Regional Decrease of Subcutaneous Adipose Tissue in Patients with Type 2 Familial Partial Lipodystrophy Is Associated with Changes in Thyroid Hormone Metabolism

Summary Proteinuric renal disease is prevalent in congenital or acquired forms of generalized lipodystrophy. In contrast, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases. A 22-year-old female patient presented with impaired glucose tolerance, hyperinsulinemia, hirsutism and oligomenorrhea. On examination, there was partial loss of subcutaneous adipose tissue in the face, upper and lower limbs, bird-like facies with micrognathia and low set ears and mild acanthosis nigricans. Laboratory investigations revealed hyperandrogenism, hyperlipidemia, elevated serum creatine kinase and mild proteinuria. A clinical diagnosis of FPLD of the non-Dunnigan variety was made; genetic testing revealed a heterozygous c.1045C > T mutation in exon 6 of the LMNA gene, predicted to result in an abnormal LMNA protein (p.R349W). Electromyography and muscle biopsy were suggestive of non-specific myopathy. Treatment with metformin and later with pioglitazone was initiated. Due to worsening proteinuria, a renal biopsy was performed; histological findings were consistent with mild focal glomerular mesangioproliferative changes, and the patient was started on angiotensin-converting enzyme inhibitor therapy. This is the fourth report of FPLD associated with the c.1045C > T missense LMNA mutation and the second with co-existent proteinuric renal disease. Patients carrying this specific mutation may exhibit a phenotype that includes partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy. Learning points: Lipodystrophy is a rare disorder characterized by the complete or partial loss of subcutaneous adipose tissue, insulin resistance, diabetes mellitus and hyperlipidemia. Proteinuric renal disease is a prevalent feature of generalized lipodystrophy but rare in familial partial lipodystrophy. Patients carrying the c.1045C > T missense LMNA mutation (p.R349W) may present with familial partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.

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Familial Partial Lipodystrophy: A Case Study and Review of Recent Literature

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.629 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A308-A309

Author(s):

Ali Tipu ◽

Farhad Hasan ◽

Michael Grimes

Keyword(s):

Adipose Tissue ◽

Autosomal Dominant ◽

Recent Literature ◽

Subcutaneous Fat ◽

Metabolic Abnormalities ◽

Partial Lipodystrophy ◽

Type 2 Dm ◽

Familial Partial Lipodystrophy ◽

Subcutaneous Adipose

Abstract Introduction: Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by loss of subcutaneous adipose tissue, mainly from the extremities and gluteal region. FPLD is associated with a variety of metabolic abnormalities including severe hypertriglyceridemia (HTG), insulin resistance (IR), and hepatic steatosis. We present a case of FPLD and summarize recent literature on the metabolic features and their management in patients with this rare disease. Case: A 44 year old female with medical history of Type 2 DM, hypertension, hypothyroidism and recurrent pancreatitis from severe HTG was referred to our clinic. She was diagnosed with Type 2 DM in her 30s. Over the ensuing years she had significant IR requiring increasing doses of concentrated insulin (up to 250 units/day). She reported progressive loss of subcutaneous fat from extremities in the preceding 2–3 years. She had recurrent pancreatitis, including a recent hospitalization with TG>8000 mg/dL. On examination, she had typical features of FPLD including loss of subcutaneous adipose tissue from upper and lower extremities including gluteal region, visible skeletal muscles and veins in the extremities, and neck and truncal obesity (Fig. 1). Family history was significant for similar physical and metabolic manifestations in her father and brother. For HTG, she is treated with fibrates and high intensity statin. We avoided the use of fish oil in the patient, because she did not feel well when she was previously on this. Results of the genetic testing are pending. Discussion: FPLD is rare, predominantly autosomal dominant, disorder characterized phenotypically by variable loss of subcutaneous fat and metabolically by severe HTG and insulin resistance. The severity of metabolic derangements is proportional to the degree of the lipodystrophy. The proposed mechanism is limited capacity of adipose tissue to store fat leading to ectopic fat deposition, lipotoxicity and vascular inflammation. Diagnosis is often clinical, especially the loss of subcutaneous fat in the extremities and signs of IR, and is confirmed by genetic testing. Dunnigan syndrome is the most common type of FPLD, which occurs from an autosomal dominant missense mutation in lamin A/C (LMNA). Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much less common. Treatment of FPLD is challenging, and mostly focuses on managing the metabolic abnormalities. Recent evidence suggests that fish oil may in fact worsen HTG when the main defect driving increased TG is impaired chylomicron clearance, which our patient had on lipid NMR profile. Metreleptin, a human leptin analog, has recently been approved for the management of FPLD with evidence of improved metabolic abnormalities. Recent data also suggests that GLP1 agonists and SGLT2 inhibitors improved glycemic control and reduced daily insulin requirements.

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Pathogenic Microenvironment from Diabetic–Obese Visceral and Subcutaneous Adipocytes Activating Differentiation of Human Healthy Preadipocytes Increases Intracellular Fat, Effect of the Apocarotenoid Crocetin

Nutrients ◽

10.3390/nu13031032 ◽

2021 ◽

Vol 13 (3) ◽

pp. 1032

Author(s):

Lesgui Alviz ◽

David Tebar-García ◽

Raquel Lopez-Rosa ◽

Eva M. Galan-Moya ◽

Natalia Moratalla-López ◽

...

