Insulin-mediated pseudoacromegaly: a case report and review of the literature.
A 23 year old female patient presented with oligoamenorrhea. She
had excessive weight gain and had noticed hirsutism, enlargement of the
jaw, increase in her ring and shoe size, increased sweating and
darkening of her skin in flexural areas. Examination revealed a large
framed woman with coarse facial features, large hands and feet,
prognathism, acanthosis nigricans, hirsutism, acne and many skin tags.
GH and IGF-1 were normal. MRI of pituitary showed a 7mm microadenoma,
believed to be non-secretory with normal pituitary hormonal workup. She
had marked elevation of serum insulin, elevated testosterone and mixed
The occurrence of acromegaloid manifestations is an unusual phenomenon seen in a subset of patients with insulin resistance. In vitro studies in fibroblasts obtained from such patients have revealed impairment of metabolic, but preservation of mitogenic insulin signaling. Insulin-mediated pseudoacromegaly is an unusual syndrome that combines severe insulin resistance and an acromegaloid phenotype. Physicians should consider this possibility while evaluating patients with similar clinical and laboratory features.
|Article Type:||Case study|
Insulin resistance (Genetic aspects)
Cellular signal transduction (Research)
Acromegaly (Genetic aspects)
Acromegaly (Case studies)
|Publication:||Name: West Virginia Medical Journal Publisher: West Virginia State Medical Association Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 West Virginia State Medical Association ISSN: 0043-3284|
|Issue:||Date: Sept-Oct, 2008 Source Volume: 104 Source Issue: 5|
|Topic:||Event Code: 310 Science & research Canadian Subject Form: Somatotrophin|
|Geographic:||Geographic Scope: West Virginia Geographic Code: 1U5WV West Virginia|
Insulin-mediated pseudoacromegaly is an unusual syndrome that combines severe insulin resistance and an acromegaloid phenotype. Pseudoacromegaly is defined as presence of acromegaloid features in absence of elevated levels of growth hormone (GH) or insulin-like growth factor (IGF-1). These patients may have many progressive anatomical changes that resemble those found in acromegaly but lack the biochemical hallmarks of this disorder. Since Flier et. al. first described this unusual syndrome about 13 years ago, at least 5 more patients with clinical and biochemical features consistent with this diagnosis have been reported in the literature. Studies done on cultured skin fibroblasts of such patients have been a valuable source of understanding the complex cellular signaling pathways through which insulin exerts its metabolic and mitogenic effects. We describe here a case of pseudoacromegaly whose presentation is made complex by the incidental finding of pituitary microadenoma.
A 23-year old female presented with recent excessive weight gain. She had gained 115 pounds over 2 years. She had oligo-amenorrhea with a history of irregular menstrual periods since menarche at age 12. She also complained of occasional headaches and excessive fatigability. She noticed increase in her ring size ('can not wear my wedding ring') and shoe size. She also noticed enlargement of her jaw, progressive teeth spacing, increased sweating and darkening of her skin in flexural areas. She complained of increased coarse hair growth over the upper lip, sideburns, chin, around the nipples and along the midriff area. She had to shave everyday to remove excessive hair from her face. There was no history of galactorrhea. She was diagnosed with polycystic ovarian syndrome at age 18 and with type 2 diabetes at 21 years. She also had a history of 'fatty liver'. Medications included metformin 1 gram twice daily
Examination revealed a large framed woman with a BMI of 34. Coarse facial features were evident with acral enlargement and large hands and feet. She had prognathism with interdental spacing. Skin examination revealed acanthosis nigricans, moderate hirsutism, acne, and numerous skin tags (Figures 1,2,3).
Pseudoacromegaly is a rare disorder characterized by pathological tissue overgrowth and acromegaloid changes without excessive growth hormone or IGF-1. It combines severe insulin resistance and an acromegaloid phenotype (1). Very high circulating concentrations of insulin, as found in our patient, are believed to provide the stimulus for abnormal tissue growth seen in these individuals.
Flier and colleagues were the first to report this syndrome of selective insulin resistance in a 19-year old female patient. They coined the term 'insulin-mediated pseudoacromegaly' to describe this unusual syndrome. They studied their patient's cultured dermal fibroblast and demonstrated that there was resistance to insulin-mediated glucose disposal but insulin's effects on amino acid metabolism were relatively preserved (1).
Since Flier's index case report in 1993, there have been 5 more cases of insulin-mediated pseudoacromegaly described in literature (2, 3, and 4). In studies involving cultured dermal fibroblasts of these patients, insulin-stimulated mitogenesis and amino acid uptake have been shown to be normal, whereas insulin stimulation of glucose uptake is impaired. These studies have demonstrated a consistent and marked disparity between the ability of insulin to activate pathways related to glucose disposal on one hand, and those related to protein metabolism and growth on the other.
Excessive acral growth and changes in the composition of tissues such as fat and muscle are due to supraphysiological insulin levels providing stimulus to growth through an intact mitogenic signaling pathway. Genetic and biochemical studies indicate selective impairment of phosphoinositide-3kinase activation by insulin in this disorder, a defect that occurs despite the normal structure, expression, and function of the insulin receptor and its major substrate, IRS-1(2). Promiscuous activation of IGF-1 at supraphysiological concentrations of plasma insulin has been suggested as a possible explanation for nonmetabolic clinical features of insulin resistance (5). However, the absence of similar acromegaloid features despite pathologically high plasma insulin levels found in patients with insulin receptor mutations makes this hypothesis less plausible.
