Hyperandrogenism, Insulin Resistance, and Acanthosis Nigricans (HAIR-AN) Syndrome Reflects Adipose Tissue Dysfunction ("Adiposopathy" or "Sick Fat") in Asian Indian Girls.

BACKGROUND: Whether HAIR-AN syndrome and polycystic ovarian syndrome (PCOS) are distinct entities or represent a phenotypic spectrum of the same syndrome is still unclear. HAIR-AN syndrome is characterized by high insulin resistance, obesity, and hyperinsulinemia as compared to PCOS and could represent adipose tissue dysfunction as the primary pathophysiologic trigger. This study was undertaken to study the role of adipose tissue dysfunction in HAIR-AN syndrome and PCOS using adipocytokines as surrogate markers of "adiposopathy." MATERIALS AND METHODS: A cross-sectional observational study was conducted at a tertiary care hospital over a period of 1 year. Serum adiponectin, leptin, IL-6, and TNF-α levels were measured in 30 women with HAIR-AN syndrome and in 30 women with PCOS. Correlations between adipocytokines, inflammatory markers, serum testosterone, and serum insulin were determined. Data analysis was performed using the SPSS version 23.0 (IBM SPSS Statistics Inc., Chicago, IL, USA) software program. RESULTS: Women with HAIR-AN syndrome had significantly higher hyperandrogenemia, hyperinsulinemia, and insulin resistance as compared to PCOS women. They also had high leptin levels and lower adiponectin levels (p < 0.001). However, the levels of inflammatory markers (TNF-α and IL-6) were similar in both the groups (p > 0.05). Serum adiponectin showed a negative correlation with HOMA-IR and testosterone levels, while leptin showed a positive correlation with both in HAIR-AN patients while no such correlation was found in the PCOS group. CONCLUSION: The significantly raised adipocytokines in HAIR-AN syndrome patients as compared to PCOS patients indicates the primary role of adipose tissue dysfunction ("adiposopathy") in the pathogenesis of HAIR-AN syndrome while only a minor role, if any, in PCOS. Both these syndromes stand as distinct entities pathogenically with an overlapping phenotype.

Laparoscopic sleeve gastrectomy improves body composition and alleviates insulin resistance in obesity related acanthosis nigricans.

BACKGROUND: Acanthosis nigricans (AN) has a close relationship with obesity. It is believed that obesity and AN have the common pathophysiological basis such as hyperinsulinism. This study is aimed to observe the effect of laparoscopic sleeve gastrectomy (LSG) on body composition and insulin resistance in Chinese obese patients with acanthosis nigricans. METHODS: A total of 37 obese patients who underwent LSG in our hospital were selected for analysis. They were divided into simple obesity (OB n = 14) and obesity with acanthosis nigricans (AN n = 23) group respectively. Body composition was measured by dual-energy X-ray absorptiometry (DEXA). Anthropometric measurements and glucolipid metabolism before and 3 months post LSG were collected for analysis. RESULTS: Patients with AN got noticeable improvement in skin condition and their AN score was significantly decreased (3.52 ± 0.79 vs. 1.48 ± 0.73, P < 0.001).Alleviated insulin resistance and more trunk fat loss than limbs' were observed in both groups (P value < 0.01). In AN group, preoperative android fat mass (FM) was positively correlated with fasting insulin and natural logarithm of HOMA-IR (LNIR) (r = 0.622, 0.608, respectively; all P < 0.01). Besides, changes in android FM and visceral adipose tissue (VAT) also showed significantly positive correlation with changes in LNIR (r = 0.588, r = 0.598, respectively; all P < 0.01). CONCLUSIONS: LSG had a positive impact on body composition and skin condition in Chinese obese patients with AN. Loss of android FM and VAT might result in the alleviation of insulin resistance in AN patients. Android fat distribution seems to be a potential indicator of postoperative metabolic benefits for obese patients with AN.

[Association between acanthosis nigricans and metabolic syndrome in children with obesity].

