Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

A cohort analysis of familial partial lipodystrophy from two Mediterranean countries.

AIM: To assess the disease burden of familial partial lipodystrophy (FPLD) caused by LMNA (FPLD2) and PPARG (FPLD3) variants to augment the knowledge of these rare disorders characterized by selective fat loss and metabolic complications. MATERIALS AND METHODS: An observational longitudinal study, including 157 patients (FPLD2: 139 patients, mean age 46 ± 17 years, 70% women; FPLD3: 18 patients, mean age: 44 ± 17 years, 78% women) from 66 independent families in two countries (83 from Turkey and 74 from Spain), was conducted. RESULTS: Patients were diagnosed at a mean age of 39 ± 19 years, 20 ± 16 years after the first clinical signs appeared. Men reported symptoms later than women. Symptom onset was earlier in FPLD2. Fat loss was less prominent in FPLD3. In total, 92 subjects (59%) had diabetes (age at diagnosis: 34 ± 1 years). Retinopathy was more commonly detected in FPLD3 (P < .05). Severe hypertriglyceridaemia was more frequent among patients with FPLD3 (44% vs. 17%, P = .01). Hepatic steatosis was detected in 100 subjects (66%) (age at diagnosis: 36 ± 2 years). Coronary artery disease developed in 26 patients (17%) and 17 (11%) suffered from a myocardial infarction. Turkish patients had a lower body mass index, a higher prevalence of hepatic steatosis, greater triglyceride levels and a tendency towards a higher prevalence of coronary artery disease. A total of 17 patients died, with a mean time to death of 75 ± 3 years, which was shorter in the Turkish cohort (68 ± 2 vs. 83 ± 4 years, P = .01). Cardiovascular events were a major cause of death. CONCLUSIONS: Our analysis highlights severe organ complications in patients with FPLD, showing differences between genotypes and Mediterranean countries. FPLD3 presents a milder phenotype than FPLD2, but with comparable or even greater severity of metabolic disturbances.

Assessment of aortomesenteric distance and mesenteric and retroperitoneal adipose tissue thickness in genetic forms of lipodystrophy.

INTRODUCTION: Lipodystrophy is a rare disease characterized by the loss of adipose tissue. Visceral adipose tissue loss in certain forms of lipodystrophy may affect the amount of mesenteric fat. METHOD: We studied visceral adipose tissue by measuring the thickness of mesenteric and retroperitoneal adipose tissue and the aortomesenteric (AOM) distance in patients with genetic forms of lipodystrophy (n = 48; 7 males; 41 females; mean age 39.1 ± 11.9 years; 19 with congenital generalized lipodystrophy [CGL], and 29 with familial partial lipodystrophy [FPLD]). An age- and gender-matched control group with a ratio of 1:2 was generated. RESULTS: Patients with CGL had severely depleted mesenteric adipose tissue (2.0 [IQR: 1.5-3.5] mm vs. 18.8 [IQR: 4.4-42.2] mm in FPLD, P < .001; 30.3 [IQR: 13.9-46.6] mm in controls, P < .001) and retroperitoneal adipose tissue (1.3 [IQR: 0.0-5.3] mm vs. 33.7 [IQR: 21.6-42.1] mm in FPLD, P < .001; 29.7 [IQR: 23.1-36.7] mm in controls, P < .001). The AOM distance was shorter in patients with CGL (8.1 [IQR: 6.0-10.8] mm) compared to patients with FPLD (vs. 13.0 [IQR: 8.8-18.1] mm; P = .023) and controls (vs. 11.3 [IQR: 8.4-15.5] mm, P = .016). Leptin levels were positively correlated with AOM distance in lipodystrophy (r = .513, P < .001). Multivariate linear regression analysis identified body mass index as a significant predictor of AOM distance (data controlled for age and sex; beta = 0.537, 95% CI: 0.277-0.798, P < .001). Twelve of 19 patients (63%) with CGL had an AOM distance of < 10 mm, a risk factor that may predispose patients to developing superior mesenteric artery syndrome. CONCLUSION: CGL is associated with a severe loss of mesenteric adipose tissue, which leads to a narrowing of the space between the superior mesenteric artery and the aorta.

Clinical features of generalized lipodystrophy in Turkey: A cohort analysis.

AIM: To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. METHODS: This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. RESULTS: The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. CONCLUSIONS: Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.

Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes.

BACKGROUND: Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2'-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. METHODS: Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. RESULTS: All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. CONCLUSIONS: The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.

