Gestational diabetes and adverse perinatal outcomes from 716,152 births in France in 2012.

AIMS/HYPOTHESIS: The aim of this study was to assess the risk of adverse perinatal outcomes in gestational diabetes mellitus (GDM) in a large national cohort. METHODS: All deliveries taking place after 22 weeks in France in 2012 were included by extracting data from the hospital discharge database and the national health insurance system. The diabetic status of mothers was determined by the use of glucose-lowering agents and by hospital diagnosis. Outcomes were analysed according to the type of diabetes and, in the GDM group, whether or not diabetes was insulin-treated. RESULTS: The cohort of 796,346 deliveries involved 57,629 (7.24%) mothers with GDM. Mother-infant linkage was obtained for 705,198 deliveries. The risks of adverse outcomes were much lower with GDM than with pregestational diabetes. After limiting the analysis to deliveries after 28 weeks to reduce immortal time bias, the risks of preterm birth (OR 1.3 [95% CI 1.3, 1.4]), Caesarean section (OR 1.4 [95% CI 1.4, 1.4]), pre-eclampsia/eclampsia (OR 1.7 [95% CI 1.6, 1.7]), macrosomia (OR 1.8 [95% CI 1.7, 1.8]), respiratory distress (OR 1.1 [95% CI 1.0, 1.3]), birth trauma (OR 1.3 [95% CI 1.1, 1.5]) and cardiac malformations (OR 1.3 [95% CI 1.1, 1.4]) were increased in women with GDM compared with the non-diabetic population. Higher risks were observed in women with insulin-treated GDM than those with diet-treated GDM. After limiting the analysis to term deliveries, an increased risk of perinatal mortality was observed. After excluding women suspected to have undiagnosed pregestational diabetes, the risk remained moderately increased only for those with diet-treated GDM (OR 1.3 [95% CI 1.0, 1.6]). CONCLUSIONS/INTERPRETATION: GDM is associated with a moderately increased risk of adverse perinatal outcomes, which is higher in insulin-treated GDM than in non-insulin-treated GDM for most outcomes.

Prevalence and Description of the Skin Reactions Associated with Adhesives in Diabetes Technology Devices in an Adult Population: Results of the CUTADIAB Study.

Objective: The use of continuous glucose monitoring (CGM) systems and continuous subcutaneous insulin infusion (CSII) devices adhering to the skin can lead to skin reactions. The objective was to determine the prevalence and consequences of skin reactions at CGM or CSII sites in a large unbiased population. Research Design and Methods: This is a cross-sectional multicenter study. All adult patients with diabetes seen in consultation over a period of 7 months and using or having used a system with skin adhesives (in the last 10 years) were included and filled out a self-assessment questionnaire. Results: Among 851 patients, skin reaction was reported in 28% with CGM and 29% with CSII. Patients reporting reactions were more frequently women using CGM and CSII, and CGM users had type 1 more often than type 2 diabetes (P < 0.001). Manifestations were similar for reactions to CGM and CSII: redness and pruritus in 70%-75% of patients with reactions, pain in 20%-25%, and vesicles and desquamation in 12%-15%. Manifestations occurred within the first 24 h of first use in 22%-24% of patients with reactions to CGM and CSII, but after more than 6 months in 38% and 47% of patients with reactions to CGM and CSII, respectively. Device use was definitively stopped in 12% of patients with reactions to CGM (3.2% of all users) and 7% with reactions to CSII (2.1% of all users). Conclusions: Skin reactions were common, with similar presentations in CGM and CSII users. Manifestations suggested skin irritation rather than allergies. These reactions rarely led to the definitive discontinuation of the use of the device.

Intensive versus subcutaneous insulin in patients with hyperacute stroke: results from the randomized INSULINFARCT trial.

