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Clinical Course of Genetic Diseases of the Insulin Receptor (Type A and Rabson-Mendenhall Syndromes): A 30-Year Prospective

Musso, Carla MD; Cochran, Elaine MSN, CRNP; Moran, Stephanie Ann MD; Skarulis, Monica C. MD; Oral, Elif Arioglu MD; Taylor, Simeon MD, PhD; Gorden, Phillip MD

doi: 10.1097/01.md.0000133625.73570.54
Article

Abstract: The interaction of insulin with its cell surface receptor is the first step in insulin action and the first identified target of insulin resistance. The insulin resistance in several syndromic forms of extreme insulin resistance has been shown to be caused by mutations in the receptor gene.

We studied 8 female patients with the type A form of extreme insulin resistance and 3 patients (2 male and 1 female) with the Rabson-Mendenhall syndrome and followed the natural history of these patients for up to 30 years. The 11 patients ranged in age from 7 to 32 years at presentation. All 11 patients had extreme insulin resistance, acanthosis nigricans, and hyperandrogenism in the female patients, and all but 1 were of normal body weight. This phenotype strongly predicts mutations in the insulin receptor: of the 8 patients studied, 7 were found to have mutations. Similar results from the literature are found in other patients with type A and Rabson-Mendenhall syndromes and leprechaunism.

The hyperandrogenic state resulting from hyperinsulinemia and insulin resistance in these patients was extreme: 6 of 8 patients had ovarian surgery to correct the polycystic ovarian syndrome and elevation of serum testosterone. By contrast, a larger group of insulin-resistant patients who were obese with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) did not have a high probability of mutations in the insulin receptor.

The morbidity and mortality of these patients were high: 3 of 11 died, 9 of 11 were diabetic and 1 had impaired glucose tolerance, and 7 of 9 patients had 1 or more severe complication of diabetes. Our literature review revealed that the mortality of leprechaunism is so high that the term leprechaunism should be restricted to infants or young children under 2 years of age.

Analogous to patients with the common forms of type 2 diabetes, these patients had a heterogeneous course. In 2 patients who were able to maintain extremely high endogenous insulin production, the fasting blood glucose remained normal even though post-glucose-challenge levels were elevated. Most patients, however, required large doses of exogenous insulin to ameliorate the severe hyperglycemia. Preliminary results of a recent study suggest that recombinant leptin administration may benefit these patients with severe insulin resistance.

From National Institute of Diabetes and Digestive and Kidney Diseases (CM, EC, SAM, MCS, EAO, ST, PG), National Institutes of Health, Bethesda, Maryland; Bristol-Myers Squibb (SAM, ST), Princeton, New Jersey; and Department of Internal Medicine (EAO), Division of Endocrinology and Metabolism, University of Michigan, Ann Arbor, Michigan.

Address reprint requests to: Carla Musso, NIDDK/NIH, Bldg 10; Rm 8D20, 10 Center Drive, MSC 1770, Bethesda, MD 20892-1770. Fax: 301-402-0573; e-mail: carlam@intra.niddk.nih.gov.

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INTRODUCTION

In 1976 we described 6 patients with extreme insulin resistance that comprised 2 distinct syndromes40. These syndromes were described in the context of the emerging concept that the insulin receptor is a cell surface protein and therefore might be a distinct disease target. Further, it was shown that insulin binding to the cell surface receptor was reduced in these patients. One syndrome, referred to as type B3, was characterized by the presence of an autoantibody against the insulin receptor. The other syndrome, called type A, was later shown to be predominantly due to mutations in the receptor40.

In 2002 we reported on the natural history of patients with the type B form of insulin resistance3. In addition to the distinct phenotype that these patients present, the diagnosis is confirmed by the demonstration of the autoantibody in their serum.

The phenotype of the type A (OMIM 147670*) form includes extreme insulin resistance, acanthosis nigricans, hirsutism, and polycystic ovarian disease in a patient who is usually not obese. However, there is no distinctive serum marker, and, therefore, categorization of these patients is more difficult. The Rabson-Mendenhall68a (RM) syndrome (OMIM 262190) is similar, with the focal point of the disease based on a presumed abnormality of the insulin receptor92.

