From our own experience and that in the literature, infants categorized under the phenotype of leprechaunism (Donohue syndrome)17a,49 also have a high probability of having an insulin receptor mutation. In the 44 cases from the literature, 30 were shown to have a mutation (Table 8), and most of the others were reported before the availability of technology to define mutations. Even if there is a bias toward reporting mutations for all these syndromes, these syndromes still appear to be strong predictors of insulin receptor mutations. Given the extremely high mortality in leprechaunism, it is probably best to limit this term to infants or young children less than 2 years of age. For instance, our patient A9 was originally reported as LEP Ark147 but since the patients designated as having leprechaunism usually do not survive infancy, we can avoid ambiguity by designating this patient as an example of the type A syndrome.
Although we have used weight or body mass index as a primary phenotypic distinction between patients with type A and HAIR-AN syndromes, the latter group are further distinguished by the nature of the insulin receptor interaction. In type A patients either insulin binding affinity or tyrosine kinase activity is low and is not increased by dieting or starvation, whereas in obesity and the HAIR-AN syndrome, low receptor binding is reversed by a low calorie diet or starvation; that is, there is a regulated defect in binding.
A more confusing aspect of the nomenclature issue is that 6 of 26 patients classified as type A are male (see Table 6). Further, 19 of 44 patients with leprechaunism are male (see Table 8). On the basis of these data, it would appear that nonobese males with extreme insulin resistance and acanthosis nigricans also form a group that strongly predicts mutations in the insulin receptor. We note, however, just as in females with the HAIR-AN syndrome, that there is a group of obese males who are insulin resistant and have severe acanthosis nigricans. Thus, there is a male type A variant and a HAIR-AN variant.
Extreme insulin resistance is the most characteristic feature of type A and RM syndromes (Figure 3). However, there is heterogeneity in the degree of insulin resistance. Patients A1, A5, A8, A9, and RM2 are similar to each other, and all could have been defined as having leprechaunism since the insulin resistance has been recognized since early childhood. These patients all have α-subunit mutations or homozygosity in the β-subunit mutations which tend to predict a more severe clinical course. By contrast, A3 did not come to medical attention until puberty, when she developed hirsutism and acanthosis nigricans. Upon investigation she was found to have relatively normal glucose tolerance with basal and 2-hour insulin values at least 10 times above normal. Over the past 30 years she has maintained essentially the same glucose and insulin levels. This patient has a heterozygous mutation in the β subunit, which appears to predict a less severe clinical course.
A more paradoxical situation is the α-subunit mutation in type A patients who are of normal height and the α-subunit mutation in RM2, who was severely growth retarded. While a variety of hypotheses have been suggested, none really clarifies this situation83.
Hyperandrogenism and polycystic ovarian syndrome are more striking features of the type A and RM syndromes and of leprechaunism. When these disorders were first described, it became clear that extreme endogenous or exogenous hyperinsulinemia was a potent drive for the ovary to increase testosterone production and become polycystic. In the type A patients in the current study, extreme measures such as total or partial removal of the ovaries have been carried out to control the hyperandrogenism and the massively enlarged ovaries (see Table 2). Why insulin is so potent in stimulating the ovaries when the insulin receptor is defective has never been explained completely. The idea that insulin in high concentration is acting through the IGF-1 receptor has been suggested but never validated. The fact remains that ovarian enlargement and the degree of hyperandrogenism correlate with the degree of hyperinsulinemia.
Previously, the more common form of polycystic ovarian syndrome was thought to be associated with congenital or acquired abnormalities of the ovary, which was associated with gonadotrophin dysregulation. However, more recently insulin resistance has been recognized as an important pathogenic feature of the common form of polycystic ovarian syndrome. This is especially important because insulin-sensitizing drugs cause amelioration of the syndrome19.
The very high morbidity and mortality of the type A and RM syndromes and of leprechaunism are clear from our own long-term follow-up of patients and from the literature review (see Tables 6, 7, and 8). It is apparent that current treatment is unsatisfactory.