Cardiac phenotype in familial partial lipodystrophy.

OBJECTIVES: LMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations. STUDY DESIGN: Retrospective cohort study. METHODS: Clinical data from 122 patients (age range: 13-77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with an LMNA variant were studied as proof-of-concept for future studies. RESULTS: Subjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45-9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04-32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34-9.27). Non-codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41-15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45-127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37-23.76 for conduction disease). LMNA mutant hiPSC-CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC-CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure. CONCLUSIONS: Our results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC-CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.

Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study.

BACKGROUND: Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. METHODS: This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA). RESULTS: Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count. CONCLUSIONS: Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

Metreleptin replacement treatment improves quality of life and psychological well-being in congenital generalized lipodystrophy.

The near total lack of subcutaneous fat in congenital generalized lipodystrophy (CGL) leads to the accumulation of fat in ectopic organs and severe insulin resistance, which are associated with serious metabolic abnormalities. Cosmetic aspects of the disease are likely to affect the quality of life (QoL) and physiological well-being in these individuals. Metreleptin, recombinant human leptin, replacement treatment has been shown to have benefits in treating the metabolic abnormalities of CGL. In a patient with CGL caused by a homozygous AGPAT2 pathogenic variant, we examined QoL and mood alterations (depression and anxiety) caused by this chronic disease. Metreleptin replacement treatment led to dramatic metabolic improvement in our patient. It was also was associated with improvements in QoL, depression and anxiety scores. We suggest that there is need for studies to document the benefit of metreleptin replacement treatment on QoL and physiological well-being in patients with CGL.

A subset of patients with acquired partial lipodystrophy developing severe metabolic abnormalities.

Purpose/Aim of the study: Acquired partial lipodystrophy (APL) is a rare disease characterized by selective loss of adipose tissue. In this study, we aimed to present a subset of patients with APL, who developed severe metabolic abnormalities, from our national lipodystrophy registry. MATERIALS AND METHODS: Severe metabolic abnormalities were defined as: poorly controlled diabetes (HbA1c above 7% despite treatment with insulin more than 1 unit/kg/day combined with oral antidiabetics), severe hypertriglyceridemia (triglycerides above 500 mg/dL despite treatment with lipid-lowering drugs), episodes of acute pancreatitis, or severe hepatic involvement (biopsy-proven non-alcoholic steatohepatitis (NASH)). RESULTS: Among 140 patients with all forms of lipodystrophy (28 with APL), we identified 6 APL patients with severe metabolic abnormalities. The geometric mean for age was 37 years (range: 27-50 years; 4 females and 2 males). Five patients had poorly controlled diabetes despite treatment with high-dose insulin combined with oral antidiabetics. Severe hypertriglyceridemia developed in five patients, of those three experienced episodes of acute pancreatitis. Although all six patients had hepatic steatosis at various levels on imaging studies, NASH was proven in two patients on liver biopsy. Our data suggested that APL patients with severe metabolic abnormalities had a more advanced fat loss and longer disease duration. CONCLUSIONS: We suggest that these patients represent a potential subgroup of APL who may benefit from metreleptin or investigational therapies as standard treatment strategies fail to achieve a good metabolic control.

Osteoprotegrin interacts with biomarkers and cytokines that have roles in osteoporosis, skin fibrosis, and vasculopathy in systemic sclerosis: A potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors.

Objectives: We explored the interactions of osteoprotegerin (OPG) with biomarkers of bone turnover and cytokines, including soluble receptor activator for nuclear factor kappa beta ligand (sRANKL), tumor necrosis factor-related apoptosis-induced ligand (TRAIL), and Wnt inhibitors in osteoporosis, vasculopathy and fibrosis related to systemic sclerosis (SSc). Methods: The study included 46 SSc patients and 30 healthy controls. Skin thickness, pulmonary fibrosis and/or hypertension, digital ulcers, and calcinosis cutis of SSc patients were assessed. We determined bone mineral density (BMD), and OPG, sRANKL, TRAIL, secreted frizzled-related protein 1 (sFRP-1), Dickkopf-related protein 1 (DKK-1), sclerostin in the serum of both patients and controls. Results: OPG, sclerostin, and sFRP-1 levels were similar between patients and controls (P > 0.05). Femoral neck and lumbar spine BMD and vitamin D levels were lower, and the OC, NTX, sRANKL, DKK1 and TRAIL levels were significantly higher, in patients than in controls (p < 0.05). In subgroup analysis, patients with higher modified Rodnan skin score (mRodnan) had higher DKK-1, sclerostin, and TRAIL levels (p < 0.05); those with diffuse SSc subtype had lower BMD values than those with limited SSc (p < 0.05). Skin and pulmonary fibrosis linked negatively with BMD measures. Conclusion: we showed that sRANKL levels were higher and correlated with bone turnover markers. It may be related to osteoporosis in SSc. The OPG level was unaltered in SSc patients. Higher TRAIL levels associated with skin thickness may indicate vascular dysfunction or injury. Higher DKK-1 and sclerostin levels may be related to a reactive increase in cells and be prominently linked to fibrosis in SSc.