BACKGROUND AND PURPOSE: Intensive insulin therapy (IIT) has not yet proven its efficacy on stroke prognosis or in the reduction of MRI infarct growth. The INSULINFARCT study aims at determining in patients with hyperacute stroke whether IIT, with a better control of poststroke hyperglycemia, would reduce subsequent MRI infarct growth than usual care with subcutaneous insulin. METHODS: One hundred eighty patients with MRI-proven ischemic stroke and with National Institutes of Health Stroke Scale from 5 to 25 at admission (<6 hours) were randomized to receive IIT or usual subcutaneous insulin for 24 hours. Admission hyperglycemia was not required for recruitment. Control MRI and 3-month follow-up (with functional outcome and serious adverse events) were planned. The primary objective was to detect a difference in the proportion of patients with mean capillary glucose test <7 mmol/L during 24 hours. The secondary objective was to investigate whether IIT would reduce infarct growth. The analysis was planned in intention-to-treat. Patients with >3 missing capillary glucose test were excluded (n=4). RESULTS: The proportion of patients with mean capillary glucose test <7 mmol/L in the first 24 hours was higher in the IIT group (95.4% [83 of 87] versus 67.4% [60 of 89]; P<0.0001). The infarct growth was lower in the subcutaneous insulin group (median, 10.8 cm(3); 95% CI, 6.5-22.4 versus 27.9 cm(3); 14.6-40.7; 60% of increase; P=0.04). The 3-month functional outcome (45.6% [41 of 90] versus 45.6% [41 of 90]), death (15.6% [14 of 90] versus 10% [9 of 90]), and serious adverse events (38.9% [35 of 90] versus 35.6% [32 of 90]) were similar in the subcutaneous insulin and IIT group. CONCLUSIONS: The IIT regimen improved glucose control in the first 24 hours of stroke but was associated with larger infarct growths. IIT cannot be recommended in hyperacute ischemic stroke. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique Identifier: NCT00472381.

How Can Maternal Lifestyle Interventions Modify the Effects of Gestational Diabetes in the Neonate and the Offspring? A Systematic Review of Meta-Analyses.

Gestational diabetes (GDM) has deleterious effects on the offspring. Maternal obesity and excessive gestational weight gain (GWG), often associated with diabetes, also contribute to these adverse outcomes. OBJECTIVES: To assess the benefit for the offspring of maternal lifestyle interventions, including diets and physical activity, to prevent or to improve GDM and to limit excessive GWG. METHOD: Systematic review of meta-analyses published in English between December 2014 and November 2019. RESULTS: Lifestyle interventions to reduce the risk of GDM reported a decreased risk of 15% to 40%, with a greater effect of exercise compared to diet. Combined lifestyle interventions specifically designed to limit GWG reduced GWG by 1.6 kg in overweight and obese women, and on average by 0.7 to 1 kg in all pregnant women. In these trials, adverse neonatal outcomes were poorly studied. Combined lifestyle interventions in women with GDM significantly reduced fetal growth. Altogether, lifestyle interventions reduced the risk of preterm birth and shoulder dystocia, but individually, diets or exercise alone had no effect on neonatal adverse outcomes. CONCLUSION: Specific maternal, neonatal and offspring benefits of lifestyle interventions during pregnancy to prevent or improve GDM control or to limit GWG still require clarification.

Relative Contribution of Gestational Weight Gain, Gestational Diabetes, and Maternal Obesity to Neonatal Fat Mass.

Maternal nutritional and metabolic status influence fetal growth. This study investigated the contribution of gestational weight gain (GWG), gestational diabetes (GDM), and maternal obesity to birthweight and newborn body fat. It is a secondary analysis of a prospective study including 204 women with a pregestational body mass index (BMI) of 18.5-24.9 kg/m2 and 219 women with BMI ≥ 30 kg/m2. GDM was screened in the second and third trimester and was treated by dietary intervention, and insulin if required. Maternal obesity had the greatest effect on skinfolds (+1.4 mm) and cord leptin (+3.5 ng/mL), but no effect on birthweight. GWG was associated with increased birthweight and skinfolds thickness, independently from GDM and maternal obesity. There was an interaction between third trimester weight gain and GDM on birthweight and cord leptin, but not with maternal obesity. On average, +1 kg in third trimester was associated with +13 g in birthweight and with +0.64 ng/mL in cord leptin, and a further 32 g and 0.89 ng/mL increase in diabetic mothers, respectively. Maternal obesity is the main contributor to neonatal body fat. There is an independent association between third trimester weight gain, birthweight, and neonatal body fat, enhanced by GDM despite intensive treatment.

Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a liver disease that complicates insulin-resistant states. This trial tested the efficacy and safety of rosiglitazone, an insulin-sensitizing agent, in patients with NASH. METHODS: Sixty-three patients with histologically proven NASH were randomly assigned to receive rosiglitazone (4 mg/day for the first month and 8 mg/day thereafter; n = 32) or placebo (n = 31) for 1 year. Liver biopsy was performed at the end of treatment. End points were improvement in the histologic score of steatosis, normalization of serum transaminase levels, and improvement in necroinflammation and fibrosis. RESULTS: More patients treated with rosiglitazone than receiving placebo had improved steatosis (47% vs 16%; P = .014) and normalized transaminase levels (38% vs 7%; P = .005), although only half of patients responded. There was no improvement in other histologic lesions, including fibrosis, and a composite score of activity, the nonalcoholic fatty liver disease activity score. Improvement of steatosis correlated with reduction of transaminase levels (r = 0.36; P < .005), improvement in insulin sensitivity (r = 0.34; P = .008), and increase in adiponectin levels (r = -0.54; P < .01) but not with weight variations. Independent predictors of response were rosiglitazone treatment, the absence of diabetes, and massive steatosis. Weight gain was the main adverse effect (mean gain of 1.5 kg in the rosiglitazone group vs -1 kg in the placebo group; P < .01), and painful swollen legs was the main reason for dose reduction/discontinuation. Serum hemoglobin level was slightly but significantly reduced. There was no hepatic toxicity. CONCLUSIONS: In patients with NASH, rosiglitazone improves steatosis and transaminase levels despite weight gain, an effect related to an improvement in insulin sensitivity. However, there is no improvement in other parameters of liver injury.

Insulin Pump Combined with Flash Glucose Monitoring: A Therapeutic Option to Improve Glycemic Control in Severely Nonadherent Patients with Type 1 Diabetes.

Some patients with type 1 diabetes (T1D) are severely noncompliant; they rarely perform self-blood glucose measures and miss insulin injections. Their HbA1c is far above the target rate. Current guidelines do not recommend starting treatment with an insulin pump (continuous subcutaneous insulin infusion [CSII]) for these persons. The aim of this study was to determine whether a CSII associated with a flash glucose monitoring (FGM) device could reduce HbA1c without increasing the risk of acute events, diabetic ketoacidosis (DKA) and severe hypoglycemia (SH), in these patients. We conducted a 6-month nonrandomized, pilot prospective study. Patients with T1D on multiple daily injections who performed less than two self-blood glucose tests/day and had an HbA1c >9% were equipped with CSII and an FGM device. The primary composite endpoint was defined by a change in HbA1c ≥1% without any episode of DKA or SH during 6 months. Change in mean HbA1c, weight, treatment satisfaction, frequency of minor hypoglycemia, and ketoacidosis were secondary endpoints. Nineteen adults were included. Median (Q1-Q3) HbA1c at baseline was 10.8 (10.3-13.0), 14 participants did not perform any self-monitoring and 5 performed maximum two tests daily. Twelve participants (63%) (95% confidence interval 41%-81%) met the primary composite endpoint. Seventeen patients completed the study. HbA1c decreased by 2% (1.0-3.3) (P < 0.001), and satisfaction with treatment significantly improved. Three participants experienced SH and one a DKA, versus, respectively, five and eight in the year preceding the study. Participants scanned the sensor 4 (3-6) times per day and injected 3 (2.7-4.1) boluses per day. Weight increased significantly. An association of an insulin pump with an FGM device can be an effective and safe therapeutic option in severely nonadherent and noncompliant patients with high HbA1c.

Screening for liver fibrosis by using a noninvasive biomarker in patients with diabetes.

