Two adrenalectomies py -45erformed fourteen years apart notoriously alleviated insulin resistance in a female teenager with Congenital Generalized Lipoatrophy (CGL, 1988) and in a murine model of CGL (2002). Following a successful therapeutic trial with anti-glucocorticoids, we performed the first surgical procedure on an 18-year-old girl. Before surgery, the anti-glucocorticoid therapy produced a rapid and striking drop in fasting serum insulin levels (from over 400 to 7.0 mU/L) and a slower -but impressive- fall in fasting serum triglycerides from 7,400 to 220-230 mg/dL. In contrast, fasting serum glucose levels dropped more slowly, from 225-290 to 121-138 mg/dL. Two weeks following total adrenalectomy, the fasting serum glucose level was 98 mg/dL, with a corresponding serum insulin level of 10 mU/L. During an Oral Glucose Tolerance Test, the 2-hour serum glucose was 210 mg/dL, and serum insulin values during the test did not exceed 53 mU/L. In 2002, the A-ZIP/F1 hypoleptinemic mouse had its adrenal glands removed. Even though this CGL model does not respond well to leptin replacement, an infusion of recombinant leptin reduced the characteristic hypercorticosteronemia of this murine model of CGL. Adrenalectomy in this transgenic mouse improved insulin sensitivity in the liver and muscle. In summary, adrenalectomy -in both a human and a mouse case of CGL- limited adipose tissue exposure to corticosteroid action and led to a notorious metabolic improvement. On a broader scenario, given that leptin restrains the adrenal axis, the reduced leptin activity of the leptin resistance displayed by obese subjects should lead to adrenal axis overactivity. This overactivity should result in elevated serum levels of free cortisol, free fatty acids, and glycerol. In this manner, leptin resistance should lead to peripheral (adipose tissue, liver, and muscle) insulin resistance and islet beta-cell apoptosis, paving the way to Type 2 diabetes.

Subjects with Familial Partial Lipodystrophy type 2 (FPLD2) are at high risk to develop diabetes. To better understand the natural history and variability of this disease, we studied glucose tolerance, insulin response to an oral glucose load, and metabolic markers in the largest cohort to date of subjects with FPLD2 due to the same LMNA variant.
A total of 102 patients aged > 18 years, with FPLD2 due to the LMNA \'Reunionese\' variant p.(Thr655Asnfs*49) and 22 unaffected adult relatives with normal glucose tolerance (NGT) were enrolled. Oral Glucose Tolerance Tests (OGTT) with calculation of derived insulin sensitivity and secretion markers, and measurements of HbA1c, C-reactive protein, leptin, adiponectin and lipid profile were performed.
In patients with FPLD2: 65% had either diabetes (41%) or prediabetes (24%) despite their young age (median: 39.5 years IQR 29.0-50.8) and close-to-normal BMI (median: 25.5 kg/m2 IQR 23.1-29.4). Post-load OGTT values revealed insulin resistance and increased insulin secretion in patients with FPLD2 and NGT, whereas patients with diabetes were characterized by decreased insulin secretion. Impaired glucose tolerance with normal fasting glucose was present in 86% of patients with prediabetes. Adiponectin levels were decreased in all subjects with FPLD2 and correlated with insulin sensitivity markers.
OGTT reveals early alterations of glucose and insulin metabolism in patients with FPLD2, and should be systematically performed before excluding a diagnosis of prediabetes or diabetes to adapt medical care. Decreased adiponectin is an early marker of the disease. Adiponectin replacement therapy warrants further study in FPLD2.

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.
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.
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.
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.

Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.

暂无摘要。

Lipodystrophy (LD) syndromes are a group of rare and heterogeneous diseases characterized by a congenital deficiency or acquired loss of adipose tissue. Due to the resulting disorder of metabolism, sometimes severe sequelae can develop, such as hypertriglyceridemia, marked insulin resistance and early manifestation of type 2 diabetes, recurrent pancreatitis, fatty liver disease and liver fibrosis. Lipodystrophies are clinically recognizable due to the complete lack of subcutaneous adipose tissue or a conspicuous pattern of the distribution of body fat. Acanthosis nigricans in slimly built persons, a high fasting triglyceride level and elevated concentrations of liver enzymes as well as a positive history of pancreatitis can be indications of LD.

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.

Obesity is one of the major risk factors for the development of cardiovascular diseases and is characterized by abnormal accumulation of adipose tissue, including perivascular adipose tissue (PVAT). However, brown adipose tissue (BAT) activation reduces visceral adiposity. To demonstrate that severe brown fat lipoatrophy might accelerate atherosclerotic process, we generated a new mouse model without insulin receptor (IR) in BAT and without apolipoprotein (Apo)E (BAT-specific IR knockout [BATIRKO];ApoE(-/-) mice) and assessed vascular and metabolic alterations associated to obesity. In addition, we analyzed the contribution of the adipose organ to vascular inflammation. Brown fat lipoatrophy induces visceral adiposity, mainly in gonadal depot (gonadal white adipose tissue [gWAT]), severe glucose intolerance, high postprandial glucose levels, and a severe defect in acute insulin secretion. BATIRKO;ApoE(-/-) mice showed greater hypertriglyceridemia than the obtained in ApoE(-/-) and hypercholesterolemia similar to ApoE(-/-) mice. BATIRKO;ApoE(-/-) mice, in addition to primary insulin resistance in BAT, also showed a significant decrease in insulin signaling in liver, gWAT, heart, aorta artery, and thoracic PVAT. More importantly, our results suggest that severe brown fat lipoatrophy aggravates the atherosclerotic process, characterized by a significant increase of lipid depots, atherosclerotic coverage, lesion size and complexity, increased macrophage infiltration, and proinflammatory markers expression. Finally, an increase of TNF-α and leptin as well as a decrease of adiponectin by BAT, gWAT, and thoracic PVAT might also be responsible of vascular damage. Our results suggest that severe brown lipoatrophy aggravates atherosclerotic process. Thus, BAT activation might protect against obesity and its associated metabolic alterations.

The proposed hypothesis suggests that major function of insulin is stimulation of triglyceride accumulation in adipose tissue and glycogen synthesis in liver and muscles. The impairment of insulin functioning diminishes triglyceride storage in adipose tissue, elevates the level of its metabolite in periphery and suppresses glucose intake by cells. Leptin disturbs direct insulin action on adipocytes, and prevents fat accumulation. Leptin deficiency or impairment of its functioning facilitate lipogenic effect of insulin, and induce obesity. Lipodystrophy decreases leptin secretion and enhances triglyceride production activated by insulin. Triglycerides are not accumulated in adipose tissue because of its deficiency, and overwhelm peripheral tissues. Lipid metabolites decrease glucose consumption and induce lipoatrophic diabetes. The hypothesis on the lipogenic insulin functioning is confirmed by specific knockout of Insr gene in only tissue: muscles, adipose tissue and other, and by the restoration of its expression in transgenic mice.

Berardinelli-Seip syndrome is a rare autosomal recessive disease characterized by inadequate metabolism and inefficient storing of lipids in fat cells, generating accumulation of fat in organs such as the liver, spleen, pancreas, heart, arterial endothelium and skin. Classically, patients manifest generalized lipoatrophy at birth or until 2 years of age, and in adolescence usually develop marked insulin resistance with rapid progression to diabetes and dyslipidemia. We report the case of a 17-year-old Berardinelli-Seip syndrome patient with eruptive xanthoma associated with severe hypertriglyceridemia. It is worth noting Eruptive xanthoma as a dermatological manifestation that is not generally highlighted in the reports of cases of this genetic metabolic disorder.