Non-insulin-dependent diabetes mellitus (
NIDDM) is caused by peripheral
insulin resistance and impaired beta cell function.
Phosphofructo-1-kinase (PFK1) is a rate-limiting
enzyme in glycolysis, and its muscle subtype (PFK1-M) deficiency leads to the autosomal recessively inherited
glycogenosis type VII
Tarui's disease. It was evaluated whether PFK1-M deficiency leads to alterations in
insulin action or secretion in humans. A core family of four members was evaluated for PFK1-M deficiency by
DNA and
enzyme-activity analyses. All members underwent oral and intravenous
glucose tolerance tests (oGTT and ivGTT) and an
insulin-sensitivity test (IST) using
octreotide.
Enzyme activity determinations in red blood cells showed that the father (46 yr, body mass index [BMI] 22. 4 kg/m2) and older son (19 yr, BMI 17.8 kg/m2) had a homozygous, while the mother (47 yr, BMI 28.4 kg/m2) and younger son (13 yr, BMI 16.5 kg/m2) had a heterozygous PFK1-M deficiency.
DNA analyses revealed an exon 5 missense mutation causing missplicing of one allele in all four family members, and an exon 22 frameshift mutation of the other allele of the two homozygously affected individuals. The father showed
impaired glucose tolerance, and the mother showed
NIDDM. By ivGTT, both parents and the older son had decreased first-phase insulin secretion and a diminished
glucose disappearance rate. The IST showed marked
insulin resistance in both parents and the older, homozygous son, and moderate resistance in the younger son. PFK1-M deficiency causes impaired insulin secretion in response to
glucose, demonstrating its participation in islet
glucose metabolism, and peripheral
insulin resistance. These combined metabolic sequelae of PFK-1 deficiency identify it as a candidate gene predisposing to
NIDDM.