Renal complications of lipodystrophy: A closer look at the natural history of kidney disease.

OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.

Phenotypic and Genetic Characteristics of Lipodystrophy: Pathophysiology, Metabolic Abnormalities, and Comorbidities.

PURPOSE OF REVIEW: This article focuses on recent progress in understanding the genetics of lipodystrophy syndromes, the pathophysiology of severe metabolic abnormalities caused by these syndromes, and causes of severe morbidity and a possible signal of increased mortality associated with lipodystrophy. An updated classification scheme is also presented. RECENT FINDINGS: Lipodystrophy encompasses a group of heterogeneous rare diseases characterized by generalized or partial lack of adipose tissue and associated metabolic abnormalities including altered lipid metabolism and insulin resistance. Recent advances in the field have led to the discovery of new genes associated with lipodystrophy and have also improved our understanding of adipose biology, including differentiation, lipid droplet assembly, and metabolism. Several registries have documented the natural history of the disease and the serious comorbidities that patients with lipodystrophy face. There is also evolving evidence for increased mortality rates associated with lipodystrophy. Lipodystrophy syndromes represent a challenging cluster of diseases that lead to severe insulin resistance, a myriad of metabolic abnormalities, and serious morbidity. The understanding of these syndromes is evolving in parallel with the identification of novel disease-causing mechanisms.

Update on Therapeutic Options in Lipodystrophy.

PURPOSE OF REVIEW: The purpose of this review is to summarize the therapeutic approach for lipodystrophy syndromes with conventional treatment options and metreleptin therapy in detail and to point out the current investigational treatments in development. RECENT FINDINGS: The observation of leptin deficiency in patients with lipodystrophy and the potential of leptin replacement to rescue metabolic abnormalities in animal models of lipodystrophy were followed by the first clinical study of leptin therapy in patients with severe lipodystrophy. This and several other long-term studies demonstrated important benefits of recombinant human leptin (metreleptin) to treat metabolic abnormalities of lipodystrophy. These studies ultimately led to the recent FDA approval of metreleptin for the treatment of generalized lipodystrophy and EMA approval for both generalized and partial lipodystrophy. Additional research efforts in progress focus on novel treatment options, predominantly for patients with partial lipodystrophy. Current treatment of generalized lipodystrophy includes metreleptin replacement as an adjunct to diet and standard treatment approach for metabolic consequences of lipodystrophy. Beyond metreleptin, a number of different compounds and treatment modalities are being studied for the treatment of partial lipodystrophy.

A new type of familial partial lipodystrophy: distinctive fat distribution and proteinuria.

PURPOSE: To describe an interesting subtype of familial partial lipodystrophy (FPLD). METHODS: The phenotype of this distinctive FPLD subtype was studied in three Turkish female siblings. RESULTS: Mutation testing was negative for the genes associated with lipodystrophy syndromes. In MRI studies, fat loss was prominent in the posterior aspects of the proximal lower limbs, whilst some fat was preserved in the anterior, medial and lateral aspects. Remarkably, fat tissue was preserved in the distal part of the limbs. Local fat accumulation was observed in the mons pubis area. Asymmetrical fat loss was also remarkable in the upper extremities. All three patients had severe insulin resistance associated with diabetes mellitus, acanthosis nigricans, hypertriglyceridemia and hepatic steatosis. Abnormal amounts of proteinuria were detected in all three subjects. Renal biopsy showed mild tubular atrophy, interstitial fibrosis, irregular thickening and wrinkling of glomerular basal membranes, small areas of segmental sclerosis and pedicel effacement. CONCLUSIONS: We reported a form of FPLD characterized by a striking pattern of highly selective partial fat loss and proteinuria.

The Effect of Retraining on Treatment Success, Quality of Life, and Metabolic Parameters in Patients with Type 1 Diabetes Using an Insulin Pump.