OBJECTIVE: To investigate adipokines levels in obese children with acanthosis nigricans (AN) and to explore the relationship between AN and metabolic syndrome (MS). METHODS: A cross-sectional study was performed on 109 obese children and 47 age- and gender-matched normal controls. The obese children were divided into two groups with AN and without AN. Serum levels of adiponectin, leptin, TNF-α and retinol-binding protein 4 (RBP4) were measured using ELISA. Multiple logistic regression analysis was performed to estimate the association of clinical parameters with MS. RESULTS: Waist-hip ratio, systolic blood pressure, triglyceride, fasting insulin and insulin resistance index (HOMA-IR) were significantly higher in obese children with AN than in those without AN and normal controls (P<0.05). The obese children with AN and without AN had lower adiponectin levels than normal controls (P<0.05), on the contrary, the obese children with AN had higher leptin levels than those without AN and normal controls (P<0.05). Multiple logistic regression analysis revealed that AN (OR=3.469, 95%CI: 1.518-7.929) and BMI (OR=7.108, 95%CI: 2.359-21.416) were independent risk factors for MS. CONCLUSIONS: As a visible marker of insulin resistance, AN is associated with abnormal adipokines secretion. Reducing the incidence of AN and losing weight may prevent obesity associated MS.

[Diagnosis of insulin resistance by indirect methods in obese school children]. / Diagnóstico de resistencia a la insulina por métodos indirectos en escolares obesos.

UNLABELLED: Obesity leads to a deterioration of glucose tolerance and the action of insulin. The purpose of this study was to determine insulin resistance (IR) by indirect methods, and its correlation with clinical, anthropometric and biochemical variables in obese normoglycemic school children. This was a descriptive-correlational study of 72 school prepubescent children, who attended the ambulatory "El Concejo" of the University of Carabobo (UC) and at the Gastroenterology and Pediatric Nutrition service of the city hospital "Enrique Tejera" (CHET), in Valencia, Venezuela, between January-April 2011. INCLUSION CRITERIA: exogenous obesity. We assessed personal and family history, presence of Acanthosis Nigricans and nutritional and biochemical status. We found a higher percentage of IR, through the use of the QUICKI method (66.7%), followed by the HOMA (55.6%) and basal insulin (45.9%). The mean (chi) indexes of body mass and waist circumference were significantly greater (p < 0.05) in patients with IR, by HOMA and QUICKI techniques. The QUICKI method detected significant differences (p < 0.05) in the values of glycemia, basal insulin and postprandial insulin, among patients with diminished and normal insulin sensitivities. While HOMA, detected these differences (p < 0.05) in the values of glycemia and basal insulin. A statistically significant relationship was observed (p < 0.05), between the presence of Acanthosis Nigricans and IR, by the HOMA, QUICKI and basal insulin methods. In conclusion, the evaluated techniques, QUICKI, HOMA and basal insulin indexes, were most effective for detecting the IR.

Serum levels of pigment epithelium-derived factor (PEDF) are positively associated with acanthosis nigricans in obese adolescents.

INTRODUCTION: Circulating pigment epithelium-derived factor, or serine protease inhibitor F1, is upregulated during adipogenesis, contributing to obesity-induced insulin resistance. Furthermore, pigment epithelium-derived factor is abundant in stage I melanosomes and has been reported to increase pigment granules and the appearance of mature melanosomes in retinal pigment epithelium. As acanthosis nigricans is a well-recognized clinical marker of insulin resistance, we hypothesized that increased pigment epithelium-derived factor might be associated with the generation of acanthosis nigricans. METHODS: Acanthosis nigricans, anthropometric measurements, circulating total PEDF and metabolic profiles were assessed in 28 obese adolescents in a hospital-based obesity clinic. RESULTS: Subjects with acanthosis nigricans (n = 10) showed greater plasma levels of pigment epithelium-derived factor (PEDF) than those without [geometric mean 23.55 (range 15.2-40.2) vs. 9.01 (range 5.5-18.7) µg/ml; P < 0.001]. Although pigment epithelium-derived factor was positively correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.779, P < 0.001; 95% CI 0.573-0.892), as previously reported, for the same degree of insulin resistance, those with acanthosis nigricans exhibited a 2.1-fold (95%CI 2.0-2.3) higher level of pigment epithelium-derived factor. CONCLUSIONS: While acanthosis nigricans is undoubtedly associated with insulin resistance, its appearance is not ubiquitous in patients at any given level of HOMA-IR. The higher levels of pigment epithelium-derived factor in those with acanthosis nigricans compared with those without, with similar levels of resistance, suggest that pigment epithelium-derived factor levels are associated with acanthosis nigricans.