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It appears likely that our patient, in the presence of marked hyperinsulinemia and in the absence of elevated growth hormones or IGF-1, progressively developed various acromegaloid features. Her presentation was made more complex by the incidental finding of a 7mm pituitary microadenoma. In fact, several physicians who had examined her in the past considered acromegaly as the most likely diagnosis. Since the proposed mechanism for pseudoacromegaly in these patients clearly differs from normal mechanism for acromegaly (IGF-1 acting through IGF-1 receptors), such patients resemble but do not mirror the classic phenotype of acromegaly (2). Although our patient had various acromegaloid features, she did not have the classic presentation. Our patient also had hyperandrogenism with elevated total testosterone and low sex-hormone binding globulin (SHBG). Insulin decreases SHGB production by liver resulting in elevation of free testosterone and free androgen index (FAI), thus producing clinical manifestations of androgen excess. Because of low SHBG, the magnitude of elevation in FAI and free testosterone was much more pronounced than a rise in total testosterone. The presence of hypertriglyceridemia points towards resistance to the action of insulin in adipose tissue, where it normally stimulates lipoprotein lipase and inhibits hormone-sensitive triglyceride lipase. The resistance to these actions results in increased production and decreased clearance of triglyceride-rich lipoprotein from the circulation (4). The presence of diabetes, hypertriglyceridemia, hyperandrogenism and acromegaloid features in our patient indicate the presence of selective insulin resistance which appears to be characteristic of the syndrome of insulin-mediated pseudoacromegaly.
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Insulin-mediated pseudoacromegaly is an unusual syndrome that combines insulin resistance and an acromegaloid phenotype. Presence of a selective post receptor defect in insulin signaling results in impairment of metabolic but preservation of mitogenic signaling, resulting in abnormal tissue growth, that produces acromegaloid features in affected patients. Physicians should consider this possibility while evaluating patients with similar clinical and laboratory features.
(1.) Flier JS, Moller DE, Moses AC, et al. Insulin-mediated pseudoacromegaly: clinical and biochemical characterization of a syndrome of selective insulin resistance. J Clin Endocrinol Metab. 1993;76(6):1533-41
(2.) Dib K, Whitehead JP, Humphreys PJ, et al. Impaired activation of PI 3-kinase by insulin in fibroblasts from patients with severe insulin resistance and pseudoacromegaly. J Clin Invest. 1998;101(5):1111-20
(3.) Kausch C, Bergemann C, Hamann A, et al. Insulin mediated pseudoacromegaly in a patient with severe insulin resistance: association of defective insulin-stimulated glucose transport with impaired PI 3-kinase activity in fibroblasts. Exp Clin Endocrinol Diabetes. 1999;107(2);148-54
(4.) Kumar S, Durrington PN, O'Rahilly S, et al. Severe insulin resistance, diabetes Mellitus, hypertriglyceridemia, and pseudoacromegaly. J Clin Endocrinol Metab. 1996;81(10):3465-68
(5.) Friskin JE, Eastman RC, Leonia MA, et al. Specificity spillover at the hormone receptor-exploring its role in human disease. N Eng. J. Med. 1989; 320:640-45
Abid Yaqub MD
Assistant Professor of Medicine
Nadia Yaqub MD
Assistant Professor of Medicine
Section of Endocrinology
Department of Medicine
Joan C. Edwards School of Medicine
Table 1: Patient's pituitary hormonal evaluation Test Patient Normal Value IGF-1 (ng/ml) 203 116-358 Prolactin (ng/ml) 7.0 2.8-29.2 TSH (mIU/ml) 1.06 0.35-4.5 Free T4 (ng/dl) 1.27 0.8-1.8 FSH (mIU/ml) 4.8 1.4-9.6 LH (mIU/ml) 12.0 0.8-26 Cortisol (1mg DST-mcg/dl) 0.8 <2.5 IGF-I: Insulin-like growth factor-I; DST: Dexamethasone suppression test Table 2: 75-Gram Oral Glucose Tolerance Test Time (min) Glucose (mg/dl) Growth Hormone (ng/ml) 0 98 0.2 60 101 0.1 120 74 0.2 Table 3: Selected endocrine laboratory tests Tests Patient Normal Value Fasting Insulin (uIU/ml) 128 <17 17[alpha]-OH Progesterone (ng/dl) 91 30-100 Testosterone (ng/dl) 110 14-76 Free testosterone (pg/ml) 32.1 0.6-6.8 SHBG (nmol/L) 12 15-85 Free Androgen Index 31.8 0-11 DHEAS (mcg/dl) 182 65-380 Triglycerides (mg/dl) 224 <150 HDL (mg/dl) 35 >50 LDL (mg/dl) 119 <100 17[alpha]OH Progesterone: 17[alpha]-hydroxyprogesterone; SHBG: Sex-hormone binding globulin; DHEAS: Dehydroepiandrosterone sulfate
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