OBJECTIVE: To investigate the effect of insulin pump user retraining on treatment success, quality of life, and metabolic parameters of patients with type 1 diabetes using continuous subcutaneous insulin infusion. SUBJECTS AND METHODS: A total of 35 subjects participated in this prospective study. All patients were given insulin pump user retraining. Their knowledge level and application skills, metabolic parameters, quality of life, and satisfaction from treatment were evaluated at baseline and after 6 months. RESULTS: There was significant improvement in patients' knowledge and application skills after insulin pump user retraining (self-assessment of user skills: 69.7 ± 11.5 vs. 76.3 ± 11.3, p < 0.001; knowledge level on technical issues: 3.3 ± 1.1 vs. 4.1 ± 1.8, p = 0.003; glucose monitoring: 27.1 ± 5.8 vs. 29.2 ± 5.6, p = 0.006; management of hyperglycemia: 13.1 ± 3.2 vs. 15.7 ± 3.4, p < 0.001; management of pump and infusion site problems: 8.8 ± 2.6 vs. 10.6 ± 2.6, p = 0.001). Hemoglobin (Hb)A1c levels of patients with poor glycemic control improved after retraining (8.61% ± 0.78 vs. 8.23% ± 0.79, p = 0.02). However, no significant improvement in quality of life and treatment satisfaction parameters were found. CONCLUSION: Management of type 1 diabetes in insulin pump users can be significantly improved by retraining. Even a basic short-term retraining program helps patients to increase their knowledge level and ability to more effectively use the insulin pump. The fact that retraining significantly improves glycemic parameters in patients with poor metabolic control indicates that priority should be given to this group of patients. Further studies with individualized training programs in larger sample sizes with long-term follow-up are needed to establish the importance of retraining and create re-education plans for patients with type 1 diabetes using an insulin pump.

Circulating apelin levels are associated with cardiometabolic risk factors in women with previous gestational diabetes.

PURPOSE: Women with previous gestational diabetes mellitus (pGDM) are at high risk for type 2 diabetes and cardiovascular disorders. In this study, we aimed to compare plasma apelin levels between women with and without pGDM, and to investigate the possible association of apelin with cardiometabolic risk factors. METHODS: Among 252 consecutive Caucasian women with GDM being included in a prospective postpartum follow-up protocol, 141 women eligible for the study protocol were enrolled. Control group consisted of 49 age- and body mass index-matched healthy women without pGDM. Circulating apelin, IL-6 and plasminogen activator inhibitor levels, and carotid intima media thickness (IMT) were measured. To evaluate carbohydrate intolerance, 75-g oral glucose tolerance test was performed. Fasting insulin and lipids were measured, and homeostasis model assessment index was calculated. RESULTS: Plasma apelin levels were reduced in women with pGDM (p < 0.001). In multiple regression analysis, apelin was negatively associated with fasting (r (2) 0.090, ß -0.273, p = 0.001) and post-load glucose (r (2) 0.061, ß -0.187, p = 0.022), serum IL-6 (r (2) 0.082, ß -0.234, p = 0.002), and carotid IMT (r (2) 0.057, ß -0.168, p = 0.033). CONCLUSIONS: Our results suggested that suppressed apelin levels were associated with increased cardiovascular risk in women with pGDM.

Diagnosis, treatment and management of lipodystrophy: the physician perspective on the patient journey.

BACKGROUND: Lipodystrophy syndromes are a heterogeneous group of rare, life-limiting diseases characterized by a selective loss of adipose tissue and severe metabolic complications. There is a paucity of information describing the experiences and challenges faced by physicians who have seen and treated patients with lipodystrophy. This study aimed to provide a better understanding of the physician's perspective regarding the patient journey in lipodystrophy, including diagnosis, the burden of disease, and treatment approaches. METHODS: Thirty-three physicians from six countries who had seen or treated patients with lipodystrophy were interviewed using a semi-structured questionnaire. Interviews were transcribed, anonymized, and analyzed for themes and trends. Four main themes were developed: (1) the diagnostic journey in lipodystrophy including the disease features or 'triggers' that result in the onward referral of patients to specialist medical centers with experience in managing lipodystrophy; (2) the impact of lipodystrophy on patient quality of life (QoL); (3) the use of standard therapies and leptin replacement therapy (metreleptin) in lipodystrophy, and (4) barriers to metreleptin use. RESULTS: Participants reported that, due to their rarity and phenotypic heterogeneity, lipodystrophy cases are frequently unrecognized, leading to delays in diagnosis and medical intervention. Early consultation with multidisciplinary specialist medical teams was recommended for suspected lipodystrophy cases. The development and progression of metabolic complications were identified as key triggers for the referral of patients to specialist centers for follow-up care. Participants emphasized the impact of lipodystrophy on patient QoL, including effects on mental health and self-image. Although participants routinely used standard medical therapies to treat specific metabolic complications associated with lipodystrophy, it was acknowledged that metreleptin was typically required in patients with congenital generalized lipodystrophy and in some acquired generalized and partial lipodystrophy cases. A lack of experience among some participants and restrictions to access remained as barriers to metreleptin use. CONCLUSIONS: To our knowledge, this is one of the first studies describing the qualitative experiences of physicians regarding the diagnosis and management of lipodystrophy. Other physician-centered studies may help increase the awareness of lipodystrophy among the wider medical community and support clinical approaches to this rare disease.