Is there any relation between serum insulin and insulin-like growth factor-I in non-diabetic patients with skin tag?

BACKGROUND: Skin tags are common benign lesion occurring mainly on the neck and major flexures as a small soft pedunculated protrusion. This study evaluate insulin and insulin-like growth factor-I (IGF-I) in non-diabetic ones. METHODS AND MATERIALS: A case-control study was conducted in non-diabetic persons. Comparing insulin and IGF-I between matched cases (n = 40) and controls (n = 40) by radioimmunoassay test. Cases and controls were recruited from patients consecutively seen at an academic outpatient dermatology clinic. RESULTS: The insulin level in patients with skin tags was significantly higher than controls (P = 0.00) but IGF-I level was not significantly different (P = 0.43). CONCLUSION: These results show an increased insulin level in non-diabetics ones and overall importance of insulin effect in pathogenesis of skin tags.

Changes in inflammatory markers correlated with increased testosterone after laparoscopic sleeve gastrectomy in obese Chinese men with acanthosis nigricans.

Bariatric surgery is an effective method for severe obesity and its related comorbidities. This study was performed to explore the alterations of sex hormones and inflammatory markers following laparoscopic sleeve gastrectomy (LSG) among obese Chinese men with acanthosis nigricans (AN). Sixty-five obese men who underwent LSG were enrolled, comprising simple obesity without AN (OB group, n = 20) and obesity with AN (AN group, n = 45). There were 31 healthy male controls with normal body mass index (BMI) included. Anthropometry data, inflammatory markers, sex hormones and metabolic parameters were compared preoperatively and 12 months post-operatively. At baseline, patients in the AN group were associated with more severe metabolic abnormalities than the OB and control groups. Twelve months after surgery, AN patients obtained significant improvement in skin condition and reduction in AN score. BMI, fasting insulin (FINS), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), tumor necrosis factor-α (TNF-α) and total testosterone (TT) were significantly changed in both groups, while interleukin (IL)-6, IL-8 and C-reactive protein were changed significantly only in the AN group. Moreover, FINS, HOMA-IR, TT and IL-6 levels were changed more in the AN group than those in the OB group. Multivariate regression analysis revealed that TT increase correlated significantly with reduction in FINS and HOMA-IR in both groups, but correlated with changes in IL-6 only in the AN group. In conclusion, LSG is effective in improving the skin condition of obese men with AN. The increased TT in AN patients correlated with amelioration of inflammatory state in addition to insulin resistance after LSG.

Prevalence of insulin resistance and its association with metabolic syndrome criteria among Bolivian children and adolescents with obesity.

BACKGROUND: Obesity is a one of the most common nutritional disorder worldwide, clearly associated with the metabolic syndrome, condition with implications for the development of many chronic diseases. In the poorest countries of Latin America, malnourishment is still the most prevalent nutritional problem, but obesity is emerging in alarming rates over the last 10 years without a predictable association with metabolic syndrome. The objective of our study was to determine the association between insulin-resistance and components of the metabolic syndrome in a group of Bolivian obese children and adolescents. The second objective was determining the relation of acanthosis nigricans and insulin-resistance. METHODS: We studied 61 obese children and adolescents aged between 5 and 18 years old. All children underwent an oral glucose tolerance test and fasting blood sample was also obtained to measure insulin, HDL, LDL and triglycerides serum level. The diagnosis of metabolic syndrome was defined according to National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP III) criteria adapted for children. RESULTS: Metabolic syndrome was found in 36% of the children, with a higher rate among males (40%) than females (32.2%) (p = 0.599). The prevalence of each of the components was 8.2% in impaired glucose tolerance, 42.6% for high triglyceride level, 55.7% for low levels of high-density lipoprotein cholesterol, and 24.5% for high blood pressure. Insulin resistance (HOMA-IR > 3.5) was found in 39.4% of the children, with a higher rate in males (50%) than females (29%). A strong correlation was found between insulin resistance and high blood pressure (p = 0.0148) and high triglycerides (p = 0.002). No statistical significance was found between the presence of acanthosis nigricans and insulin resistance. CONCLUSION: Metabolic syndrome has a prevalence of 36% in children and adolescent population in the study. Insulin resistance was very common among children with obesity with a significant association with high blood pressure and high triglycerides presence.

