Impact of moderate exercise on fatty acid oxidation in pancreatic ß-cells and skeletal muscle.

Fatty acids (FA) play a crucial role in glycaemia regulation in healthy and metabolic disorders conditions through various mechanisms. FA oxidation is one of the processes involved in lipid metabolism and can be modulated by exercise. Nowadays, physical activity is known to be an effective strategy for the prevention and treatment of Type 2 Diabetes. Moreover, its intensity, its duration, the sex-gender, the prandial state, exerkines… are as many parameters that can influence glycaemic control. However, the widely debated question is to determine the best type of exercise for patients with metabolic disorders. In this review, we will discuss the impact of exercise intensity, especially moderate activity, on glycaemic control by focussing on FA oxidation in pancreatic ß-cells and skeletal muscle. Finally, thanks to all the recent data, we will determine whether moderate physical activity is a good therapeutic strategy and if FA oxidation represents a target of interest to treat diabetic, obese and insulin-resistant patients.

Clinical use of the co-formulation of insulin degludec and insulin aspart.

AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. METHODS: Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. RESULTS: In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. CONCLUSIONS: IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Early effects of liver regeneration on endocrine pancreas: in vivo change in islet morphology and in vitro assessment of systemic effects on ß-cell function and viability in the rat model of two-thirds hepatectomy.

Liver and pancreas share key roles in glucose homeostasis. Liver regeneration is associated with systemic modifications and depends especially on pancreatic hormones. The aim of the study was to investigate the role of systemic factors released after two-thirds hepatectomy (2/3H) on early possible consequences of liver regeneration on endocrine pancreas structure and function. The pancreas and serum were harvested 1, 2, or 3 days after 2/3H or sham operation in Lewis rats. The HGF and VEGF serum concentrations and plasma microparticles levels were measured. The fate of endocrine pancreas was examined through islets histomorphometry and function in sham and 2/3H rats. ß-Cell line RIN-m5F viability was assessed after 24 h of growth in media supplemented with 10% serum from 2/3H or sham rats instead of FCS. Three days after surgery, the pancreas was heavier in 2/3H compared to sham rats (0.56 vs. 0.40% of body weight, p < 0.05) and the proportion of islets of intermediate size was lower in 2/3H rats (5 vs. 15%, p < 0.05). Compared to Sham, sera obtained 3 days after hepatectomy were more efficient to maintain the viability of RIN-m5F cells (99 vs. 67%, p < 0.01). Three days after surgery, no significant differences in serum HGF, a trend to significant increase in VEGF concentration and a significant increase in microparticles levels, were observed in 2/3H vs. sham rats (9.8 vs. 6.5 nM Phtd Ser Eq., p < 0.05). Liver regeneration is associated with early effects on islets and could influence ß-cell viability and function by systemic effect.

Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P).

AIMS: To compare the efficacy and safety of once-daily prandial lixisenatide with placebo in type 2 diabetes mellitus (T2DM) insufficiently controlled by pioglitazone ± metformin. METHODS: This randomized, double-blind study included a 24-week main treatment period and a ≥52-week variable extension period. Patients were randomized 2 : 1 to receive lixisenatide 20 µg once daily or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) at week 24. RESULTS: In total, 484 patients were randomized: 323 to lixisenatide; 161 to placebo. After 24 weeks, lixisenatide once daily significantly improved HbA1c (-0.56% vs. placebo; p < 0.0001) and increased the proportion of patients achieving HbA1c <7% compared with placebo (52.3% vs. 26.4%, respectively; p < 0.0001) and significantly improved fasting plasma glucose (-0.84 mmol/l vs. placebo; p < 0.0001). There was a small decrease in body weight with lixisenatide once daily and a small increase with placebo, with no statistically significant difference between the two groups. Overall, lixisenatide once daily was well tolerated, with a similar proportion of treatment-emergent adverse events (TEAEs) and serious TEAEs between groups (lixisenatide: 72.4% and 2.5%; placebo: 72.7% and 1.9%). Symptomatic hypoglycaemia rates were also relatively low in both groups (lixisenatide 3.4% and placebo 1.2%), with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable extension period. CONCLUSIONS: Lixisenatide once daily significantly improved glycaemic control with a low risk of hypoglycaemia, and was well tolerated over 24 weeks and during the long-term, double-blind extension period in patients with T2DM insufficiently controlled on pioglitazone ± metformin.

