Lipoatrophic diabetes in familial partial lipodystrophy type 2: From insulin resistance to diabetes.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer.

BACKGROUND: In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits. METHODS: In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization. RESULTS: Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of -0.3 percentage points (two-sided 90% CI, -2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported. CONCLUSIONS: In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years. (Funded by the French National Cancer Institute; ESTIMABL2 ClinicalTrials.gov number, NCT01837745.).

A recurrent familial partial lipodystrophy due to a monoallelic or biallelic LMNA founder variant highlights the multifaceted cardiac manifestations of metabolic laminopathies.

AIMS: LMNA-linked familial partial lipodystrophy type 2 (FPLD2) leads to insulin resistance-associated metabolic complications and cardiovascular diseases. We aimed to characterise the disease phenotype in a cohort of patients carrying an LMNA founder variant. METHODS: We collected clinical and biological data from patients carrying the monoallelic or biallelic LMNA p.(Thr655Asnfs*49) variant (n = 65 and 13, respectively) and 19 non-affected relative controls followed-up in Reunion Island Lipodystrophy Competence Centre, France. RESULTS: Two-thirds of patients with FPLD2 (n = 51) and one-third of controls (n = 6) displayed lipodystrophy and/or lean or android morphotype (P = 0.02). Although age and BMI were not statistically different between the two groups, the insulin resistance index (median HOMA-IR: 3.7 vs 1.5, P = 0.001), and the prevalence of diabetes, dyslipidaemia, and non-alcoholic fatty liver disease were much higher in patients with FPLD2 (51.3 vs 15.8%, 83.3 vs 42.1%, and 83.1 vs 33.3% (all P ≤ 0.01), respectively). Atherosclerosis tended to be more frequent in patients with FPLD2 (P = 0.07). Compared to heterozygous, homozygous patients displayed more severe lipoatrophy and metabolic alterations (lower BMI, fat mass, leptin and adiponectin, and higher triglycerides P ≤ 0.03) and tended to develop diabetes more frequently, and earlier (P = 0.09). Dilated cardiomyopathy and/or rhythm/conduction disturbances were the hallmark of the disease in homozygous patients, leading to death in four cases. CONCLUSIONS: The level of expression of the LMNA 'Reunionese' variant determines the severity of both lipoatrophy and metabolic complications. It also modulates the cardiac phenotype, from atherosclerosis to severe cardiomyopathy, highlighting the need for careful cardiac follow-up in affected patients.

Aging and glycation promote erythrocyte phagocytosis by human endothelial cells: Potential impact in atherothrombosis under diabetic conditions.

BACKGROUND AND AIMS: Atherothrombotic plaques of type 2 diabetic (T2D) patients are characterized by an increased neovascularization and intraplaque hemorrhage. The clearance of erythrocytes may be carried out by vascular cells. We explored the potential of human endothelial cells to bind and phagocyte in vitro aged and/or glycated erythrocytes as well as erythrocytes obtained from diabetic patients. METHODS: Fresh, aged and glycated-aged erythrocytes from healthy volunteers and T2D patients were tested for their binding and phagocytosis capacity as well as the potential functional consequences on endothelial cells (viability, proliferation and wound healing capacity). Immunohistochemistry was also performed in human carotid atherothrombotic samples (from patients with or without T2D). RESULTS: Aging and glycation of erythrocytes induced phosphatidylserine (PS) exposure and oxidative stress leading to enhanced endothelial cell binding and engulfment. Phagocytosis by endothelial cells was more pronounced with aged and glycated erythrocytes than with fresh ones. Phagocytosis was enhanced with T2D versus healthy erythrocytes. Furthermore, endothelial wound healing potential was significantly blunted after exposure to glycated-aged versus fresh erythrocytes. Finally, we show that interactions between erythrocytes and endothelial cells and their potential phagocytosis may occur in vivo, in atherothrombotic conditions, in neovessels and in the luminal endothelial lining. CONCLUSIONS: Endothelial cells may play an important role in erythrocyte clearance in an atherothrombotic environment. Under diabetic conditions, erythrocyte glycation favors their engulfment by endothelial cells and may participate in endothelial dysfunction, thereby promoting vulnerable atherothrombotic plaques to rupture.

Relationship between pre-pregnancy maternal BMI and optimal weight gain in singleton pregnancies.