Significance of acanthosis nigricans in childhood obesity.

AIM: Acanthosis nigricans (AN) is among the most common dermatologic manifestations of obesity and hyperinsulinism. In this study, we aimed to find the clinical and laboratory differences in obese children with AN and without AN (non-AN). METHODS: In total, 160 obese children were included in the study. The duration of obesity, body mass index (BMI), BMI z-scores, birth weight, parental BMI, lipid profile, fasting and post-meal (PM) glucose and insulin levels were compared in 67 obese with AN and 93 obese without AN. RESULTS: Age was similar in both groups. AN group had higher male to female ratio (42/25 in AN, 43/50 in non-AN; P = 0.03), higher BMI (30.3 +/- 6.1 in AN, 26.4 +/- 3.6 in non-AN; P < 0.001) and weight for height (162.6 +/- 28.8 in AN, 144.6 +/- 15.8 in non-AN; P < 0.001) than non-AN group. There were no significant differences between the groups in birth weight, parental BMI and blood pressure. AN group had higher fasting (19.9 +/- 16.2 mU/L in AN, 10.4 +/- 7.6 mU/L in non-AN; P < 0.001) and PM insulin (88.6 +/- 87.3 mU/L in AN, 51.1 +/- 42.0 mU/L in non-AN; P = 0.01) and homeostasis model assessment for insulin resistance (HOMA-IR) (4.0 +/- 2.5 in AN, 2.2 +/- 1.8 in non-AN; P < 0.001) than non-AN group. However, fasting and PM glucose, triglyceride, low-density lipoprotein-, high-density lipoprotein- and total cholesterol levels were similar in both groups. BMI was correlated with HOMA-IR in both groups (r = 0.40 for AN, r = 0.28 for non-AN). PM glucose and PM insulin were correlated in both groups (r = 0.56 for AN, r = 0.39 for non-AN). However, fasting glucose and fasting insulin were correlated in only non-AN (r = 0.25), but not in AN group. CONCLUSIONS: Obese children with AN show higher insulin levels and HOMA-IR. AN is an important predictor of the insulin resistance in childhood obesity. Insulin secretory dynamics seem to be disrupted in fasting state initially, which is reflected as the loss of fasting insulin-glucose correlation in AN group.

Prevalence of dermatologic manifestations and metabolic biomarkers in women with polycystic ovary syndrome in north China.

BACKGROUND: Cutaneous features of hyperandrogenism in polycystic ovary syndrome (PCOS) include acne, hirsutism, seborrhea, androgenic alopecia (AGA), and acanthosis nigricans (AN). However, the relationships have not been well known broadly in terms of clinical hyperandrogenism and biochemical markers. OBJECTIVES: The aim of this study was to investigate biochemical and metabolic parameters in relation to cutaneous characters women in with and without PCOS. METHODS: This was a cross-sectional retrospective study including 186 women with PCOS and 113 age-matched without PCOS women. Acne grade, hirsutism, seborrhea, AGA, and AN were recorded. Hormonal and metabolic parameters were measured. RESULTS: The most common finding was acne, and AN was the least dermatological manifestations between PCOS and non-PCOS groups. The severity location and type of acne did not differ in PCOS women compared to non-PCOS women. Significant differences were found with respect to free androgen index (FAI) (P = .036), sex hormone-binding globulin (SHBG) (P = .023), and body mass index (BMI) (P = .001) between PCOS with acne and PCOS without acne groups. Overall, age (P = .005) was significantly decreased, while BMI (P = .004) was significantly higher in PCOS with hirsutism. The mean serum total testosterone (TT), dehydroepiandrosterone sulfate, and FAI were significantly elevated, but SHBG was decreased between PCOS with and without hirsutism groups. There were significantly different BMI (P = .018) and triglyceride (P = .024) except other hormonal parameter of without AGA group. CONCLUSION: This study indicated a strong correlation between hirsutism and metabolic abnormalities. Hirsutism is the most common cutaneous finding in PCOS women. Acne and AGA are associated with other manifestations of clinical hyperandrogenism, but not obvious markers of biochemical hyperandrogenemia and metabolic dysfunction.

