Clinical Course of the Syndrome of Autoantibodies to the Insulin Receptor (Type B Insulin Resistance)

Arioǧlu, Elif; Andewelt, Alexa; Diabo, Crystal; Bell, Melissa J.; Taylor, Simeon I.; Görden, Phillip

doi:10.1097/00005792-200203000-00001

Cited by 193 publications

(266 citation statements)

References 72 publications

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“…Although a hallmark of the metabolic syndrome, insulin resistance alone does not appear sufficient for the development of steatosis or NASH. In our experience, patients with extreme insulin resistance as a result of receptor mutations 17,18 or autoantibodies 19 do not have NASH-associated findings such as hypertriglyceridemia, hepatomegaly, or abnormal liver function tests. Fat accumulation outside of adipose tissue appears to be the common link contributing to both insulin resistance and NASH in the general population and in these patients.…”

Section: Discussionmentioning

confidence: 73%

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy

et al. 2005

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Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P ‫؍‬ .006) and ballooning injury (P ‫؍‬ .005), with a reduction of mean NASH activity by 60% (P ‫؍‬ .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (12063226 mg/dL, P ‫؍‬ .002), glucose (2203144 mg/dL, P ‫؍‬ .02), insulin (46.4324.8 IU/mL, P ‫؍‬ .004), ALT (54324 U/L, P ‫؍‬ .02), AST (47322 U/L, P ‫؍‬ .046), liver volume (320932391 cm 3 , P ‫؍‬ .007), and liver fat content (31311%, P ‫؍‬ .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH. (HEPATOLOGY 2005;41:753-760.) N onalcoholic steatohepatitis (NASH), a progressive metabolic liver disease, is one of the major consequences of the current obesity epidemic. 1-3 It lies on a spectrum of nonalcoholic fatty liver disease that ranges from ectopic lipid accumulation (steatosis) to cirrhosis. 4 Steatosis is believed to sensitize the liver to metabolic injury, leading to inflammation, necrosis, and fibrosis. 2,5-7 Thus, steatosis is a constant feature of NASH, but NASH is only distinguishable by liver biopsy. The assessment and severity of NASH is made histologically based on the patterns and degrees of hepatic steatosis, inflammation, and injury, in the absence of significant alcohol consumption. 8 Although steatosis is seen in both animal and human models, NASH is only fully appreciated in the human condition. 7 Thus, human models of NASH are critical for the development of therapeutic strategies for this condition.Steatosis occurs with decreased leptin action, whether due to leptin deficiency or resistance. 9 Lipodystrophy repr...

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Section: Discussionmentioning

confidence: 73%

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy

et al. 2005

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“…After the introduction of human insulin produced with recombinant DNA technology, this form of resistance has declined dramatically (6)(7)(8)(9)(10)(11). It also occurs in conditions associated with elevated circulating levels of autoantibodies, such as autoimmune disorders and certain medications (12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

“…The syndrome has been described in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome as well as less clearly defined autoimmune disorders (12,21,(25)(26)(27). Acanthosis nigricans (a marker of insulin resistance), amenorrhea in women, and hyperandrogenism are usually present (4,12,(28)(29)(30).…”

mentioning

confidence: 99%

Treatment of systemic lupus erythematosus–associated type B insulin resistance syndrome with cyclophosphamide and mycophenolate mofetil

Gehi¹,

Webb²,

Nolte³

et al. 2003

Arthritis & Rheumatism

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immunologic self-tolerance and the subsequent development of autoantibodies. These antibodies are thought to be important in relation to the clinical manifestations of the disease. One example is the development of multiple cytopenias secondary to cytolytic or cytotoxic antibodies directed toward red blood cells, platelets, and white blood cells. Other antibodies may mediate abnormal cellular mechanisms such as those seen with neuropsychiatric manifestations of SLE. We report the occurrence of autoantibodies directed toward insulin receptors and the subsequent development of type B insulin resistance syndrome in a woman with SLE. This syndrome was treated successfully with cyclophosphamide and mycophenolate mofetil.

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“…Therapy is directed at the underlying process, which most commonly is lupus and requires a form of immunosuppression (4). Another therapy that has been used in this syndrome is Rituximab (a monoclonal anti-CD20 antibody), which showed a striking amelioration of the insulin-resistant diabetes in two patients (23,24).…”

Section: Autoantibodies To the Insulin Receptormentioning

confidence: 99%

“…Therefore, the diabetic syndrome may spontaneously remit independent of the nephropathy or may remit in the context of the therapeutic regimen for the renal disease. It is important to consider both of these issues independently (4,6).…”

Section: Autoantibodies To the Insulin Receptormentioning

confidence: 99%

Spectrum of Renal Diseases Associated with Extreme Forms of Insulin Resistance

Musso

Javor

Cochran

et al. 2006

Clinical Journal of the American Society of Nephrology

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Diabetic nephropathy is the leading cause of ESRD in the United States. Why the pathogenic mechanisms lead to nephropathy in certain patients with type 1 and 2 diabetes and spare others is unclear, but it is clear that hyperglycemia and glomerular hyperfiltration are important factors. In patients with syndromes of extreme insulin resistance, proteinuric forms of renal disease are common, but it is surprising to find that the renal pathology usually is not diabetic nephropathy. For instance, in the lipodystrophy syndromes, membranoproliferative glomerulonephritis type 1 and type 2, focal segmental glomerulosclerosis, and also diabetic nephropathy are seen. In the syndromes of autoantibodies to the insulin receptor, the various forms of lupus glomerulonephritis are seen. Even in patients with type 2 diabetes, the renal pathology may not be diabetic nephropathy. Therefore, in patients with syndromic forms of insulin resistance and type 2 diabetes, renal biopsy has an important role in defining the pathology that leads to proteinuric nephropathy and in formulating a therapeutic approach. It is the purpose of this article to review these unusual aspects of proteinuric nephropathy in patients with diabetes.

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Clinical Course of the Syndrome of Autoantibodies to the Insulin Receptor (Type B Insulin Resistance)

Cited by 193 publications

References 72 publications

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy

Treatment of systemic lupus erythematosus–associated type B insulin resistance syndrome with cyclophosphamide and mycophenolate mofetil

Spectrum of Renal Diseases Associated with Extreme Forms of Insulin Resistance

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