BACKGROUND: There is a peculiar phenomenon: two separate individuals (mother and foetus) have a mutually interactive dependency concerning their respective weight. Very thin mothers have a higher risk of small for gestational age (SGA) infants, and rarely give birth to a large for gestational age (LGA) infant. While morbidly obese women often give birth to LGA infants, and rarely to SGA. Normal birthweight (AGA) infants (>10th and <90th centile of a neonatal population) typically have the lowest perinatal and long-term morbidity. The aim of the current study is (1) to determine the maternal body mass index (BMI) range associated with a balanced risk (10% SGA, 10% LGA), and (2) to investigate the interaction between maternal booking BMI, gestational weight gain (GWG) and neonatal birthweight centiles. METHODS: 16.5 year-observational cohort study (2001-2017). The study population consisted of all consecutive singleton term (37 weeks onward) live births delivered at University's maternity in Reunion island, French Overseas Department. FINDINGS: Of the 59,717 singleton term live births, we could define the booking BMI and the GWG in 52,092 parturients (87.2%). We had 2 major findings (1) Only women with a normal BMI achieve an equilibrium in the SGA/LGA risk (both 10%). We propose to call this crossing point the Maternal Fetal Corpulence Symbiosis (MFCS). (2) This MFCS shifts with increasing GWG. We tested the MFCS by 5 kg/m2 incremental BMI categories. The result is a linear law:opGWG (kg) = -1.2 ppBMI (Kg/m²) + 42 ± 2 kg. INTERPRETATION: IOM-2009 recommendations are adequate for normal and over-weighted women but not for thin and obese women: a thin woman (17 kg/m2) should gain 21.6 ± 2 kg (instead of 12.5-18). An obese 32 kg/m2 should gain 3.6 kg (instead of 5-9). Very obese 40 kg/m2 should lose 6 kg.

Sexual dimorphism in the association between gestational diabetes mellitus and overweight in offspring at 5-7 years: The OBEGEST cohort study.

Evidence from literature is mixed regarding a possible association of maternal gestational diabetes mellitus (GDM) and overweight in the offspring. Sexual dimorphism, or sex disparities in the pathogenesis linking GDM exposure to overweight, could be at play. The objective of this study was to investigate the association between GDM and child overweight at 5-7 years. Six hundred pairs (1:1) of Reunionese liveborn singletons selected from a hospital-based birth registry, matched for sex, gestational age, and birth period, underwent a prospective in-home follow-up and were analyzed with respect to their exposure to GDM. The primary outcome was child overweight at 5-7 years, as defined by the International Obesity Task Force. The association between GDM exposure and child overweight was estimated by the odds ratio (OR) using conditional logistic regression models. For the subset of children exposed to GDM with available maternal glycemic data, we analyzed the relationship between maternal glycemic levels during pregnancy and child body mass index (BMI) at 5-7 years with a linear regression model. In light of the significant interaction between sex and GDM, all statistical analyses were then stratified by sex. After controlling for pre-pregnancy BMI and maternal sociodemographic characteristics, the risk of overweight increased with exposure to GDM for boys (adjusted OR: 2.34; 95% confidence interval = 1.26-4.34, P = 0.007) but not for girls (adjusted OR: 0.56; 95%CI = 0.28-1.10, P = 0.093). Consistent with this, the linear increase of boys' BMI at 5-7 years with maternal blood glucose levels during pregnancy, in the exposed group, displayed a dose-response relationship. Our findings indicate that exposure to GDM is a risk factor for childhood overweight in boys but not in girls, which adds to the growing body of evidence suggesting greater sensitivity of male offspring to intrauterine hyperglycemia.

Glycation of human serum albumin impairs binding to the glucagon-like peptide-1 analogue liraglutide.

The long-acting glucagon-like peptide-1 analogue liraglutide has proven efficiency in the management of type 2 diabetes and also has beneficial effects on cardiovascular diseases. Liraglutide's protracted action highly depends on its capacity to bind to albumin via its palmitic acid part. However, in diabetes, albumin can undergo glycation, resulting in impaired drug binding. Our objective in this study was to assess the impact of human serum albumin (HSA) glycation on liraglutide affinity. Using fluorine labeling of the drug and 19F NMR, we determined HSA affinity for liraglutide in two glycated albumin models. We either glycated HSA in vitro by incubation with glucose (G25- or G100-HSA) or methylglyoxal (MGO-HSA) or purified in vivo glycated HSA from the plasma of diabetic patients with poor glycemic control. Nonglycated commercial HSA (G0-HSA) and HSA purified from plasma of healthy individuals served as controls. We found that glycation decreases affinity for liraglutide by 7-fold for G100-HSA and by 5-fold for MGO-HSA compared with G0-HSA. A similarly reduced affinity was observed for HSA purified from diabetic individuals compared with HSA from healthy individuals. Our results reveal that glycation significantly impairs HSA affinity to liraglutide and confirm that glycation contributes to liraglutide's variable therapeutic efficiency, depending on diabetes stage. Because diabetes is a progressive disease, the effect of glycated albumin on liraglutide affinity found here is important to consider when diabetes is managed with this drug.

Prevalence, treatment and control of hypertension in La Réunion: the RÉDIA population-based cohort study.