Glycemic management of diabetes by insulin therapy.

Recent technological innovations as insulin analogue formulation, devices for insulin delivery and glucose monitoring have allowed diabetic patients to improve their glycemic control and decrease their level of burden due to diabetes. Intensive insulin therapy via insulin pens, subcutaneous or intraperitoneal insulin infusions using pumps instead of vials and syringes, are associated with improved absorption reproducibility, HbA1c levels, reduced risk of hypo- or hyperglycemia, and increased quality of patient's life. These currently used systems are discussed in this review as well as the future of exogenous insulin therapy: closed loop system, the artificial pancreas, and oral insulin delivery. Glucose homeostasis is directly linked to glycemic regulated by portal insulin administration, thus endogenous insulin therapy might be the most promising treatment to "cure" diabetes. Consequently, pancreas and islet transplantation, and the bioartificial pancreas are described.

Evidence for humoral rejection of a pancreatic islet graft and rescue with rituximab and IV immunoglobulin therapy.

We describe the decline in islet function, in relation to HLA sensitization, in an islet transplant recipient and the recovery of this function after treatment with anti-CD20 monoclonal antibody and IV immunoglobulins. A 51-year-old woman with type 1 diabetes received one intraportal islet infusion. Following this transplantation, she became insulin independent. A search for HLA antibodies by using an ELISA technique remained consistently negative for HLA class I and II. It was only 2 years after the islet transplantation that this search became positive against class II antigens, reaching a peak of reactivity concomitantly with the appearance of a deterioration of glucose control requiring low-dose insulin therapy. Luminex screening and single-antigen assays then revealed the presence of both nondonor-specific and donor-specific antibodies against HLA class II molecules. This immunization, already present in the pretransplant serum, had increased during the 6 months preceding the clinical deterioration. Since these data nevertheless pointed to antibody-mediated rejection of the islet allograft, treatment with anti-CD20 monoclonal antibody and IV immunoglobulins was initiated. One month later, the search by ELISA for antibodies against HLA class II antigens became negative, the Luminex tests normalizing more gradually. As the result of an improvement in glucose control, the patient was again insulin-free.

Type 1 diabetes and idiopathic retroperitoneal fibrosis: case report.

Retroperitoneal fibrosis is characterized by the presence of a retroperitoneal tissue, consisting of chronic inflammation and marked fibrosis, which entraps the retroperitoneal organs. In two-thirds of cases, the retroperitoneal fibrosis is idiopathic. The pathogenic mechanism is not clearly identified. We report a case of idiopathic retroperitoneal fibrosis associated with type 1 diabetes mellitus. A 61-year-old woman with C peptide negative insulindependent diabetes developed retroperitoneal fibrosis revealed by bilateral hydronephrosis. Anti-GAD 65 antibodies were positive. There were no signs of autoimmune pancreatitis: no steatorrhea, normal IgG4 isotype levels, and absence of pancreas morphological abnormalities.

Treatment of diabetes mellitus using an external insulin pump: the state of the art.