Effects of autoantibodies to the insulin receptor on isolated adipocytes. Studies of insulin binding and insulin action.

Autoantibodies to the insulin receptor have been detected in the sera of several patients with the Type B syndrome of insulin resistance and acanthosis nigricans. In this study we have used three of these sera (B-1, B-2, and B-3) as probes of the insulin receptor in isolated rat adipocytes. Preincubation of adipocytes with each of the three sera resulted in an inhibition of subsequent [(125)I]insulin binding. 50% inhibition of binding occurred with serum dilutions of 1:5 to 1:7,500. As in our previous studies with other tissues, Scatchard analysis of the insulin-binding data was curvilinear consistent with negative cooperativity. Computer analysis suggested that in each case the inhibition of binding was due to a decrease in receptor affinity rather than a change in available receptor number. In addition to the effects on insulin binding, adipocytes pretreated with antireceptor sera also showed alterations in biological responses. All three sera produced some stimulation of basal glucose oxidation. With serum B-3, maximal stimulation of glucose oxidation occurred at a serum concentration that inhibited binding by only 10-15%, whereas with serum B-2 the dilution curves for inhibition of binding and stimulation of glucose oxidation were superimposable. Serum B-1 behaved as a partial agonist; that is, it inhibited binding more effectively than it stimulated glucose oxidation. Cells pretreated with this serum in a concentration which inhibited binding by 80% also showed a five-fold shift to the right in the dose response of insulin-stimulated glucose oxidation, whereas spermine-stimulated glucose oxidation was unaffected. Serum B-2, which contained the highest titer of antireceptor antibodies, also stimulated 2-deoxy-glucose transport, as well as glucose incorporation into lipid and glycogen. Both the ability of the serum to inhibit binding and stimulate glucose utilization were enriched in purified immunoglobulin fractions and retained in the F(ab')(2) fragment of the IgG. In addition, the bioactivity was blocked by antihuman IgG but not by anti-insulin antibodies. Enzymatic digestion of adipocytes with trypsin resulted in a complete loss of insulin-stimulated bioactivity of serum B-3, but had only minor effects on the glucose oxidation produced by serum B-1 or B-2.These data suggest that the antibodies present in these three sera bind to different determinants on the insulin receptor. Thus, these antibodies may be useful probes of receptor structure and function.

The Clinical Characteristics of Obese Patients with Acanthosis Nigricans and Its Independent Risk Factors.

Objective: This study aimed to investigate the clinical characteristics and risk factors for acanthosis nigricans (AN) in obese patients. Methods: 80 obese patients without AN (OB group) and 128 obese patients with AN (AN group) were included in this study. Clinical data for each patients were collected. Serum levels of leptin were measured by ELISA. Results: Body mass index (BMI), uric acid (UA) levels, fasting insulin, and HOMA-IR were higher in AN than OB (P<0.05). The levels of leptin were significantly higher in AN than OB (P<0.001) after adjustment for BMI and gender. In male patients, AN showed lower serum levels of testosterone than OB (P<0.001). Multiple Logistic-regression analysis demonstrated that UA (OR 4.627, 95%CI 2.443-8.762, P<0.001) and Leptin (OR 4.098, 95%CI 1.237-13.581, P=0.021) were independent risk factors for AN. In addition, low testosterone level was an independent risk factor for AN in male obese patients (OR 39.062, 95%CI 5.523-283.808, P<0.001). Conclusions: AN is associated with more severe hyperinsulinemia and hyperuricemia in obese patients, as well as lower serum testosterone levels in male patients. UA and Leptin were independent risk factors for AN in obese patients. Low testosterone may be a valuable predictor of AN in male obese patients.