A better knowledge of prevalence, management and determinants of hypertension is needed in regions in epidemiological transition to adapt the strategies of public health screening and prevention, and to reduce the burden of cardiovascular diseases. We conducted a prospective cohort study including 4610 participants aged between 18 and 69 years and representative of the general population of La Réunion, a French overseas island located in the western Indian Ocean. The median time between inclusion and follow-up was 7.4 years. Blood pressure data at baseline and follow-up of 3087 participants were analyzed. We found a high prevalence of hypertension, especially in women (36.7% [34.5-39.0]) and in men (40.3% [37.6-43.0]) and in the under 30s (17.1% [14.0-20.5]), with an increase of 10% at follow-up. Treatment rates were very low in men (19.5% versus 39.1% in women) as was awareness of their condition (25.7% versus 44.6%). Blood pressure control rates were similar (18% at baseline and 34% at follow-up for both sexes). Diagnosis of hypertension at follow-up among subjects normotensive at baseline was independently associated with obesity at baseline (relative risk (RR) = 1.40 [1.12-1.75] for BMI between 27 and 30 kg/m2 and 1.72 [1.33-2.25] for BMI ≥30 kg/m2 as compared with BMI <27 kg/m2) and HbA1C (RR =1.12 [1.05-1.19] per %), suggesting a prominent role of insulin resistance in our population. Our study provides original data that cannot be assimilated to any existing model and should guide the implementation of original community-based programs in such countries.

Long-Term Effectiveness of a Lifestyle Intervention for the Primary Prevention of Type 2 Diabetes in a Low Socio-Economic Community--An Intervention Follow-Up Study on Reunion Island.

In type 2 diabetes (T2D) prevention research, evidence for maintenance of risk factor reduction after three years of follow-up is needed. The objective of this study was to evaluate the long-term effectiveness of a combined lifestyle intervention aiming at controlling body weight (BW) and waist circumference (WC) in non-diabetic, overweight/obese adults living in a low socio-economic community. On Reunion Island, 445 adults living in deprived areas, aged 18-40 and at high-risk for T2D, were included in an intervention versus control trial for primary prevention (2001-2002). The intervention promoted a healthy diet and moderate regular physical activity, through actions strengthening individuals or community and improving living conditions. The control group received a one-shot medical information and nutritional advices. After the end of the trial (2003), 259 of the subjects participated in a follow-up study (2010-2011). The outcomes were the nine-year changes from baseline in BW, body mass index (BMI) and WC measurements, separately. Statistical analyses were performed on an intention-to-treat basis, using available and imputed datasets. At inclusion, T2D risk factors were prevalent: family history of diabetes in first-degree relatives (42%), women with a personal history of gestational diabetes (11%), total obesity (43%, median BMI 29.1 kg/m²) and central obesity (71%). At follow-up, the adjusted effect on imputed dataset was significant for WC -2.4 cm (95% confidence interval: -4.7 to -0.0 cm, p = 0.046), non-significant for BW -2.2 kg (-4.6 to +0.2 kg, p = 0.073) and BMI -0.81 kg/m² (-1.69 to +0.08 kg/m², p = 0.074). A specific long-term effect was the increased likelihood of reduction in adiposity: BW loss, BMI reduction, and WC reduction were more frequent in the intervention group. In the context of low socio-economic communities, our data support the assumption of long-term effect of lifestyle interventions targeting total obesity and central obesity two major drivers of T2D.

Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in 157 adult patients.

BACKGROUND: Chikungunya is a reemerging disease. In 2005-2006, a severe outbreak occurred on Reunion Island in the southwestern part of the Indian Ocean. Other islands in this area were affected during the same period. METHODS: Adult patients with acute chikungunya (defined as onset of fever and/or polyarthralgia in the 5 days preceding consultation) and laboratory-confirmed chikungunya who were referred to Groupe Hospitalier Sud Reunion during the period from March 2005 through April 2006 were included in this retrospective study. Their clinical and laboratory features are reported. RESULTS: Laboratory-confirmed acute chikungunya was documented in 157 patients. The mean age of patients was 57.9 years, and the ratio of male to female patients was 1.24 : 1. Sixty percent of patients had at least 1 comorbidity. Ninety-seven patients (61.8%) were hospitalized, and 60 (38.2%) were treated as outpatients. Five fatalities were reported. One hundred fifty-one patients (96.1%) experienced polyarthralgia, and 129 (89%) experienced fever. Gastrointestinal symptoms were reported by 74 patients (47.1%), and skin rash was reported by 63 (40.1%). Hemorrhagic signs were rare. Lymphopenia and hypocalcemia were the prominent laboratory findings. Severe thrombocytopenia was rarely observed. CONCLUSIONS: Chikungunya virus can be responsible for explosive outbreaks of disease. Polyarthralgia and fever are the 2 main clinical features. In this era of travel and globalization, chikungunya should be considered in the differential diagnosis of febrile polyarthralgia with an abrupt onset.