as a combination of peripheral insulin resistance and impaired be ta-cell Function. Phosphofructo-1-kinase (PFK1) is a rate limiting enzyme i n glycolysis, and its muscle subtype (PFK1-M) deficiency leads to an autoso mal recessively inherited disorder known as glycogenosis type VII or Tarui' s disease. It was evaluated whether PFK1-M deficiency leads to NIDDM in hum ans. A core family of four was evaluated for PFK1-M deficiency by DNA- and enzym e-activity-analyses. All members underwent oral and intravenous glucose tol erance test (oGTT/ivgtt), as well as an insulin sensitivity test (IST) usin g octreotide. Results: Father (46 years, BMI 22.4 kg/m(2)) and older son (19 years, BMI 1 7.8 kg/m5) showed homozygous PFK1-M deficiency, while mother (47 years, BMI 28.4 kg/m5) and younger son (13 years, BMT 16.5 kg/m5) were shown to be he terozygously PFK1-M-deficient on enzyme activity levels. DNA analysis revea led an exon 5-missense-mutation at one allele of all four members, and an e xon 22-frameshift-mutation at the other allele of the two homozygously affe cted individuals. By oGTT the father showed impaired glucose tolerance, and the mother clinical diabetes. By ivGTT both parents and the older son had a decreased first phase insulin secretion, and a diminished glucose disappe arance rate. The IST showed marked insulin resistance in both parents and t he older son, and moderate resistance in the younger son, previously not de scribed. Conclusion: PFK1-M-deficiency leads to a metabolic state typical for early NIDDM in homozygously affected humans, especially concerning insulin resist ance and loss of first phase beta-cell insulin secretion, and may contribut e to the manifestation of NIDDM in a subgroup of patients.