Concomitant confluent and reticulated papillomatosis and acanthosis nigricans in an obese girl with insulin resistance successfully treated with oral minocycline: Case report and published work review.

Concomitant confluent and reticulated papillomatosis (CRP) and acanthosis nigricans (AN) is rare. We present a case of concomitant CRP and obesity-associated AN in a 12-year-old obese Japanese girl. Curiously, oral minocycline therapy, which has been shown to be effective for CRP, was effective against both CRP and AN. Possible mechanisms by which minocycline could have improved skin lesions of CRP and obesity-associated AN are discussed. In addition, reports of concomitant CRP and obesity-associated AN are reviewed. CRP and obesity-associated AN share common clinicopathological features and some reports have described concomitant CRP and obesity-associated AN. Together with the observation that skin lesions of CRP and obesity-associated AN in the present case responded to oral minocycline therapy, these facts suggest a tight relationship or a common pathogenetic pathway between these pathologies.

Comparison of metformin versus rosiglitazone in patients with Acanthosis nigricans: a pilot study.

BACKGROUND: Acanthosis nigricans (AN) is a skin condition commonly present on the neck of obese subjects. Obesity is often accompanied by insulin resistance and/or hyperinsulinemia. Metformin and rosiglitazone are 2 pharmacologic agents useful in conditions characterized by insulin resistance. OBJECTIVE: The aim of our study was to compare the efficacy of metformin versus rosiglitazone on AN lesions of the neck as well as their effects on metabolic and anthropometric variables. METHODS: This 12-week randomized, open-label pilot study involved overweight or obese subjects with AN treat with either metformin (n=4) or rosiglitazone (n=3). RESULTS: Only the rosiglitazone group showed a significant reduction in insulin levels. No effect on the severity of AN was observed, but modest improvements of skin texture occurred in both treatment groups. CONCLUSIONS: Metformin and rosiglitazone were well-tolerated. Although efficacy on skin lesions was very modest, their use in acanthotic subjects might be useful during longer treatment periods.

Acanthosis Nigricans, insulin resistance (HOMA) and dyslipidemia among Native American children.

OBJECTIVE: It is controversial whether acanthosis nigricans is an independent marker of insulin resistance. In this study, we evaluated whether insulin resistance (as reflected by HOMA) was associated with acanthosis nigricans, Native American heritage, BMI, fasting insulin, and plasma lipids in Native American children and adolescents. DESIGN/METHODS: Retrospective chart review of Native American children (3.6 to 17.8 yrs) seen in 4 tribal or Indian Health Service clinics after referral for exceptionally high type 2 diabetes risk (family history, extreme obesity, and/or severe acanthosis nigricans). RESULTS: All but 2 had a family history of type 2 diabetes in at least one first or second degree relative, all but 3 had acanthosis nigricans (12 severe and 11 mild/not severe), and all but 2 were obese (BMI Z score of +3 to +8). Those with severe acanthosis nigricans had higher BMI and fasting insulin levels and lower HDL-C (p < 0.05) than those with acanthosis nigricans that was not severe. HDL-C correlated with BMI Z-score (p = 0.046) and approached significance with fasting insulin. HOMA correlated with BMI (p = 0.0005), with 82.4% of males and 33.3% of females having a HOMA greater than the 90th percentile for normal children. A multiple regression model indicated that acanthosis nigricans severity remained a predictor (p = 0.015) of HOMA after association of BMI Z score, Native American blood quantum, and gender were removed. CONCLUSIONS: These data indicate that among Native American children at high risk for developing type 2 diabetes, acanthosis nigricans is an independent marker of insulin resistance (as reflected by HOMA).