Keyword(s):

Adipose Tissue ◽

Subcutaneous Adipose Tissue ◽

Bioactive Components ◽

Hypertrophic Growth ◽

Visceral Adipose ◽

Subcutaneous Adipose ◽

Oil Red O Staining ◽

Oil Red O ◽

Excessive Accumulation

In diabetes mellitus type 2 (DM2), developed obesity is referred to as diabesity. Implementation of a healthy diet, such as the Mediterranean, prevents diabesity. Saffron is frequently used in this diet because of its bioactive components, such as crocetin (CCT), exhibit healthful properties. It is well known that obesity, defined as an excessive accumulation of fat, leads to cardiometabolic pathology through adiposopathy or hypertrophic growth of adipose tissue (AT).This is related to an impaired adipogenic process or death of adipocytes by obesogenic signals. We aimed to evaluate the effect of the pathogenic microenvironment and CCT, activating differentiation of healthy preadipocytes (PA). For this, we used human cryopreserved PA from visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) depots obtained from healthy and obese-DM2 donors. We studied the effect of a metabolically detrimental (diabesogenic) environment, generated by obese-DM2 adipocytes from VAT (VdDM) or SAT (SdDM), on the viability and accumulation of intracellular fat of adipocytes differentiated from healthy PA, in the presence or absence of CCT (1 or 10 μM). Intracellular fat was quantified by Oil Red O staining. Cytotoxicity was measured using the MTT assay. Our results showed that diabesogenic conditions induce cytotoxicity and provide a proadipogenic environment only for visceral PA. CCT at 10 μM acted as an antiadipogenic and cytoprotective compound.

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The Mineralocorticoid Receptor Antagonist Eplerenone Suppress Interstitial Fibrosis in Subcutaneous Adipose Tissue in Type 2 Diabetes Patients

10.2337/figshare.13050743.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Marie Louise Johansen ◽

Jaime Ibarrola ◽

Amaya Fernández-Celis ◽

Morten Schou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Receptor Antagonist ◽

Subcutaneous Adipose Tissue ◽

Mineralocorticoid Receptor ◽

Prostaglandin D2 ◽

Type I ◽

Mineralocorticoid Receptor Antagonist ◽

Subcutaneous Adipose

Activation of the mineralocorticoid receptor (MR) may promote dysfunctional adipose tissue in patients with type 2 diabetes, where increased pericellular fibrosis has emerged as a major contributor. The knowledge of the association between the MR, fibrosis and the effects of an MR antagonist (MRA) in human adipocytes remains very limited. The present sub-study including 30 participants was prespecified as part of the Mineralocorticoid Receptor Antagonist in type 2 Diabetes (MIRAD) trial, randomizing patients to either high dose eplerenone or placebo for 26 weeks. In adipose tissue biopsies, changes in fibrosis were evaluated by immunohistological examinations and by the expression of mRNA and protein markers of fibrosis. Treatment with an MRA reduced pericellular fibrosis, synthesis of the major subunits of collagen type I and VI, and the profibrotic factor α-smooth muscle actin, as compared to placebo in subcutaneous adipose tissue. Furthermore, we found decreased expression of the MR and downstream molecules neutrophil gelatinase–associated lipocalin, galectin-3, and lipocalin-like prostaglandin D2 synthase with an MRA. In conclusions, we present original data demonstrating reduced fibrosis in adipose tissue with inhibition of the MR, which could be a potential therapeutic approach to prevent the extracellular matrix remodeling of adipose tissue in type 2 diabetes.

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The Mineralocorticoid Receptor Antagonist Eplerenone Suppresses Interstitial Fibrosis in Subcutaneous Adipose Tissue in Patients With Type 2 Diabetes

Diabetes ◽

10.2337/db20-0394 ◽

2020 ◽

Vol 70 (1) ◽

pp. 196-203

Author(s):

Marie Louise Johansen ◽

Jaime Ibarrola ◽

Amaya Fernández-Celis ◽

Morten Schou ◽

Mette Pauli Sonne ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Receptor Antagonist ◽

Subcutaneous Adipose Tissue ◽

Mineralocorticoid Receptor ◽

Interstitial Fibrosis ◽

Mineralocorticoid Receptor Antagonist ◽

Subcutaneous Adipose

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Adiponectin expression in adipose tissue is reduced in first-degree relatives of type 2 diabetic patients

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00358.2002 ◽

2003 ◽

Vol 284 (2) ◽

pp. E443-E448 ◽

Cited By ~ 43

Author(s):

