Context:
Lipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD).
Objective:
The ...objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response.
Design:
This was a prospective, single-arm, open-label study since 2000 with continuous enrollment. Current analysis included metreleptin treatment for 6 months or longer as of January 2014.
Setting:
The study was conducted at the National Institutes of Health (Bethesda, Maryland).
Participants:
Patients clinically diagnosed with lipodystrophy, leptin less than 8 ng/mL (males) or less than 12 (females), age older than 6 months, and one or more metabolic abnormalities (diabetes, insulin resistance, or hypertriglyceridemia) participated in the study.
Intervention:
The interventions included sc metreleptin injections (0.06–0.24 mg/kg · d).
Main Outcomes and Measures:
Changes in glycated hemoglobin A1c (HbA1c) and triglycerides after 6 and 12 months of metreleptin were measured.
Results:
Baseline metabolic parameters were similar in 55 GLD HbA1c 8.4% ± 2.3%; triglycerides, geometric mean (25th, 75th percentile), 467 mg/dL (200, 847) and 31 PLD patients HbA1c 8.1% ± 2.2%, triglycerides 483 mg/dL (232, 856) despite different body fat and endogenous leptin. At 12 months, metreleptin decreased HbA1c (to 6.4% ± 1.5%, GLD, P < .001; 7.3% ± 1.6%, PLD, P = .004) and triglycerides to 180 mg/dL (106, 312), GLD, P < .001; 326 mg/dL (175, 478), PLD, P = .02. HbA1c and triglyceride changes over time significantly differed between GLD and PLD. In subgroup analyses, metreleptin improved HbA1c and triglycerides in all GLD subgroups except those with baseline triglycerides less than 300 mg/dL and all PLD subgroups except baseline triglycerides less than 500 mg/dL, HbA1c less than 8%, or endogenous leptin greater than 4 ng/mL.
Conclusions:
In addition to its proven efficacy in GLD, metreleptin is effective in selected PLD patients with severe metabolic derangements or low leptin.
Background & Aims Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver ...disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement. Methods This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N = 50) and after leptin replacement (N = 27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A1c and liver enzymes were measured at baseline and at the time of the final liver biopsy. Results In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 ± 3.7 months (mean ± SE, p = 0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score ( p <0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis. Conclusions The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients.
Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway ...is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a . Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.
Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis ...contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.
Context: Selective intraarterial calcium injection of the major pancreatic arteries with hepatic venous sampling calcium arterial stimulation (CaStim) has been used as a localizing tool for ...insulinomas at the National Institutes of Health (NIH) since 1989. The accuracy of this technique for localizing insulinomas was reported for all cases until 1996.
Objectives: The aim of the study was to assess the accuracy and track record of the CaStim over time and in the context of evolving technology and to review issues related to result interpretation and procedure complications. CaStim was the only invasive preoperative localization modality used at our center. Endoscopic ultrasound (US) was not studied.
Design and Setting: We conducted a retrospective case review at a referral center.
Patients: Twenty-nine women and 16 men (mean age, 47 yr; range, 13–78) were diagnosed with an insulinoma from 1996–2008.
Intervention: A supervised fast was conducted to confirm the diagnosis of insulinoma. US, computed tomography (CT), magnetic resonance imaging (MRI), and CaStim were used as preoperative localization studies. Localization predicted by each preoperative test was compared to surgical localization for accuracy.
Main Outcome: We measured the accuracy of US, CT, MRI, and CaStim for localization of insulinomas preoperatively.
Results: All 45 patients had surgically proven insulinomas. Thirty-eight of 45 (84%) localized to the correct anatomical region by CaStim. In five of 45 (11%) patients, the CaStim was falsely negative. Two of 45 (4%) had false-positive localizations.
Conclusion: The CaStim has remained vastly superior to abdominal US, CT, or MRI over time as a preoperative localizing tool for insulinomas. The utility of the CaStim for this purpose and in this setting is thus validated.
The CaStim is vastly superior to abdominal ultrasound, CT or MRI as a preoperative localizing tool for insulinomas.
Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy
Edward D. Javor 1 ,
Elaine K. Cochran 1 ,
Carla Musso 1 ,
Janice Ryan Young 1 ,
Alex M. DePaoli 2 and
Phillip ...Gorden 1
1 Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, Maryland
2 Amgen, Thousand Oaks, California
Address correspondence and reprint requests to Edward D. Javor, 10 Center Dr., CRC Room 6-5940, Bethesda, MD 20892. E-mail:
edwardj{at}intra.niddk.nih.gov
Abstract
Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human
model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by
a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduced adipokines, including
leptin. Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia.
Excess fuel consumption, coupled with a lack of adipose tissue, contributes to the significant ectopic triglyceride accumulation
in the muscle and liver seen in these subjects. This ectopic fat, along with the deficiency in leptin signaling and perhaps
other adipokines, likely contributes to insulin resistance, diabetes, and hepatic steatosis. We report here the long-term
effects of leptin replacement in a cohort of these subjects. Fifteen patients with generalized lipodystrophy were treated
with twice-daily recombinant methionyl human leptin (r-metHuLeptin) for 12 months. We evaluated metabolic parameters at baseline
and every 4 months. Antidiabetes medications were decreased or discontinued as necessary. Reductions were seen in serum fasting
glucose (from 205 ± 19 to 126 ± 11 mg/dl; P < 0.001), HbA 1c (from 9 ± 0.4 to 7.1 ± 0.5%; P < 0.001), triglycerides (from 1,380 ± 500 to 516 ± 236 mg/dl; P < 0.001), LDL (from 139 ± 16 to 85 ± 7 mg/dl; P < 0.01), and total cholesterol (from 284 ± 40 to 167 ± 21 mg/dl; P < 0.01). HDL was unchanged (from 31 ± 3 to 29 ± 2 mg/dl; P = 0.9). Liver volumes were significantly reduced (from 3,663 ± 326 to 2,190 ± 159 cm 3 ; P < 0.001), representing loss of steatosis. Decreases were seen in total body weight (from 61.8 ± 3.6 to 57.4 ± 3.4 kg; P = 0.02) and resting energy expenditure (from 1,929 ± 86 to 1,611 ± 101 kcal/24 h; P < 0.001). R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis. Leptin
represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.