BACKGROUND & AIMS: Patients with diabetes are at risk for nonalcoholic fatty liver disease leading to advanced fibrosis, cirrhosis, and liver cancer. We examined the efficacy of a screening strategy with a noninvasive fibrosis biomarker (FibroTest) in patients with diabetes. METHODS: We prospectively studied 1131 consecutive patients without a history of liver disease seen for diabetes. The biomarker data were obtained, and patients with presumed advanced fibrosis were reinvestigated by a hepatologist using elastography and, if necessary, ultrasonography, endoscopy, or liver biopsy. RESULTS: The biomarker predicted advanced fibrosis in 63 of 1131 (5.6%) patients. A total of 45 patients was reinvestigated, and advanced fibrosis was confirmed in 32 patients, a 2.8% (32/1131) prevalence of confirmed advanced fibrosis, 5 cases of cirrhosis, and 4 cases of hepatocellular carcinoma. In the population with type 2 diabetes who were 45 years or older, the prevalence of confirmed advanced fibrosis was 4.3% (30/696), and hepatocellular carcinoma was 5.7 of 1000 (4/696). CONCLUSIONS: The fibrosis biomarker might be used for the detection of advanced fibrosis in patients with type 2 diabetes.

Perioperative management of adult diabetic patients. Preoperative period.

In diabetic patients undergoing surgery, we recommend assessing glycaemic control preoperatively by assessing glycated haemoglobin (HbA1c) levels and recent capillary blood sugar (glucose) levels, and to adjust any treatments accordingly before surgery, paying particular attention to specific complications of diabetes. Gastroparesis creates a risk of stasis and aspiration of gastric content at induction of anaesthesia requiring the use of a rapid sequence induction technique. Cardiac involvement can be divided into several types. Coronary disease is characterised by silent myocardial ischaemia, present in 30-50% of T2D patients. Diabetic cardiomyopathy is a real cause of heart failure. Finally, cardiac autonomic neuropathy (CAN), although rarely symptomatic, should be investigated because it causes an increased risk of cardiovascular events and a risk of sudden death. Several signs are suggestive of CAN, and confirmation calls for close perioperative surveillance. Chronic diabetic kidney disease (diabetic nephropathy) aggravates the risk of perioperative acute renal failure, and we recommend measurement of the glomerular filtration rate preoperatively. The final step of the consultation concerns the management of antidiabetic therapy. Preoperative glucose infusion is not necessary if the patient is not receiving insulin. Non-insulin drugs are not administered on the morning of the intervention except for metformin, which is not administered from the evening before. The insulins are injected at the usual dose the evening before. The insulin pump is maintained until the patient arrives in the surgical unit. It should be remembered that insulin deficiency in a T1D patient leads to ketoacidosis within a few hours.

Perioperative management of adult diabetic patients. Review of hyperglycaemia: definitions and pathophysiology.

Diabetes mellitus is defined by chronic elevation of blood glucose linked to insulin resistance and/or insulinopaenia. Its diagnosis is based on a fasting blood-glucose level of ≥1.26g/L or, in some countries, a blood glycated haemoglobin (HbA1c) level of >6.5%. Of the several forms of diabetes, type-2 diabetes (T2D) is the most common and is found in patients with other risk factors. In contrast, type-1 diabetes (T1D) is linked to the autoimmune destruction of ß-pancreatic cells, leading to insulinopaenia. Insulin deficiency results in diabetic ketoacidosis within a few hours. 'Pancreatic' diabetes develops from certain pancreatic diseases and may culminate in insulinopaenia. Treatments for T2D include non-insulin based therapies and insulin when other therapies are no longer able to control glycaemic levels. For T1D, treatment depends on long (slow)-acting insulin and ultra-rapid analogues of insulin administered according to a 'basal-bolus' scheme or by continuous subcutaneous delivery of insulin using a pump. For patients presenting with previously undiagnosed dysglycaemia, investigations should determine whether the condition corresponds to pre-existing dysglycaemia or to stress hyperglycaemia. The latter is defined as transient hyperglycaemia in a previously non-diabetic patient that presents with an acute illness or undergoes an invasive procedure. Its severity depends on the type of surgery, the aggressiveness of the procedure and its duration. Stress hyperglycaemia may lead to peripheral insulin resistance and is an independent prognostic factor for morbidity and mortality.

Perioperative management of adult diabetic patients. Intraoperative period.