Serum Irisin Level is Higher and Related with Insulin in Acanthosis Nigricans-related Obesity.

OBJECTIVE: Acanthosis nigricans (AN) is proved to be a skin phenotype of hyperinsulinemia especially in obese patients. Irisin is a new myokine which plays an important role in metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes. The role of irisin in the development of AN-related obesity is not yet understood. In this study, we aimed to investigate the relationship between irisin and AN-related obesity. Patients & Measurements: 30 obese patients without AN (OB group), 30 obese patients with AN (AN group), and 20 age-matched healthy volunteers (control group, CON) were included in this study. Weight, BMI, lipid profile, FFA, UA, and CRP were measured in all participants. Oral Glucose Tolerance tests (OGTT) were performed and serum glucose and plasma insulin were measured at 0, 30, 60,120 and 180 min. The AUC (area under curve) of glucose and insulin was calculated. Serum irisin was measured by ELISA. RESULTS: Hyperinsulinemia is found in both AN and OB groups. The AN group had higher levels of insulin but better blood glucose tolerance and insulin response. The difference in irisin levels between the 3 groups was statistically significant, with the AN group showing the highest serum level of irisin. Serum irisin levels were positively correlated with BMI, and fasting insulin. CONCLUSION: AN is a state of hyperinsulinmia and has better insulin response and glucose tolerance compared to obese patients without AN. Serum irisin may be a protective factor against impaired beta cell function in obesity with AN.

A novel insulin receptor mutation in an adolescent with acanthosis nigricans and hyperandrogenism.

Insulin receptor mutations cause extreme insulin resistance resulting in acanthosis nigricans and hyperandrogenism. We report a pre-menarchal adolescent female with normal weight, with severe acanthosis nigricans, acne, and hirsutism. Initial investigation revealed elevated fasting and post-prandial insulin and high testosterone and androstenedione levels. Her father had frequent complaints of hypoglycemia. Coding sequence and splice junction analysis of the INSR gene, in our patient and her father, revealed a heterozygous missense mutation in the ß subunit of the insulin receptor (Arg1131Trp), resulting in receptor loss of function. Metformin therapy and carbohydrate control improved acanthosis and menarche ensued within 3 months. Our case highlights the importance of distinguishing insulin resistance commonly associated with obesity from monogenic defects. Although, there is no consensus on treatment of children with monogenic forms of insulin resistance due to its rarity, dietary and lifestyle modifications and insulin-sensitizing agents play a key role in management.

Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes.

Acanthosis nigricans and hyperandrogenism are commonly found in patients with extreme target cell resistance to insulin, as in the type A and B syndromes of insulin resistance. However, the significance of concurrent acanthosis nigricans and hyperandrogenism in other clinical settings is not clear. We observed acanthosis nigricans to be present in 5% (15 of 300) of patients being evaluated for hyperandrogenism, and carried out studies of insulin binding and action in a group (7) of these women. Although none were diabetic, all were insulin resistant as assessed by hyperinsulinemia when fasting and after oral glucose administration. All patients were obese (mean IBW, 169%). However, when matched to hyperandrogenized women of similar body weight, patients with acanthosis nigricans were clearly more hyperinsulinemic. Insulin binding to monocytes and red cells was decreased in patients with acanthosis, and the extent of decrease was predicted by the fasting insulin level. There was also marked resistance to exogenous insulin during euglycemic insulin clamp studies in the two patients so tested. Anti-insulin receptor antibodies were not detectable, ruling out the type B syndrome. Unlike the type A syndrome, insulin binding to monocytes of these patients increased after acute (2/2) and chronic (1/1) caloric restriction. In the latter patient, acanthosis nigricans remitted as insulin resistance and the insulin binding defect improved. We conclude that acanthosis nigricans is present in as many as 5% of women with clinically significant hyperandrogenism. These women, although not diabetic, have fairly marked insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

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 microU/ml] and/or peak during an oral glucose tolerance test (OGTT) > 1,800 pM [300 microU/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 beta-subunit.(ABSTRACT TRUNCATED AT 250 WORDS)