AGL, acquired generalized lipodystrophy
CGL, congenital generalized lipodystrophy
NAFLD, nonalcoholic fatty liver disease
PPAR, peroxisome proliferator-activated receptor
REE resting energy expenditure
r-metHuLeptin, recombinant methionyl human leptin
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted April 7, 2005.
Received January 6, 2005.
DIABETES
Insulinoma is a rare neuroendocrine tumor that causes oversecretion of insulin and, as a result, patients present with symptoms of hypoglycemia. Fortunately, insulinomas are usually benign and ...solitary, and surgical cure rates are highly favorable. Most of these tumors occur sporadically, but they can also be associated with multiple endocrine neoplasia type-1 syndrome. The diagnosis is confirmed by a supervised fast, and early detection is important. Several preoperative and intraoperative techniques with various success rates have been employed in order to localize the lesion. When technically feasible, tumor enucleation is the procedure of choice; however, a more formal resection may be necessary for certain tumors. In the age of laparoscopy, the role of laparoscopic surgery in the management of insulinomas is continuing to attract attention. This review will discuss the historical background, pathogenesis, diagnosis, localization and management of insulinomas.
Plasma Adiponectin as a Marker of Insulin Receptor Dysfunction
Clinical utility in severe insulin resistance
Robert K. Semple , MB, PHD 1 ,
Elaine K. Cochran , MSN, CRNP 2 ,
Maria A. Soos , PHD 1 ,
...Keith A. Burling , MPHIL 1 ,
David B. Savage , MD 1 ,
Phillip Gorden , MD 2 and
Stephen O'Rahilly , MD 1
1 Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K.
2 Clinical Endocrinology Branch, Digestive and Kidney Diseases, National Institute of Diabetes, Bethesda, Maryland
Corresponding author: Dr. R. Semple, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, U.K. E-mail:
rks16{at}cam.ac.uk
Abstract
OBJECTIVE —Severe insulin resistance is associated with high morbidity. Identification of severely insulin-resistant patients who have
genetic or acquired insulin receptor dysfunction may aid therapeutic decision making; however, onerous diagnostic tests allied
to a low frequency of insulin receptor dysfunction often preclude formal diagnosis. Our previous observation of paradoxical
hyperadiponectinemia in insulin receptoropathy provides a possible basis for a simpler and cheaper screening test.
RESEARCH DESIGN AND METHODS —Receiver operating characteristics analysis was used to determine diagnostic thresholds for insulin receptoropathy in severe
insulin resistance for adiponectin and for the insulin-regulated hepatic proteins sex hormone–binding globulin (SHBG) and
IGF binding protein-1 (IGFBP-1).
RESULTS —Adiponectin >7 mg/l in severe insulin resistance had a 97% positive predictive value for insulin receptoropathy and <5 mg/l
a 97% negative predictive value. IGFBP-1 and SHBG had lesser, though still significant, utility.
CONCLUSIONS —Use of these markers is likely to have significant value in accelerating the diagnosis of insulin receptoropathies.
IGFBP-1, IGF binding protein-1
NPV, negative predictive value
PPV, positive predictive value
SHBG, sex hormone–binding globulin
Footnotes
Published ahead of print at http://care.diabetesjournals.org on 25 February 2008. DOI: 10.2337/dc07-2194.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/dc07-2194 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 13, 2008.
Received November 18, 2007.
DIABETES CARE
Purpose
It has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for ...intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring.
Methods
A retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24 h) was performed. Hyperglycemia was defined as glucose greater than 180 mg/dL (10 mmol/l).
Results
Twelve patients (36%) developed hyperglycemia within 24 h (range 1–16 h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5 mg/dL (range 97–325 mg/dL) (12.3 mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents.
Conclusions
Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.
Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with ...lipodystrophy are unknown.
We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naïve and leptin-treated subjects with lipodystrophy.
In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2). Leptin-naïve subjects (n = 8) were studied without leptin in period 1 and with leptin replacement in period 2. LH secretory dynamics were assessed (23:00-07:00 h, sampling every 10 min, analyzed by multiparameter deconvolution algorithm) at the end of each period.
Mean (on vs. off: 5.0 ± 3.1 vs. 3.2 ± 1.3 IU/l, p = 0.04) and integrated LH concentrations (2,403 ± 1,495 vs. 1,534 ± 642 IU × l-1 × min-1, p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7± 15.4 vs. 7.0 ± 11.2 IU/l, p = 0.03) and tended to nonsignificantly increase LH burst frequency (0.77 ± 0.26 vs. 0.67 ± 0.24 h-1, p = 0.08). Consequently, leptin therapy increased the pulsatile production rate (64 ± 101 vs. 57 ± 73 IU × l-1 × 8 h-1, p = 0.01). On leptin, testosterone (507 ± 286 vs. 360 ± 174 ng/dl, p = 0.09) and estradiol levels (74 ± 36 vs. 29 ± 24 pg/ml, p = 0.01) were higher in males and females, respectively.
Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy.
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