Perioperative hyperglycaemia (>1.80g/L or 10mmol/L) increases morbidity (particularly due to infection) and mortality. Hypoglycaemia can be managed in the perioperative period by decreasing blood sugar levels with insulin between 0.90 and 1.80g/L but it may occur more frequently when the goal is strict normoglycaemia. We propose continuous administration of insulin therapy via an electronic syringe (IVES) in type-1 diabetes (T1D) and type-2 diabetes (T2D) patients if required or in cases of stress hyperglycaemia. Stopping a personal insulin pump requires immediate follow on with IVES insulin. We recommend 4mg dexamethasone for the prophylaxis of nausea and vomiting, rather than 8mg, combined with another antiemetic drug. The use of regional anaesthesia (RA), when possible, allows for better control of postoperative pain and should be prioritised. Analgesic requirements are higher in patients with poorly controlled blood sugar levels than in those with HbA1c<6.5%. The struggle to prevent hypothermia, the use of RA and multimodal analgesia (which allow for a more rapid recovery of bowel movements), limitation of blood loss, early ambulation and minimally invasive surgery are the preferred measures to regulate perioperative insulin resistance. Finally, diabetes does not change the usual rules of fasting or of antibiotic prophylaxis.

Perioperative management of adult diabetic patients. Specific situations.

Ambulatory surgery can be carried out in diabetic patients. By using a strict organisational and technical approach, the risk of glycaemic imbalance is minimised, allowing the patients to return to their previous way of life more quickly. Taking into account the context of ambulatory surgery, with a same day discharge, the aims are to minimise the changes to antidiabetic treatment, to maintain adequate blood sugar control and to resume oral feeding as quickly as possible. The preoperative evaluation is the same as for a hospitalised patient and recent glycaemic control (HbA1c) is necessary. Perioperative management and the administration of treatment depend on the number of meals missed. The patient can return home after taking up usual feeding and treatment again. Hospitalisation is necessary if significant glycaemic imbalance occurs. In pregnancy, it is necessary to distinguish between known pre-existing diabetes (T1D or T2D) and gestational diabetes, defined as glucose intolerance discovered during pregnancy. During labour, blood sugar levels should be maintained between 0.8 and 1.4g/L (4.4-8.25mmol/L). Control of blood sugar levels is obtained by using a continuous administration of insulin using an electronic syringe (IVES) together with a glucose infusion. Post-partum, management depends on the type of diabetes: in T1D and T2D patients a basal-bolus scheme is restarted with decreased doses while in gestational diabetes insulin therapy is stopped after delivery. Antidiabetic treatment is again necessary if blood sugar levels remain>1.26g/L (7mmol/L).

Perioperative management of adult diabetic patients. Postoperative period.

Follow on from continuous intravenous administration of insulin with an electronic syringe (IVES) is an important element in the postoperative management of a diabetic patient. The basal-bolus scheme is the most suitable taking into account the nutritional supply and variable needs for insulin, reproducing the physiology of a normal pancreas: (i) slow (long-acting) insulin (=basal) which should immediately take over from IVES insulin simulating basal secretion; (ii) ultra-rapid insulin to simulate prandial secretion (=bolus for the meal); and (iii) correction of possible hyperglycaemia with an additional ultra-rapid insulin bolus dose. A number of schemes are proposed to help calculate the dosages for the change from IV insulin to subcutaneous insulin and for the basal-bolus scheme. Postoperative resumption of an insulin pump requires the patient to be autonomous. If this is not the case, then it is mandatory to establish a basal-bolus scheme immediately after stopping IV insulin. Monitoring of blood sugar levels should be continued postoperatively. Hypoglycaemia and severe hyperglycaemia should be investigated. Faced with hypoglycaemia <3.3mmol/L (0.6g/L), glucose should be administered immediately. Faced with hyperglycaemia >16.5mmol/L (3g/L) in a T1D or T2D patient treated with insulin, investigations for ketosis should be undertaken systematically. In T2D patients, unequivocal hyperglycaemia should also call to mind the possibility of diabetic hyperosmolarity (hyperosmolar coma). Finally, the modalities of recommencing previous treatments are described according to the type of hyperglycaemia, renal function and diabetic control preoperatively and during hospitalisation.

Perioperative management of adult diabetic patients. The role of the diabetologist.