A. S. Lihn ◽

T. Østergård ◽

B. Nyholm ◽

S. B. Pedersen ◽

B. Richelsen ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Subcutaneous Adipose Tissue ◽

Diabetic Patients ◽

Mrna Levels ◽

Type 2 Diabetic Patients ◽

Adiponectin Mrna ◽

Subcutaneous Adipose ◽

Type 2 Diabetic

Adiponectin is suggested to be an important mediator of insulin resistance. Therefore, we investigated the association between adiponectin and insulin sensitivity in 22 healthy first-degree relatives (FDR) to type 2 diabetic patients and 13 matched control subjects. Subcutaneous adipose tissue biopsies were taken before and after a hyperinsulinemic euglycemic clamp. FDR subjects were insulin resistant, as indicated by a reduced Mvalue (4.44 vs. 6.09 mg · kg−1· min−1, P < 0.05). Adiponectin mRNA expression was 45% lower in adipose tissue from FDR compared with controls ( P < 0.01), whereas serum adiponectin was similar in the two groups (6.4 vs. 6.6 μg/ml, not significant). Insulin infusion reduced circulating levels of adiponectin moderately (11–13%) but significantly in both groups ( P < 0.05). In the control group, adiponectin mRNA levels were negatively correlated with fasting insulin ( P < 0.05) and positively correlated with insulin sensitivity ( P < 0.05). In contrast, these associations were not found in the FDR group. In conclusion, FDR have reduced adiponectin mRNA in subcutaneous adipose tissue but normal levels of circulating adiponectin. Adiponectin mRNA levels are positively correlated with insulin sensitivity in control subjects but not in FDR. These findings indicate dysregulation of adiponectin gene expression in FDR.

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Human subcutaneous adipose tissue Glut 4 mRNA expression in obesity and type 2 diabetes

Acta Diabetologica ◽

10.1007/s00592-011-0295-8 ◽

2011 ◽

Vol 50 (2) ◽

pp. 227-232 ◽

Cited By ~ 19

Author(s):

Soumaya Kouidhi ◽

Rym Berrhouma ◽

Kamel Rouissi ◽

Slim Jarboui ◽

Marie-Stéphanie Clerget-Froidevaux ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Mrna Expression ◽

Subcutaneous Adipose Tissue ◽

Glut 4 ◽

Subcutaneous Adipose

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Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.769069 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuan Zhu ◽

Jiao Xu ◽

Dong Zhang ◽

Xingyu Mu ◽

Yi Shi ◽

...

Keyword(s):

Systematic Review ◽

Adipose Tissue ◽

Subcutaneous Adipose Tissue ◽

Fatty Liver Disease ◽

Meta Analysis ◽

Efficacy And Safety ◽

Alcoholic Fatty Liver ◽

Subcutaneous Adipose ◽

Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is increasing and there is an urgent need for new treatment strategy to prevent progression of hepatic steatosis and fibrosis. We have performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of hepatic steatosis and fibrosis in patients with T2DM and NAFLD. The PubMed, Web of Science, Scopus, Embase and Cochrane Central Register of Controlled Trials databases were searched for articles that met the eligibility criteria to explore the efficacy and safety of GLP-1RAs in patients with T2DM and NAFLD. We assessed pooled data using a random/fixed-effects model according to the I2 and p-values. Eight trials that included a total of 468 participants were eligible for inclusion in the review. For primary outcomes, administration of GLP-1RAs significantly decreased the content of intrahepatic adipose (IHA)[p=0.007, weight mean difference (WMD) -3.01, 95% confidence interval (CI) -4.75, -1.28], subcutaneous adipose tissue (SAT) (p<0.00001,WMD -28.53,95%CI -68.09,-26.31), and visceral adipose tissue (VAT) (p<0.0001,WMD -29.05,95%CI -42.90,-15.9). For secondary outcomes, GLP-1RAs produced a significant decrease in levels of alanine aminotransferase(ALT)(p=0.02, WMD -3.82, 95%CI -7.04, -0.60), aspartate aminotransferase (AST) (p=0.03, WMD -2.4, 95%CI -4.55,-0.25, I2 = 49%), body weight (p<0.00001,WMD -3.48,95%CI -4.58,-2.37), body mass index (p<0.00001,WMD -1.07,95%CI -1.35,-0.78), circumference waist (p=0.0002,WMD -3.87, 95%CI -5.88, -1.86) fasting blood glucose (p=0.02, WMD -0.35, 95%CI -0.06, -0.05), HbA1c (p<0.00001,WMD -0.39,95%CI -0.56,-0.22), HoMA-IR(p=0.005, WMD-1.51, 95%CI-0.87,-0.16), total cholesterol (p=0.0008, WMD -0.31, 95%CI -0.48, 0.13) and triglycerides (p=0.0008, WMD -0.27, 95%CI -0.43,-0.11) in comparison with the control regimens. The main adverse events associated with GLP-1RAs included mild-to-moderate gastrointestinal discomfort and nonsense hypoglycemia that resolved within a few weeks. GLP-1RAs were an effective treatment that improved intrahepatic visceral and subcutaneous adipose tissue, inflammatory markers, the anthropometric profiles and some metabolic indices in patients with T2DM and NAFLD, GLP-1RAs could be considered for use in these if there are no contraindications. Further studies are needed to understand the direct and indirect effects of GLP-1RAs on NAFLD and the potential mechanism via which they prevent its progression.Systematic Review Registration: PROSPERO, identifier CRD42021265806.

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