The authors conclude that nuclear DNA and PCNA index cytometric studies are useful parameters to assess the biological behavior of pancreatic lesions producing hyperinsulinemic hypoglycemia.
Because IUF1 is involved not only in linking glucose metabolism to the control of the insulin, but is also a major regulator of beta-cell differentiation during embryogenesis, we propose that impaired expression of IUF1 contributes to beta-cell dysfunction in PHHI by leading to abnormal beta-cell differentiation.
The present study investigated potential defects in the regulation of the insulin gene by glucose in a beta-cell line (NES 2Y) derived from a patient with PHHI.
These findings elucidate for the first time the mechanisms of action of diazoxide and somatostatin in infants with PHHI in whom KATP channels are absent, and provide a rationale for development of new therapeutic opportunities by K+ channel manipulation in PHHI treatment.
Mutations in the SUR1 subunit are associated with familial hyperinsulinism (HI) (MIM:256450), an inherited disorder characterized by hyperinsulinism in the neonate.
R1394H and deltaF1388SUR1, a previously identified PHHI mutation, resulted in no functional channels when coexpressed with Kir6.2 in COS cells, while H125Q, N188S, F591L, T1139M, R1215Q, and G1382SSUR1 generated functional channels in the absence of ATP.
We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation in four patients with a focal form of PHHI.
Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes.
We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1.
We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1.
Our data suggest that IGF inhibition of insulin secretion does not require an intact SUR. rhIGF-I is unlikely to be effective monotherapy for HI, but may provide synergy to inhibit insulin secretion when combined with agents acting via IGF-independent mechanisms.