The Clinical Approach to the Detection of Lipodystrophy an Aace Consensus Statement

Handelsman, Yehuda; Oral, Elif A.; Bloomgarden, Zachary T.; Brown, Rebecca; Chan, Jean L.; Einhorn, Daniel; Garber, Alan J.; Garg, Abhimanyu; Garvey, W. Timothy; Grunberger, George; Henry, Robert R.; Lavin, Norman; Tapiador, Carmen D.; Weyer, Christian

doi:10.4158/endp.19.1.v767575m65p5mr06

Cited by 92 publications

(128 citation statements)

References 33 publications

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“…Patients with lipodystrophy, unable to store excess calories in adipocytes, develop ectopic lipid deposits in muscle and liver, which lead to an increase flux of free fatty acids and severe insulin resistance (39). Current therapies used to treat diabetes and severe insulin resistance (thiazolidinediones, U-500 insulin) and/or high TG (fibrates, niacin, fish oils) are not very efficacious in this patient population (40). By reducing TG levels and improving insulin sensitivity, apoC-III inhibition may improve the metabolic profile of patients with lipodystrophy, as well as those with FCS, reducing their risk of acute pancreatitis and other complications associated with diabetes and potentially of cardiovascular events.…”

Section: Discussionmentioning

confidence: 99%

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

et al. 2016

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OBJECTIVETo determine the effects of volanesorsen (ISIS 304801), a second-generation 2'-O-methoxyethyl chimeric antisense inhibitor of apolipoprotein (apo)C-III, on triglyceride (TG) levels and insulin resistance in patients with type 2 diabetes. RESEARCH DESIGN AND METHODSA randomized, double-blind, placebo-controlled trial was performed in 15 adult patients with type 2 diabetes (HbA 1c >7.5% [58 mmol/mol]) and hypertriglyceridemia (TG >200 and <500 mg/dL). Patients were randomized 2:1 to receive volanesorsen 300 mg or placebo for a total of 15 subcutaneous weekly doses. Glucose handling and insulin sensitivity were measured before and after treatment using a two-step hyperinsulinemic-euglycemic clamp procedure. RESULTSTreatment with volanesorsen significantly reduced plasma apoC-III (288%, P = 0.02) and TG (269%, P = 0.02) levels and raised HDL cholesterol (HDL-C) (42%, P = 0.03) compared with placebo. These changes were accompanied by a 57% improvement in whole-body insulin sensitivity (P < 0.001). Importantly, we found a strong relationship between enhanced insulin sensitivity and both plasma apoC-III (r = 20.61, P = 0.03) and TG (r = 20.68, P = 0.01) suppression. Improved insulin sensitivity was sufficient to significantly lower glycated albumin (21.7%, P = 0.034) and fructosamine (238.7 mmol/L, P = 0.045) at the end of dosing and HbA 1c (20.44% [24.9 mmol/mol], P = 0.025) 3 months postdosing. CONCLUSIONSVolanesorsen reduced plasma apoC-III and TG while raising HDL-C levels. Importantly, glucose disposal, insulin sensitivity, and integrative markers of diabetes also improved in these patients after short-term treatment.Insulin resistance states usually seen in the context of obesity and type 2 diabetes are commonly associated with a metabolic dyslipidemia that amplifies cardiovascular disease risk. Among patients with type 2 diabetes, insulin resistance impairs the ability to utilize glucose as fuel, prompting a switch toward fat storage that promotes free fatty acid flux, hepatic triglyceride (TG) synthesis, and secretion of large VLDL particles (1). Cholesteryl ester transfer protein-mediated exchange of

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Section: Discussionmentioning

confidence: 99%

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

et al. 2016

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“…While congenital generalized forms of lipodystrophy are often diagnosed during childhood, some forms of partial lipodystrophies, particularly familial partial lipodystrophy, may have some similarity with the most common metabolic disorders managed by adult endocrinologists, and appear after pubarche. A recent consensus statement aimed at improving the detection of all types of lipodystrophies has recently been published (68). The fact that, in the past, women with the HAIR-AN syndrome were characterized by the classic PCOS phenotype strongly supported a role of insulin excess in determining all features of PCOS, chiefly androgen excess (Fig.…”

Section: Severe Insulin-resistant Syndrome and Pcosmentioning

confidence: 99%

“…Lipodystrophy is often, though not always, accompanied by metabolic derangements, including insulin resistance, diabetes mellitus, hepatic steatosis or steatohepatitis and dyslipidemia. Other manifestations of metabolic derangements can include polycystic ovarian syndrome (PCOS), acanthosis nigricans (due to severe insulin resistance) and eruptive xanthomas (due to severe hypertriglyceridemia) (67,68). While congenital generalized forms of lipodystrophy are often diagnosed during childhood, some forms of partial lipodystrophies, particularly familial partial lipodystrophy, may have some similarity with the most common metabolic disorders managed by adult endocrinologists, and appear after pubarche.…”