The aim of diabetes treatment is to achieve tight glucose control to avoid the development of chronic diabetic complications while reducing the frequency of hypoglycaemic episodes. Continuous subcutaneous insulin infusion (CSII) using an external pump is an intensive diabetes therapy recognized to improve metabolic control and glycaemic instability, and to reduce the frequency of severe hypoglycaemia. For years, the theoretical advantages of the insulin pump (constancy of basal delivery, adjustable basal rates, and low insulin depots allowing the reduction of glycaemic variability) have contributed to its reported superiority compared with multiple daily injections (MDI). However, insulin pump therapy is now challenged by new MDI regimens based on long-acting insulin analogues that could replace the use of CSII. As a consequence, health professionals now have to determine which patients are likely to benefit the most from CSII. Recently, several studies reported that children and adolescents, and patients whose blood glucose imbalance was initially the most pronounced with basal-bolus regimens, would particularly benefit from CSII. Other indications were also proposed in marginal clinical situations with highly selected patients in whom a significant improvement of blood glucose was demonstrated. Finally, the use of CSII in type 2 diabetic patients now appears to be a good alternative to the ineffective MDI regimens observed in some of these patients. However, past experience with CSII indicates that candidates for insulin pump therapy must be carefully selected and strongly motivated to improve their glucose control. Use of CSII also requires strict medical supervision by physicians and a regular programme of patient education by paramedical teams, to ensure optimal responsible use of this technique by healthcare professionals.

Overexpression of vascular endothelial growth factor in vitro using deferoxamine: a new drug to increase islet vascularization during transplantation.

During pancreatic islet transplantation, delayed and insufficient revascularization can deprive islets of oxygen and nutrients, resulting in cell death and early graft failure. Deferoxamine (DFO), an iron chelator, increases vascular endothelial growth factor (VEGF) expression in cells. The aim of this work was to study the effect of DFO on beta-cell and pancreatic islet viability as well as VEGF expression. beta-cell lines from rat insulinoma (Rin m5f) and primary cultures of pancreatic islets from Wistar rats were incubated with DFO (10, 100, and 1000 micromol/L). The viability was evaluated using fluorescein diacetate/propidium iodide for dying pancreatic islets and using cell titers for Rin m5f. Expression of VEGF messenger RNA (mRNA) was quantified using reverse transcriptase polymerase chain reaction (RT-PCR). Finally, VEGF secretion was determined using enzyme-linked immunosorbent assays at 1 to 3 days after treatment. The addition of 10 micromol/L of DFO preserved Rin m5F viability at 24 hours after treatment (10 micromol/L; 101.33% +/- 5.66%; n = 7). However, 100 and 1000 micromol/L of DFO induced cell death (68.92% +/- 5.83% and 65.89% +/- 5.83%, respectively; n = 4). In the same way, viability of pancreatic islets in the presence of DFO was preserved. RT-PCR analysis showed stimulation of VEGF mRNA in the presence of 10 micromol/L of DFO in islets at 3 days after culture. Finally, 10 micromol/L of DFO stimulated secretion of VEGF 7.95 +/- 0.84 versus 1.80 +/- 1.10 pg/microg total protein with 10 micromol/L of DFO in rat islets at 3 days after culture, n = 3; P < .001). The use of DFO to stimulate VEGF expression and increase islet vascularization may be a realistic approach to improve islet viability during transplantation.

Perfluorocarbons: new tool for islets preservation in vitro.

Pancreatic islet transplantations to treat type 1 diabetes often fail to function because of hypoxia. Perfluorocarbons (PFCs) exhibit a high oxygen solubility coefficient and maintain high oxygen partial pressure for extended times. They also serve as oxygen "reservoirs" for harvested organs in pancreas organ transplantation. Previous studies have shown the PFCs display antiadhesive effects on beta cells. The aim of this study was to evaluate the effects of PFC on islet viability and functionality and on extracellular matrix (ECM) disruption of islets via inhibition of adhesion. Primary cultures of rat islets were incubated for 24 hours in the presence or absence of 3.5% (weight/volume) PFCs in culture media. We studied viability (FDA/PI), stimulation index linked to insulin secretion (ELISA), and expression of insulin and laminin messenger RNAs (mRNAs). Immunostaining was performed on insulin and laminin. Islet viability was similar in the presence or absence of PFCs (about 80%). Stimulation index showed preservation of islet functionality in the presence of PFC (4.9 +/- 0.7) as compared with controls (2.8 +/- 0.5). Moreover, laminin mRNA expression was lower compared with controls (55% of PFC incubated vs control islets). Immunohistochemistry studies showed preservation of ECM inside the islets in the presence of PFCs versus controls at 24 hours after islet isolation. In conclusion, PFCs preserved islet viability and functionality and prevented ECM disruption. PFCs may represent a new tool for islet preservation in vitro.