In the present study, 1) we describe the natural history of 8 patients, followed from 6 to 30 years, that we have studied extensively and categorized as type A insulin resistance. Similarly, we describe 3 patients with the RM syndrome. 2) We compare and contrast these patients to those described in the literature, where, in general, there is no long-term follow-up available. 3) We present a paradigm for describing patients whom we and others have characterized with the term "leprechaunism" (OMIM 246200) and "hyperandrogenism, insulin resistance, and acanthosis nigricans" (HAIR-AN).

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METHODS

Patients

The initial 3 patients described as having type A syndrome of insulin resistance were characterized by insulin resistance, acanthosis nigricans, and hyperandrogenism, and were nonobese. We referred to these patients as A1, A2, and A340. Subsequently, Patient A2, a Papago Indian, was thought to be an early-onset type 2 diabetic from a population with a high prevalence of diabetes, so she was no longer considered to be an example of type A and was not included in this report. Thus, the 8 patients included in this report have been characterized by us as examples of type A insulin resistance.

The 3 patients with severe insulin resistance, acanthosis nigricans, severe growth retardation, and abnormal dentition are described as examples of the RM syndrome. In the original description, other features were mentioned but were not consistently seen in other patients92.

These 11 patients have been reported in the past (Table 1). In the present study we followed the clinical history of these patients for up to 30 years. All patients were enrolled in clinical research protocols approved by the National Institute of Diabetes, Digestive and Kidney Disease Internal Review Board.

TABLE 1

TABLE 1

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Data Collection

All patients were studied at the National Institutes of Health (NIH) over the period of this report. Some of the patient data described have been previously published. Additional health information was obtained retrospectively by reviewing medical records. For 1 patient (A3), current health status was obtained in a telephone interview.

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Laboratory Tests

All patients had routine hematologic and biochemical tests on their initial examination and at multiple subsequent time points. They underwent standard glucose tolerance tests to measure glucose and insulin levels.

Glucose, cholesterol, high-density lipoprotein, and triglycerides levels were determined by standard methods using automated equipment (Boehringer Mannheim, Indianapolis, IN). Hemoglobin A1c was determined by high-pressure liquid chromatography (Bio-Rad, Hercules, CA). Insulin was determined by immunoassays. Testosterone was determined by standard methods at the Mayo Clinical Laboratory.

Insulin binding affinity and tyrosine kinase activity of the insulin receptor were determined for most patients23. Most of these patients demonstrated mutations in the insulin receptor87.

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Literature Review

We searched the PubMed electronic database (National Library of Medicine, Bethesda, MD) using the following MeSH headings: leprechaunism, Rabson-Mendenhall, and type A syndromes. We also searched manually for articles using the references cited in publications retrieved during the electronic database search.

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RESULTS

General Features of the Type A Syndrome

The 8 patients (all female) initially and subsequently designated as having the type A form of insulin resistance were characterized on the basis of clinical phenotype. All 8 had acanthosis nigricans and each had evidence of hyperandrogenism manifested by hirsutism, increased serum testosterone, virilization, and polycystic ovarian disease. At presentation all 8 type A patients had normal or near normal body mass index (Table 2). All 8 had extreme insulin resistance manifested by hyperinsulinemia or severe resistance to exogenous insulin (Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

The 8 female patients presented to the NIH between the ages of 12 and 32 years. Four were white, 3 were Hispanic-Caucasian, and 1 was African-American (see Table 1).

Six of the 8 patients (Patients A1, A3, A5, A6, A8, A9) were shown to have insulin receptor mutations that could account for their extreme insulin resistance. One patient (Patient A7) who was evaluated thoroughly was found to have an uncommon polymorphism that was not functionally significant26, and Patient A4 was not evaluated for a mutation (Table 4).

TABLE 4

TABLE 4

Six of the 8 had low binding to the insulin receptor and low tyrosine kinase activity of the receptor. One patient (Patient A6) had normal binding and normal tyrosine kinase activity, and 1 patient (Patient A7) had normal binding and low tyrosine kinase activity in peripheral blood monocytes23 (see Table 4).

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General Features of the Rabson-Mendenhall Syndrome

The 3 patients with RM syndrome were characterized on the basis of clinical phenotypes. All presented between age 7 and 9 and demonstrated extreme insulin resistance, acanthosis nigricans, extreme growth retardation and abnormal dentition. RM2, the only subject with RM studied extensively, was found to have low insulin binding to the insulin receptor, low tyrosine kinase activity and a mutation in the insulin receptor that could account for the insulin resistance71.