A patient should be referred to a diabetologist perioperatively in several circumstances: preoperative recognition of a previously unknown diabetes or detection of glycaemic imbalance (HbA1c <5% or >8%); during hospitalisation, recognition of a previously unknown diabetes, persisting glycaemic imbalance despite treatment or difficulty resuming previously used chronic treatment; postoperatively and after discharge from hospital, for all diabetic patients in whom HbA1c is >8%.

Effect of maternal obesity on birthweight and neonatal fat mass: A prospective clinical trial.

OBJECTIVE: To discriminate the effect of maternal obesity and gestational diabetes on birth weight and adipose tissue of the newborn. METHODS: Normal BMI women (group N, n = 243; 18.5≤ BMI<25 kg/m2) and obese women (group Ob, n = 253; BMI≥30 kg/m2) were recruited in a prospective study between 15 and 18 weeks of gestation. All women were submitted to a 75g oral glucose tolerance test in the second and third trimester. First trimester fasting blood glucose was also obtained from Ob women. All women with one measurement above normal values were considered positive for gestational diabetes and first treated by dietary intervention. When dietary measures were not efficient, they were treated by insulin. Neonatal anthropometrics, sum of skinfolds and cord serum hormones were measured. RESULTS: 222 N and 226 Ob mothers and their newborns were included in the analysis. Diabetes was diagnosed in 20% and 45.2% of N and Ob women, respectively. Birth weight was not statistically different between groups (boys: 3456g±433 and 3392g±463; girls: 3316g±402 and 3391g±408 for N and Ob, respectively). Multivariate analysis demonstrated that skinfold thickness and serum leptin concentrations were significantly increased in girls born to women with obesity (18.0mm±0.6 versus 19.7mm±0.5, p = 0.004 and 11.3ng/mL±1.0 versus 15.3ng/mL±1.0, p = 0.02), but not in boys (18.4mm±0.6 versus 18.5mm±0.5, p = 0.9 and 9.3ng/mL±1.0 versus 9.0ng/mL±1.0, p = 0.9). Based on data from 136 N and 124 Ob women, maternal insulin resistance at 37 weeks was also positively related to skinfold in girls, only, with a 1-point increase in HOMA-IR corresponding to a 0.33mm±0.08 increase in skinfold (p<0.0001). CONCLUSIONS: Regardless of gestational diabetes, maternal obesity and insulin resistance were associated with increased adiposity in girls only. Persistence of this sexual dimorphism remains to be explored during infancy.

Nonremovable, windowed, fiberglass cast boot in the treatment of diabetic plantar ulcers: efficacy, safety, and compliance.

OBJECTIVE: To compare the efficacy, safety, and compliance of a nonremovable fiberglass cast boot and off-loading shoes in the treatment of diabetic plantar ulcers. RESEARCH DESIGN AND METHODS: Patients (n = 93) with noninfected, nonischemic plantar ulcers were included in this prospective nonrandomized study. Treatment used a nonremovable fiberglass cast boot for longer standing and deeper ulcers (n = 42) and a half shoe or heel-relief shoe for other ulcers (n = 51). We evaluated off-loading therapy, compliance, and complications in both groups. RESULTS: The healing rate was significantly higher with the cast boot than with the off-loading shoe (81 vs. 70%, P = 0.017), with healing times of 68.6 +/- 35.1 vs. 134.2 +/- 133.0 days, respectively, and hazard ratio 1.68 (95% CI 1.04-2.70); complete compliance with treatment was 98 vs. 10% (P = 0.001), respectively. Secondary osteomyelitis developed in 3 patients in the cast boot group and 13 patients in the off-loading shoe group (P = 0.026). CONCLUSIONS: A nonremovable fiberglass cast boot was effective in healing diabetic plantar ulcers and in decreasing the risk of secondary osteomyelitis. The cast boot forced compliance with off-loading, thus promoting healing.

Below-knee arterial calcification in type 2 diabetes: association with receptor activator of nuclear factor κB ligand, osteoprotegerin, and neuropathy.