Influence of rapamycin on rat macrophage viability and chemotaxis toward allogenic pancreatic islet supernates.

The aim of this work was to evaluate the effects of rapamycin on rat macrophage viability and chemotaxis toward allogereic pancreatic islet supernates. Macrophages were isolated from rats by peritoneal lavage at 3 days after intraperitoneal injection of thioglycolate. Macrophage viability was studied after 7 days of culture by Cell Titer assays in the presence of rapamycin at 0.1, 1, and 10 ng/mL (n = 6). After 48 hours of culture, pancreatic rat islet supernates were studied for there chemotactic properties toward freshly isolated macrophages in the presence of rapamycin at 0.1, 1, and 10 ng/mL. Chemotaxis was expressed as a migration index defined as the number of macrophages attracted by the test solution (islet supernate +/- rapamycin)/number of macrophages attracted by the supernate (n = 6). After 3 days of culture, macrophage viability decreased significantly by 22%, 36%, and 32% in the presence of 0.1, 1, and 10 ng/mL rapamycin, respectively (P = .008). Macrophage viability remained stable at about 70% after 7 days of culture. In the presence of islet supernates, macrophage migration increased two-fold compared with those obtained by culture medium. Rapamycin did not influence macrophage migration toward culture medium. However, the drug significantly reduced the migration of macrophages toward islet supernates from 2 +/- 0.6 to 0.9 +/- 0.4, 0.7 +/- 0.3, or 0.8 +/- 0.4 in the presence of 0.1, 1, or 10 ng/mL rapamycin, respectively (P = .04). Rapamycin decreased the survival of cultured rat macrophages and their migration toward allogenic islet supernates. These results suggested that, besides its anti-proliferative effect on T cells, rapamycin reduced macrophage attraction to the graft site.

Association of malignant insulinoma and type 2 diabetes mellitus: a case report.

We report a case of recurrent hypoglycemia due to malignant insulinoma in a type 2 diabetic patient correctly controlled for years with the same doses of oral antidiabetic agents. A 79-year-old woman was admitted for recurrent severe hypoglycemia. She had a history of type 2 diabetes since 2000. HbA1c was 7.8% when she reported mild hypoglycemia and 5.8% when recurrent hypoglycemia appeared despite progressive diminution of glicazide. Severe hypoglycemia continued despite interrupting diabetes medications. At admission, results showed inappropriately elevated insulin, C-peptide and proinsulin levels despite significant hypoglycemia. CT scan showed "cystic" nodes in the pancreas and in the liver. Liver biopsy found a well-differentiated neuroendocrine carcinoma with positive staining for chromogranin A and negative staining for insulin. Hypoglycemia improved with diazoxide, lanreotide and dextrose infusion. Liver chemoembolization was planned. Severe edema, dyspnea, hyponatremia, and hypo-osmolarity occurred. The patient's clinical status deteriorated rapidly with severe cardiac, renal and hepatic failure. She died in a few days. Association of diabetes mellitus and insulinoma is extremely rare. Malignant insulinoma survival is less than two years, shorter when hepatic localizations are present at diagnosis. Association of diabetes with insulinoma delays the diagnosis, but does not alter prognosis or favor carcinoma frequency. Lanreotide was inefficient in our patient despite good responses described in the literature. Heart, respiratory and renal failures have been described with diazoxide independently of the doses; this may in part explain the rapid death. Insulinoma should be considered as a cause of unusual and recurrent hypoglycemia in a diabetic patient especially if it persists after interrupting antidiabetic agents.

Efficacy of pioglitazone in familial partial lipodystrophy of the Dunnigan type: a case report.