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Selected Case Reports

Case A1

Patient A1, an African-American female, was noted since birth to have increased body hair and clitoromegaly. At age 12 years, she was diagnosed as a diabetic in a routine analysis at school. She was treated with high doses of insulin (30,000 U/d) and her glucose levels were in the range of 400 mg/dL. She was admitted to the NIH in 1972. At presentation her physical examination revealed a tall, thin, hirsute girl with masculine habitus and coarse features. She also had prominent acanthosis nigricans on the neck and in the axilla. A gynecogram revealed bilaterally enlarged ovaries consistent with polycystic ovarian syndrome. Menses had not yet begun. She was among the initial patients designated as having type A syndrome40.

Over the years, she developed acute and chronic diabetic complications, nephropathy, hypertension, autonomic neuropathy (gastroparesis, diarrhea), peripheral neuropathy, retinopathy (left eye enucleation and panphotocoagulation of the right eye), and abdominal abscesses from the insulin pump. The pump was used to accommodate the very large volume of insulin required. In 1984, at age 24 years, she had a bilateral oophorectomy for massively enlarged ovaries and hyperandrogenism. Testosterone levels were very high (440-667 ng/dL) and after surgery decreased to the normal range. Her last admission to the NIH was in 1988 to receive treatment for proliferative retinopathy. Her nephropathy was rapidly progressive with proteinuria, edema, and nephrotic syndrome. She was followed for 5 years on hemodialysis.

She died in 1993 at age 33 years due to the vascular complications of nephropathy and end-stage renal disease.

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Case A3

Patient A3, a white female, presented to the NIH at age 13 years for the evaluation of acanthosis nigricans over the back of her neck and in both axillae. Hirsutism was noted over the chin, face, back, chest, and abdomen. She had acne on her upper back. She had impaired glucose tolerance (fasting glucose, 65 mg/dL and postprandial, 182 mg/dL) and marked hyperinsulinemia (fasting, 300 μU/mL and postprandial, 1000-2000 μU/mL)40.

A laparoscopy revealed small bilateral polycystic ovaries. In 1988, at the age of 26 years, she attempted to conceive and failed several cycles of clomiphene therapy, but subsequently delivered a healthy baby via cesarean section after a normal full-term pregnancy. She used oral contraceptive pills from 1992 until 1996 with withdrawal menses.

In 1999, at the age of 39 years, her plasma glucose was in the normal range (fasting, 92 mg/dL and postprandial, 125 mg/dL) and baseline insulin levels were still high (fasting, 170 μU/mL) (Figure 1). At the age of 43 years in 2003, she reported in a telephone conversation to be doing well, and she was off diabetic medication.

FIGURE 1

FIGURE 1

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Case A5

Patient A5, a Hispanic female, had darkened skin by age 3 years and was tall for her age compared with siblings and peers. At age 8 years her habitus was somewhat masculine with muscular development. She had acanthosis nigricans affecting all the body creases, and had developed pubic and axillary hair growth and clitoromegaly10.

At age 10 years, her fasting blood glucose values were normal (70 and 83 mg/dL) but plasma insulin levels were extremely high (885 and 904 μU/mL). She had an ovarian wedge resection at age 15 years and underwent total hysterectomy at age 28 years. She had a 14-cm cystoadenoma removed from 1 ovary. Following this procedure her androgen levels fell to the normal range.

When she was first seen at the NIH in 1980 at age 17 years, her fasting blood glucose was 239 mg/dL and was treated with high doses of insulin (1500-3000 units of U500) given by infusion pump. Over the years, the insulin requirement diminished, and since 1997 she has used only metformin with excellent control of her blood glucose. Her last HbA1c (August 2003, at age 40 years) was 5.2% on a dose of 1350 mg of metformin per day (Figure 2).

FIGURE 2

FIGURE 2

She had rapidly progressive diabetic proliferative retinopathy from July to October 1997 resulting in blindness, without nephropathy or neuropathy. Although the retinopathy was diabetic in nature the rapidity and severity was unusual. Throughout her course, she had recurrent infections including pyelonephritis, abdominal abscesses from insulin pump therapy, and multiple episodes of pseudomonas otitis externa.

A noteworthy aspect of her history was the development of 2 different malignancies: in 1987 at age 24 years, she developed a carcinoma of the left breast treated by modified radical mastectomy. This was followed by a prophylactic right mastectomy in 1988. In 1995 she developed thyroid papillary carcinoma, treated by thyroidectomy and I-131 and followed by suppressive doses of thyroid hormone.