The use of U500 insulin has been helpful because it permits a reduction in the volume of insulin given. This is especially important when several thousand units are given daily. While administration of large doses of insulin does not alleviate the development of diabetic complications, this form of therapy is sometimes effective in inhibiting the extreme polyuria and glycosuria that are common in these patients. Further, ketoacidosis can occur with infections and requires extreme doses of insulin.
The insulin-sensitizing drugs metformin and the glitazones may have a role in the treatment of these patients, but their effect is limited.
Two additional therapeutic approaches have been tried. The first is the treatment of a small group of patients with IGF-1 with some reported benefit63,68,90. The idea is that there may be some metabolic effect through the IGF-1 receptor. However, we administered large doses of IGF-1 to patient RM2 without any noticeable benefit. Similar results were observed by others5. The case of this patient was particularly instructive in that he had a unique mutation in the insulin receptor that did not bind insulin71. We suspect that any benefit seen with IGF-1 in milder disorders of the insulin receptor was related to IGF-1 acting though the insulin receptor.
We are especially excited by preliminary results obtained in RM-PAL and RM-PAF using recombinant human methionyl-leptin. Our early results have demonstrated a significant reduction in blood glucose over 10 months, and a more extensive trial in these and in type A patients is now underway13a.
Two of our patients are especially remarkable; A3 has maintained normal glucose tolerance over the 30 years of follow-up and confirms that in any form of non-insulin dependent diabetes, insulin resistance is constant and normal blood glucose values persist if the endogenous insulin response is maintained. The case of Patient A5 is particularly perplexing in that for a number of years she was treated with large doses of insulin with poor control of diabetes, but in the past 5 years she has maintained normal fasting glucose values on metformin alone. This patient continues to have very high endogenous insulin levels.
The various syndromic forms of insulin resistance are uncommon but have been important in providing an understanding of the etiologic basis of insulin resistance, which is central to type 2 diabetes. As mentioned, leprechaunism and the type A and RM syndromes predict mutations of the insulin receptor as the etiologic bases of resistance. RM syndrome is characterized by unexplained growth retardation, which is different from all the other syndromes.
The type B form of insulin resistance differs by the presence of an autoantibody against the insulin receptor and usually an underlying autoimmune disorder3. The congenital and acquired forms of lipodystrophy differ by low fat mass, very low leptin concentrations, and moderate to severe hypertriglyceridemia4. These syndromes of extreme insulin resistance are similar in that they are all characterized by acanthosis nigricans, hyperandrogenism, and a very high morbidity and mortality at an early age (Table 9).
We have also pointed out the overlap of these syndromic forms of insulin resistance and the more common forms of polycystic ovarian syndrome and its more severe form known as the HAIR-AN syndrome19,69. Further, while there is a female preponderance for all these syndromes, there are also male variants in each of them.
The type A and RM syndromes and leprechaunism represent the first monogenic defects in insulin action, and, therefore, provide the basis of our initial understanding of the etiology of a defect in insulin action. Further, these and related syndromes of extreme insulin resistance were the first examples of the link between insulin resistance and the hyperandrogenic states that characterized common forms of the polycystic ovarian syndrome. Perhaps the concept that insulin resistance is such a key feature in common forms of polycystic ovarian syndrome would not have been recognized without the lessons learned from these rare syndromes19,27,72.
The cases of the patients described here also provide other important lessons in our quest to understand the molecular basis of insulin resistance and type 2 diabetes. Even when the phenotype of the patients predicts the molecular target, that is, the insulin receptor, there is considerable heterogeneity. This heterogeneity of phenotype is possibly related to genetic background or other environmental interactions. This clinical approach, however, will remain an important companion of genetic technology in elucidating the molecular targets of diseases.
The long-term follow-up data reported here make it clear that the morbidity and mortality of these patients are high (Table 10) and that therapy is unsatisfactory. In 200265 we showed that leptin, a novel therapeutic agent that is a hormone/cytokine produced by fat cells, ameliorates the insulin resistance of the various forms of lipodystrophic diabetes. Preliminary data obtained in 2 of our patients with RM syndrome have demonstrated that leptin may be effective in this syndrome. Although the response to leptin is only partial, it is the best response we have seen thus far (13a).
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