A 25 year old woman consulted for a severe acanthosis nigricans and central distribution of fat. Her masculine type morphology was associated with muscular appearance of the limbs and excess fat deposits in the face and neck. Biological testing confirmed glucose intolerance associated with a severe insulin resistance, hypertriglyceridemia and polycystic ovary syndrome. The detection of a heterozygous missense mutation in LAMIN A/C gene at position 482 confirmed the diagnosis of Familial Partial Lipodystrophy (FPLD2). Due to a deterioration of clinical and metabolic status, 15 and then 30 mg per day of pioglitazone were added to her previous treatment with metformin, bezafibrate and omega-3 fatty acids. Metabolic status improved rapidly after 3 months and continued thereafter. Weight remained stable, body mass composition and waist circumference improved. After 18 months of treatment, glycaemia and triglycerides levels normalized, hepatic enzymes and liver echographic features improved. Insulin sensitivity improved dramatically with a HOMA % S value of 73% with metformin and of 98.2% when pioglitazone was added. Leptin levels increased from 6.6 to 10.2 microg/ml. We report a very rapid and good efficacy of pioglitazone added to metformin without side effects in FPLD2. If confirmed on more patients, early use of pioglitazone in association with metformin could be proposed in FPLD2.

Relationship between achieved personalized glycaemic targets and monitoring of clinical events in elderly diabetic patients.

AIM: Recent guidelines for the management of type 2 diabetes (T2DM) in the elderly recommend adjusting the therapeutic target (HbA1c) according to the patient's health. Our study aimed to explore the association between achieving the recommended personalized HbA1c target and the occurrence of major clinical events under real-life conditions. METHODS: The T2DM S.AGES cohort was a prospective multicentre study into which 213 general practitioners recruited 983 non-institutionalized T2DM patients aged>65 years. The recommended personalized HbA1c targets were<7%, <8% and <9% for healthy, ill and very ill patients, respectively. Major clinical events (death from any cause, major vascular events and/or hospitalization) were recorded during the 3-year follow-up. Mixed-effects logistic regression models were used for the analyses. RESULTS: Of the 747 patients analyzed at baseline, 551 (76.8%) were at their recommended personalized HbA1c target. During follow-up, 391 patients (52.3%) experienced a major clinical event. Of the patients who did not achieve their personalized HbA1c target (compared with those who did), the risk (OR) of a major clinical event was 0.95 (95% CI: 0.69-1.31; P=0.76). The risk of death, major vascular event and hospitalization were 0.88 (95% CI: 0.40-1.94; P=0.75), 1.14 (95% CI: 0.7-1.83; P=0.59) and 0.84 (95% CI: 0.60-1.18; P=0.32), respectively. CONCLUSION: Over a 3-year follow-up period, our results showed no difference in risk of a major clinical event among patients, regardless of whether or not they achieved their personalized recommended HbA1c target. These results need to be confirmed before implementing a more permissive strategy for treating T2DM in elderly patients.

Efficacy of short term continuous subcutaneous insulin lispro versus continuous intravenous regular insulin in poorly controlled, hospitalized, type 2 diabetic patients.

UNLABELLED: Intravenous insulin infusion (IVII) is rapidly effective in improving glycaemia in uncontrolled hospitalized diabetic patients. This significantly improves their morbidity and mortality. Intravenous insulin infusion may lead to IV infusion complications and is a heavy burden for caregivers. AIM: The aim of our work was to compare the efficacy of IV regular insulin versus lispro Continuous Subcutaneous Insulin Infusion (CSII), in improving glycaemia in patients hospitalized for uncontrolled type 2 diabetes, the efficacy being assessed on the average blood glucose level observed. METHODS: The study was designed as a prospective randomized study. Thirty-three type 2 diabetic patients, hospitalized for uncontrolled diabetes by their usual practitioner were included. After acceptation, patients were randomly assigned to lispro CSII (group 1, n=20) or IVII regular insulin (group 2, n=13) for 5 days. Ten capillary blood glucose/day were performed. Pre-meal blood glucose targets were 4.4-6.6 mmol/l. Mann Whitney, Wilcoxon and Fischer exact tests were used. RESULTS: BG levels decreased significantly (-3.4+/-0.55 mmol/l in group 1 and -3.60+/-0.55 mmol/l in group 2, P<0.01) during the first 12 hours. Mean daily blood glucose at day 5 was statistically improved in both groups compared to day 1 (P<0.05 Wilcoxon) and comparable between the 2 groups. No severe hypoglycaemia was reported. No catheter complications occurred in group 1, 7 occurred in group 2. CONCLUSION: CSII and IVII infusion were comparable in rapidly improving hyperglycaemia in uncontrolled type 2 diabetic patients. CSII, being more convenient, could be preferred in medical and surgical settings.