CONTEXT: Calcification of the arterial wall in diabetes contributes to the arterial occlusive process occurring below the knee. The osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) system is suspected to be involved in the calcification process. OBJECTIVE: The aim of the study was to investigate whether there is a link between arterial calcification in type 2 diabetes and 1) conventional cardiovascular risk factors, 2) serum RANKL and OPG levels, and 3) neuropathy. PATIENTS AND METHODS: We objectively scored, in a cross-sectional study, infrapopliteal vascular calcification using computed tomography scanning in 198 patients with type 2 diabetes, a high cardiovascular risk, and a glomerular filtration rate >30 mL/min. Color duplex ultrasonography was performed to assess peripheral arterial occlusive disease, and mediacalcosis. Peripheral neuropathy was defined by a neuropathy disability score >6. RANKL and OPG were measured in the serum by routine chemistry. RESULTS: Below-knee arterial calcification was associated with arterial occlusive disease. In multivariate logistic regression analysis, the variables significantly and independently associated with the calcification score were age (odds ratio [OR] = 1.08; 95% confidence interval [CI] = 1.04-1.13; P < .0001), male gender (OR = 3.53; 95% CI = 1.54-8.08; P = .003), previous cardiovascular disease (OR = 2.78; 95% CI = 1.39-5.59; P = .005), and neuropathy disability score (per 1 point, OR = 1.21; 95% CI = 1.05-1.38; P = .006). The association with ln OPG, significantly associated with calcification score in univariate analysis (OR = 3.14; 95% CI = 1.05-9.40; P = .045), was no longer significant in multivariate analysis. RANKL and OPG/RANKL were not significantly associated with the calcification score. CONCLUSIONS: Below-knee arterial calcification severity is clearly correlated with peripheral neuropathy severity and with several usual cardiovascular risk factors, but not with serum RANKL level.

Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial.

BACKGROUND: An improper balance of regulatory/effector T (Treg/Teff) cells is central to the development of autoimmune diseases, including type 1 diabetes. We previously showed that low-dose interleukin 2 (IL2) induced Treg cell expansion and activation and clinical improvement in patients with hepatitis-C-virus-induced vasculitis. We aimed to establish which low doses of IL2 would be safe and induce Treg cells in patients with type 1 diabetes, considering that: (1) type 1 diabetes might be linked to alteration of the IL2/IL2R activation pathway; (2) activation of pathogenic Teff cells by IL2 could exacerbate disease; and (3) the safety of low-dose IL2 is not known in type 1 diabetes. METHODS: This was a single-centre phase 1/2 study. 24 adult patients (18-55 years) with established insulin-dependent type 1 diabetes and at least one diabetes-related autoantibody were enrolled and randomly assigned (in a 1:1:1:1 ratio, by computer-generated randomisation list, with block size four) to placebo or IL2 at 0.33 MIU/day, 1 MIU/day, or 3 MIU/day for a 5-day course and were followed up for 60 days. All investigators and participants were masked to assignment. The primary outcome was change in Treg cells, measured by flow cytometry, and expressed as a percentage of CD4+ T cells, from day 1 to day 60. This trial is registered with ClinicalTrials.gov, number NCT01353833. FINDINGS: Six patients were assigned to each group between June 1, 2011, and Feb 3, 2012. IL2 was well tolerated at all doses, with no serious adverse events. However, there was a dose-response association for non-serious adverse events during the treatment phase (days 1-6); one patient in the placebo group, three patients in the 0.33 MIU group, five patients in the 1 MIU group, and six patients in the 3 MIU group had non-serious adverse events. The most common adverse events in the treatment phase were injection-site reaction (no patients with placebo vs three patients with 0.33 MIU and 1 MIU vs two patients with 3 MIU) and influenza-like syndrome (no patients with placebo vs one patient with 0.33 MIU and 1 MIU vs four patients with 3 MIU). After the treatment phase, adverse events did not differ between groups. IL2 did not induce deleterious changes in glucose-metabolism variables. IL2 induced a dose-dependent increase in the proportion of Treg cells, significant at all doses compared with placebo (placebo mean increase 0.5% [SD 0.4]; 0.33 MIU 2.8% [1.2], p=0.0039; 1 MIU 3.9% [1.8], p=0.0039; 3 MIU 4.8% [1.9] p=0.0039). INTERPRETATION: We have defined a well-tolerated and immunologically effective dose range of IL2 for application to type 1 diabetes therapy and prevention, which could be relevant to other disorders in which a Treg cell increase would be desirable.