One older sister (Patient A8) had the same insulin receptor mutation (see Table 4), 1 brother and 1 sister had seizure disorders, and 2 other siblings were healthy.

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Case A8

Patient A8 was the older sister of Patient A5. She was an obese and hirsute infant with acanthosis nigricans and clitoromegaly. Her general habitus was somewhat masculine. At age 12 years she was diagnosed with diabetes mellitus and insulin was started although doses up to 700 U daily had no effect on blood and urine glucose. The addition of phenformin decreased the urinary glucose loss but not the blood glucose values.

At age 15 years her body mass index was 20, and she began estrogen therapy to facilitate the development of female secondary sexual characteristics. Shortly thereafter, however, she discontinued all medications. At age 17 years, laparoscopy was performed to evaluate dysmenorrhea, and revealed small ovaries with multiple cysts and a hypoplastic uterus. At age 20 years, while still off medication, the patient noted enlargement of her breasts, onset of regular menses, clearing of acne, and fading of the acanthosis nigricans.

She had 2 pregnancies at age 27 and 38 years. The first pregnancy was without complications, but the second pregnancy was complicated by preeclampsia and a premature birth via cesarean section at 7 months.

Her first admission at the NIH was at age 32 years in 1984. At that time she had diabetic retinopathy, neuropathy, and nephropathy. Hemodialysis was started in 1989. She became blind in 1990. She died at age 42 years in 1994 due to end-stage diabetic renal disease. Her older son, at age 25 years, had normal clinical features, glucose, and insulin. Her younger son, at age 14 years, was obese (body mass index, 36) with acanthosis nigricans and impaired glucose tolerance, and his fasting insulin was 60 μU/mL in 2001. At the end of the study, he had lost 20 kg (body mass index, 29) and the acanthosis nigricans had diminished; his fasting insulin was less than 20 μU/mL, and he was on metformin 1700 mg/d.

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Case A9

The patient, an 18-month-old white girl, was born after a full-term, uncomplicated pregnancy and delivery47. At birth, her weight was 2600 g, she was noted to have bilateral inguinal and umbilical hernia, increased body hair, clitoromegaly, coarse facial features, and decreased subcutaneous fat. At 11 months, her mother described episodes of polyuria and polydipsia especially if she had consumed free sugar. Her mother also described periods of profound deep sleep, and the infant would be sweaty and difficult to arouse. Physical examination revealed a hirsute girl with coarse facial features; she had hypertrichosis and acanthosis nigricans in the axilla and around the neck.

She was followed at the NIH beginning in 1994. She had a bilateral oophorectomy and hysterectomy in 1999. She was 25 years old at the end of the study, when the hirsutism and acanthosis nigricans were diminished. Her body mass index was 21. She had severe diabetic neuropathy, elevated urinary protein excretion, retinopathy, vitreal hemorrhage, and bilateral cataracts. Earlier in her course, she was treated with hypoglycemic drugs. She was subsequently treated with high doses of insulin (2200 U of U-500). At the end of the study she was taking insulin (1400 U of U-500), metformin (2000 mg), rosiglitazone (8 mg), captopril (25 mg), and premarin (1.25 mg). Her HbA1c remained elevated in the range of 11.8% despite the combination therapy.

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CASE RM2

Patient RM2, a white male, was diagnosed as having Rabson-Mendenhall syndrome based on the presence of characteristic findings including acanthosis nigricans, early eruption of adult dentition, short stature and severe insulin resistance. He was first seen at the NIH in 1991 at the age of 8 years. He had a minimal response to insulin in high doses (2000 U of U-500). In 1991 insulin-like growth factor (IGF-1) was added for 15 months, but glycemic control did not improve and there was no significant improvement in growth. In 1993, at the age of 10 years, he was diagnosed as having growth hormone deficiency (after L-DOPA and arginine tests) and low levels of IGF binding proteins. Growth hormone therapy was initiated to determine if the resulting increase in IGF binding proteins would enhance the efficacy of IGF-1, however no improvement was noted. The growth hormone therapy was discontinued because of worsening glycemic control and episodes of ketoacidosis. Metformin was added to his heroic insulin regimen (in excess of 4000 units/d) when this medication became available. The dose of the metformin was titrated to 2000 mg without benefit to his metabolic parameters. His HbA1c remained >14%. He subsequently developed nephropathy (proteinuria of 0.56-0.60 g/d) and mild retinopathy.