A rapid action plan to improve diagnosis and management of lipodystrophy syndromes.

Introduction: Lipodystrophy syndromes are rare diseases that can present with a broad range of symptoms. Delays in diagnosis are common, which in turn, may predispose to the development of severe metabolic complications and end-organ damage. Many patients with lipodystrophy syndromes are only diagnosed after significant metabolic abnormalities arise. Prompt action by clinical teams may improve disease outcomes in lipodystrophy syndromes. The aim of the Rapid Action Plan is to serve as a set of recommendations from experts that can support clinicians with limited experience in lipodystrophy syndromes. Methods: The Rapid Action Plan was developed using insights gathered through a series of advisory meetings with clinical experts in lipodystrophy syndromes. A skeleton template was used to facilitate interviews. A consensus document was developed, reviewed, and approved by all experts. Results: Lipodystrophy is a clinical diagnosis. The Rapid Action Plan discusses tools that can help diagnose lipodystrophy syndromes. The roles of clinical and family history, physical exam, patient and family member photos, routine blood tests, leptin levels, skinfold measurements, imaging studies, and genetic testing are explored. Additional topics such as communicating the diagnosis to the patients/families and patient referrals are covered. A set of recommendations regarding screening and monitoring for metabolic diseases and end-organ abnormalities is presented. Finally, the treatment of lipodystrophy syndromes is reviewed. Discussion: The Rapid Action Plan may assist clinical teams with the prompt diagnosis and holistic work-up and management of patients with lipodystrophy syndromes, which may improve outcomes for patients with this rare disease.

Impact of lipodystrophy on health-related quality of life: the QuaLip study.

BACKGROUND: Lipodystrophy is a rare disease characterized by loss of adipose tissue. Natural history studies have demonstrated significant burden of disease; however, there is limited data on the impact of lipodystrophy on quality of life (QoL) and psychoemotional well-being. The QuaLip study is a prospective observational real-world study that aims to determine the impact of lipodystrophy on QoL and psychoemotional well-being and explore subjective burden of the disease. Sixty-seven adult patients and eight pediatric patients with lipodystrophy were included. Patients were followed up for 24 months and assessments were repeated every three months. Patients were examined by licensed psychiatrists at baseline, and at year 1 and year 2 visits. RESULTS: Eighteen (27.69%) of 65 adult patients (two subjects refused psychiatric assessment) were diagnosed with a psychiatric disorder (e.g., depressive episodes, mixed anxiety and depressive disorder, anxiety disorder, adjustment disorder, recurrent depression, panic disorder, generalized anxiety disorder, unspecified mood disorder, nonorganic sleep disorder, post-traumatic stress disorder, depressive episode comorbidity, social phobia and obsessive-compulsive disorder comorbidity). Lipodystrophy disease and QoL questionnaires revealed a significant disease burden over the study period. More than one-third of patients reported depression symptoms on the Beck Depression Inventory and more than one-fourth of the patients reported significant hunger throughout the study period. Physical appearance, fatigue, and pain contributed to the disease burden. QoL scores were lower in patients with psychiatric disease and in those with poor metabolic control. Attention deficit hyperactivity disorder, depressive disorder, sub-threshold depressive symptoms, obsessive-compulsive disorder, appetite problems, and issues with physical appearance were identified in selected pediatric subjects. CONCLUSIONS: Lipodystrophy has a significant impact on QoL and psychoemotional well-being. Psychiatric disorders seem to be underdiagnosed among patients with lipodystrophy.