Cardio protective effect of glucose-insulin infusion on acute digoxin toxicity in rat.

UNLABELLED: We recently observed a case of digoxin and insulin self-poisoning without cardiac repercussion. We raised the hypothesis that insulin may have a cardio-protective effect in case of digoxin toxicity. We have therefore evaluated the effect of glucose-insulin infusion on mortality and ECG abnormalities during acute digoxin toxicity in rats. Before and after a hyperinsulinemia-euglycemia clamp, rats in glucose-insulin-digoxin (GID) group (n=10) received an intravenous infusion of 12ml/h or 2,5ml/h digoxin (0.25mg/ml) respectively until death occured. Animals receiving digoxin or saline solution intravenously served as control (n=10). ECG recording was performed in all animals over the entire period. Serum insulin and digoxin concentrations were measured by ELISA method after digoxin administration. When digoxin was administered after the clamp, all animals in GID group were alive, whereas 80% of animals in the digoxin group were dead (p<0.001) after 30min. The administration of Digoxin provoked rapid death of rats in the digoxin group in 15+/-12min whereas in GID group the survival period was significantly increased to 38+/-3min (p<0.001). Twenty minutes after digoxin administration, P waves disappeared for 78% of animals in digoxin group while they were present in all rats of GID group (p<0.001). Animal death occurred after a digoxin infusion volume of 7.7+/-0.6ml and 3.0+/-2.4ml in GID and digoxin group respectively (p<0.001). Five minutes after digoxin administration, potassium plasmatic level increased significantly in digoxin group as compared to GID group: 7.1+/-2mmol/l versus 4.4+/-0.4mmol/l (p<0.001). When digoxin was infused before the clamp, 40% of animals in GID group were alive after 180min and the other 60% died after 137+/-40min whereas death of rats in the digoxin group occurred within 80+/-10min (p<0.001). The death of animals was preceded by the P waves disappearing. Thirty minutes after digoxin administration, the potassium plasmatic level increased significantly in the digoxin group as compared to the GID group: 6.9+/-0.5mmol/l versus 4.9+/-0.3mmol/l (p<0.001). At the time of death, both volume of digoxin infusion and serum digoxin concentration were increased in GID group as compared to digoxin group: 5.7+/-1.6ml versus 3.3+/-0.4ml (p<0.001) and 10.7+/-8.3mg/l versus 8.5+/-4.6mg/l. CONCLUSION: Glucose-insulin infusion delayed the abnormalities in cardiac conduction and improved rat survival after acute digoxin toxicity. These results suggest a cardioprotective effect of insulin in case of acute digoxin toxicity.

[Diffuse uptake of brown fat on computed-tomography coupled positron emission tomoscintigraphy (PET-CT) for the exploration of extra-adrenal pheochromocytoma]. / Hyperfixation diffuse de la graisse brune à la tomoscintigraphie par émission de positons couplée à la tomodensitométrie (TEP-TDM) dans l'exploration d'un phéochromocytome extra surrénalien.