Section: Severe Insulin-resistant Syndrome and Pcosmentioning

confidence: 99%

“…In most cases, it is mandatory to plan adequate clinical and laboratory investigations to make a correct diagnosis. Although no formal criteria for the biochemical diagnosis of SSIR exist, there is a general consensus to consider the following conditions indicating (i) a fasting insulin value above 20.9 µg/mL and/or a peak insulin value on glucose tolerance testing above 209 µg/mL when diabetes is absent and a BMI below 30 kg/m 2 is present; (ii) or an exogenous insulin requirement of >3 units/kg per day when diabetes with absolute insulin deficiency is present with a BMI below 30 (65,68). However, the biochemical diagnosis of SSIR becomes difficult in the presence of partial β-cell compensation and/or in BMI above 30 due to background obesity-related insulin resistance, glucotoxicity impairing islet function and mixtures of endogenous and exogenous insulin in the blood.…”

Section: Severe Insulin-resistant Syndrome and Pcosmentioning

confidence: 99%

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MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

Pasquali

Diamanti-Kandarakis

Gambineri

2016

European Journal of Endocrinology

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PCOS is a clinical heterogeneous entity of female androgen excess diagnosed by exclusion of other disorders responsible for androgen excess. The concept of secondary PCOS implies that there is a primary well-defined cause leading to the PCOS phenotype with underlying androgen overproduction, regardless of the origin. In these cases, we presume the term of 'secondary PCOS' could be used. In all these conditions, the potential complete recovery of the hyperandrogenemic state as well as the remission of the PCOS phenotype should follow the removal of the cause. If accepted, these concepts could help clinicians to perform in-depth investigations of the potential factors or disorders responsible for the development of these specific forms of secondary PCOS. Additionally, this could contribute to develop further research on factors and mechanisms involved in the development of the classic and the nonclassic PCOS phenotypes. Invited author's profileRenato Pasquali is full professor of Endocrinology & Metabolism and Director of the division of Endocrinology of the S.Orsola-Malpighi Hospital, Bologna, Italy. He also heads the School of Specialization in Endocrinology and Metabolism, University Alma Mater Studiorum of Bologna, Italy. He is a member of numerous national and international scientific societies and serves on the editorial boards of international journals. His scientific interests relate to (i) the pathophysiology and treatment of the polycystic ovary syndrome; (ii) the endocrinology of obesity (sex hormones, the hypothalamic-pituitary-adrenal axis, and the endocannabinoid system).

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“…Patients with acquired generalized lipodystrophy (AGL) may show severe metabolic complications similar to patients with CGL, while patients with acquired partial lipodystrophy (Barraquer-Simmons syndrome), who invariably have well preserved lower body fat, have lesser incidence of metabolic complications compared with other lipodystrophy syndromes. Rare forms of acquired partial lipodystrophy associated with auto-inflammatory syndromes may, however, be associated with significant metabolic abnormalities [12][13][14]. The most prevalent form of lipodystrophy is seen in association with HIV infection (LD-HIV), with 40-50% of patients on long-term antiretroviral therapy being affected by either generalized lipoatrophy or partial fat loss involving the face and extremities [15].…”

mentioning

confidence: 99%

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

Simha

2014

Expert Review of Endocrinology & Metabolism

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Lipodystrophy is a group of acquired and inherited disorders characterized by selective loss of adipose tissue. Despite wide genotypic and phenotypic variety, many patients with lipodystrophy have similar metabolic complications including insulin resistance, diabetes mellitus, hypertriglyceridemia and hepatic steatosis. Often, these metabolic abnormalities are severe and difficult to treat with conventional glucose and lipid-lowering therapies. Lack of adipose tissue also results in marked hypoleptinemia, and there has recently been much interest in using leptin-replacement therapy to treat the metabolic complications of lipodystrophy. Administration of metreleptin, the human recombinant leptin analogue, has been shown in prospective, open-label studies to improve glucose control, dyslipidemia and steatohepatitis. This article summarizes the current evidence for the safety and efficacy of leptin-replacement therapy in patients with lipodystrophy.

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The Clinical Approach to the Detection of Lipodystrophy an Aace Consensus Statement

Cited by 92 publications

References 33 publications

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

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