He was hospitalized in 1997 because of right-sided heart failure associated with pulmonary hypertension. He died at age 14 years, in December 1997, due to pulmonary hypertension as he was being evaluated for a combined heart and lung transplant.

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Clinical Course of Metabolic Syndrome and Diabetes

Six of 8 type A patients and all 3 RM patients had diabetes at presentation (see Table 3). Seven had fasting hyperglycemia, 2 had elevated 120-minute values on glucose tolerance testing, and 1 varied between normal and mild impaired glucose tolerance. All had marked hyperinsulinemia. In spite of their young age, 2 patients developed severe diabetic neuropathy, 5 developed diabetic nephropathy, and 6 patients developed moderate to severe retinopathy (see Table 3).

In spite of the extreme doses of insulin and/or oral agents, most patients maintained poor glycemic control. The mean of the HbA1c was 10.8% (range, 7.1%-16.5%). The average cholesterol level measured over the entire follow-up period for these 11 patients was 177 mg/dL, the average high-density lipoprotein was 55 mg/dL, and the average triglyceride was 100 mg/dL (Table 5).

TABLE 5

TABLE 5

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Clinical Course of Hyperandrogenic State

In the 8 type A patients hyperandrogenism was extreme (see Table 2). During the follow-up period, 4 of the 8 patients had total oophorectomies (Patients A1, A5, A7, A9) and 2 had large wedge resection (Patients A4, A6). Each of the 2 remaining patients (Patients A3, A8) became pregnant, and there were 3 live births following difficulty in conception because of continuous menstrual irregularities.

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DISCUSSION

The observations described in this paper span a period of 30 years and began shortly after the discovery of cellular and molecular techniques to study abnormalities of the insulin receptor as a focal point of disease. Kahn et al40 described 2 groups of patients with severe insulin resistance and identified 1 of the groups with a marked decrease in insulin binding to its receptor sites, suggesting that the insulin resistance in this disorder is due to an alteration in the interaction of insulin with its specific cell surface receptor. In fact the type A and RM patients provided the first examples of the genetic basis of a defect in insulin action, that is, mutations in the insulin receptor gene.

We review here the important lessons learned from the long-term study of these patients and further validate their phenotypic description as a basis for predicting mutations in the insulin receptor as the etiologic basis for their insulin resistance and, therefore, the etiologic basis for their diabetes.

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The Type A and RM Syndromes Predict Insulin Receptor Mutations

We use the phenotypic description of extreme insulin resistance, acanthosis nigricans and hyperandrogenism in a nonobese patient for type A and add severe growth retardation for RM. Of the 11 patients reported here, based on these phenotypic descriptions, 9 have been extensively screened for insulin receptor mutations. Eight of the 9 had mutations in the insulin receptor. While all 8 were nonobese when first seen, 1 subsequently became obese (Patient A6). Thus, though unusual, obesity can be a phenotypic feature of a patient with an insulin receptor mutation. Likewise, of 34 patients reported as type A and RM in the literature (Tables 6 and 7), 30 had mutations in the insulin receptor, and, again, 1 of these patients was obese. In patient A7, who has all the phenotypic features of type A syndrome23, a polymorphism but no functional mutation of the insulin receptor was found23,24,26,70a. She has been followed for 24 years and over the last several years developed a pattern of lipodystrophy similar to recently reported patients with PPARγ mutations11,63,76. This opens the possibility that other types of mutations may be discovered in these patients.

TABLE 6

TABLE 6

TABLE 7

TABLE 7

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Nomenclature of Type A, RM, and HAIR-AN Syndromes and Leprechaunism

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.

TABLE 8

TABLE 8

A larger group of patients who are obese18,19,20,69,79 also have insulin resistance, acanthosis nigricans, and hyperandrogenism. Both our own experience and the literature suggest that this syndrome, usually referred to as HAIR-AN, does not predict insulin receptor mutations. The basis for this syndrome, which at present is quantitatively distinct from obesity and typical polycystic ovarian syndrome, remains unknown9.

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.

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Insulin Resistance

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.

FIGURE 3

FIGURE 3

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.

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Hyperandrogenism

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.

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Treatment

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.

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Similarities and Differences in Syndromic Forms of Insulin Resistance

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).

TABLE 9

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.

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CONCLUSIONS

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).

TABLE 10

TABLE 10

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