Linda A. Morrow

Prevalence of Mutations in the Insulin Receptor Gene in Subjects With Features of the Type A Syndrome of Insulin Resistance

Mutations of the insulin receptor gene are a cause of the type A syndrome of extreme insulin resistance. This study assessed the prevalence of such mutations in women with clinical features of the type A syndrome including ovarian hyperandrogenism, moderate-to-severe degrees of insulin resistance, and acanthosis nigricans. We studied 22 unrelated women with insulin resistance (fasting insulin >300 pM [50 μU/ml] and/or peak during an oral glucose tolerance test (OGTT) > 1,800 pM [300 μU/ml]), acanthosis nigricans, and the polycystic ovary syndrome (hyperandrogenemia, oligoamenorrhea, and hirsutism). Two insulin-resistant probands with congenital generalized lipodystrophy and one male proband with severe insulin resistance also were included in the study. Southern blotting experiments were performed to exclude gross gene deletions, insertions, or rearrangements. Exons 2–22 of the insulin receptor gene were polymerase chain reaction (PCR) amplified from genomic DNA and screened for nucleotide variation using single-strand conformation polymorphism (SSCP). No nucleotide variation between study subjects was detected in exons 4–6, 10–12, 15, 16, 18, 19, or 21. Sequencing of amplified DNA revealed that SSCP variants in exons 2, 3, 8, 9, and 17 corresponded to known silent polymorphisms within the coding region. Variants in exons 2, 9, 13, and 14 were caused by novel silent polymorphisms; variants in exons 7 and 22 were caused by nucleotide substitutions in flanking introns. One proband was found to have a heterozygous point mutation in exon 20 (CGG→CAG, Arg1174→Gln) that involves the intracellular receptor β-subunit. Gin1174 is a novel mutant of the insulin receptor tyrosine kinase domain and is a likely cause of dominantly inherited insulin resistance. The mutation was present in an affected sister but was absent in the unaffected mother and 64 normal alleles. Two paternal aunts also are reportedly affected. The results of this study suggest that mutations at the insulin receptor locus are uncommon in insulin-resistant women with acanthosis nigricans and ovarian hyperandrogenism.

Insulin-like growth factor I (rhIGF-I) as a therapeutic agent for hyperinsulinemic insulin-resistant diabetes mellitus

Insulin resistance is one of the major underlying abnormalities in NIDDM, however, its pathophysiologic mechanisms are not well understood. Many clues about the mechanisms of insulin action have come from patients with the most severe forms of insulin resistance, including those with genetic abnormalities in the insulin signal transduction cascade. We used rhIGF-I as a probe to differentiate insulin and IGF-I action and to study the therapeutic potential of IGF in states of insulin resistance. To date, we have studied six subjects with varying phenotypes of severe insulin resistance but without mutations in the insulin receptor itself. All subjects underwent baseline physiologic monitoring to quantitate carbohydrate tolerance, insulin secretion, and insulin action prior to receiving rhIGF-I at 100 micrograms/kg body wt s.c. bid for 1 month with interval testing of glycemic control and insulin sensitivity. None of the six subjects noted significant side effects from the rhIGF-I. Four of the six subjects had overt diabetes during control testing; three of these subjects demonstrated normalization of fasting and postprandial blood glucose concentrations during rhIGF-I administration on no other therapy. In the fourth patient, insulin requirements and fasting hypertriglyceridemia decreased without improvement in glycemic control. The two subjects with normal glucose tolerance (two sisters with congenital lipodystrophy) maintained normal glucose tolerance at dramatically lower insulin levels and had a dramatic reduction in triglyceride levels. The efficacy of IGF-I continued to increase over the duration of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Epinephrine on Insulin Secretion and Action in Humans: Interaction With Aging

This study was designed to define the effects on glucose metabolism of small increases of plasma EPI, comparable to increases observed during physiological sympathoadrenal activation. This study was also designed to determine the effects of EPI on glucose metabolism in older adults, in whom changes in adrenergic responsiveness of several tissues were described. Tolbutamide-boosted IVGTTs were performed during intravenous infusions of saline (control) or EPI at 2.7, 5.5, and 10.9 mmol/min to achieve physiological levels of EPI in 7 young subjects (19–26 yr of age) and 7 old subjects (62–75 yr of age), all with a normal screening OGTT. IVGTT results were analyzed to determine the AIR and with the minimal model method of Bergman to determine SI and SG. A significant fall was observed in AIR, SI, and SG for all subjects, even with the lowest dose of EPI, which resulted in only a two- to threefold increase in plasma EPI. Older subjects had a delayed recovery from hyperglycemia during the EPI infusions, although we detected no significant differences between the young and old subjects in the ability of EPI to alter either acute phase insulin secretion or insulin action. In contrast, the impairment of SG by EPI appeared to be greater in the elderly. We conclude that small increases of plasma EPI can significantly affect determinants of glucose tolerance in both young and old people.