We report an observation of strong bilateral uptake on a PET-CT scan compatible with activation of brown adipose tissue in a patient with extra-adrenal pheochromocytoma. A 42-year-old man was hospitalized for hypersudation together with weight loss and palpitations. Heart rate was 120 bpm and fasting blood glucose 1.36 g/l. Endocrine explorations revealed elevated serum chromogranine which reached 517 ng/ml (19-38). The norepinephrine level reached 49.7 nmol/l (<4.00) and urinary norepinephrine and normetanephrine levels reached 13977 nmol/24h (<414) and 32 micromol/24h (0.4-2.5) respectively. The thoraco-abdominal and pelvic scan showed a 6 cm diameter paraaortic hypervascularized mass with an infiltrative lesion of both perirenal area and mediastinal tissue without adenopathies. The abdominal MRI revealed the mass with a low intensity signal in T1 and a slight high intensity signal in T2. MIBG and octreoscan scintigraphies were negative. 18F-DG PET showed intensed uptake in the tumor mass together with intense, diffuse and bilateral uptake above and below the diaphragm. The mass was resected. Histological examination of the surgical specimen confirmed the diagnosis of extra-adrenal pheochromocytoma with an index of 13% cellular proliferation without cell atypia. There was a hypervascularization with small islets of brown adipose tissue in the perirenal fat. Both plasmatic and urinary catecholamines decreased to the normal range after the operation and PET-scan normalized. Bilateral spread of the radiotracer uptake was probably due to brown adipose tissue activation by excessive sympathetic stimulation induced by catecholamines released by the tumor.

Improvement of islet graft function using liraglutide is correlated with its anti-inflammatory properties.

BACKGROUND AND PURPOSE: Liraglutide improves the metabolic control of diabetic animals after islet transplantation. However, the mechanisms underlying this effect remain unknown. The objective of this study was to evaluate the anti-inflammatory and anti-oxidative properties of liraglutide on rat pancreatic islets in vitro and in vivo. EXPERIMENTAL APPROACH: In vitro, rat islets were incubated with 10 µmol·L-1 liraglutide for 12 and 24 h. Islet viability functionality was assessed. The anti-inflammatory properties of liraglutide were evaluated by measuring CCL2, IL-6 and IL-10 secretion and macrophage chemotaxis. The anti-oxidative effect of liraglutide was evaluated by measuring intracellular ROS and the total anti-oxidative capacity. In vivo, 1000 islets were cultured for 24 h with or without liraglutide and then transplanted into the liver of streptozotocin-induced diabetic Lewis rats with or without injections of liraglutide. Effects of liraglutide on metabolic control were evaluated for 1 month. KEY RESULTS: Islet viability and function were preserved and enhanced with liraglutide treatment. Liraglutide decreased CCL2 and IL-6 secretion and macrophage activation after 12 h of culture, while IL-10 secretion was unchanged. However, intracellular levels of ROS were increased with liraglutide treatment at 12 h. This result was correlated with an increase of anti-oxidative capacity. In vivo, liraglutide decreased macrophage infiltration and reduced fasting blood glucose in transplanted rats. CONCLUSIONS AND IMPLICATIONS: The beneficial effects of liraglutide on pancreatic islets appear to be linked to its anti-inflammatory and anti-oxidative properties. These findings indicated that analogues of glucagon-like peptide-1 could be used to improve graft survival.

Impact of Pancreatic Rat Islet Density on Cell Survival during Hypoxia.

In bioartificial pancreases (BP), the number of islets needed to restore normoglycaemia in the diabetic patient is critical. However, the confinement of a high quantity of islets in a limited space may impact islet survival, particularly in regard to the low oxygen partial pressure (PO2) in such environments. The aim of the present study was to evaluate the impact of islet number in a confined space under hypoxia on cell survival. Rat islets were seeded at three different concentrations (150, 300, and 600 Islet Equivalents (IEQ)/cm(2)) and cultured in normal atmospheric pressure (160 mmHg) as well as hypoxic conditions (15 mmHg) for 24 hours. Cell viability, function, hypoxia-induced changes in gene expression, and cytokine secretion were then assessed. Notably, hypoxia appeared to induce a decrease in viability and increasing islet density exacerbated the observed increase in cellular apoptosis as well as the loss of function. These changes were also associated with an increase in inflammatory gene transcription. Taken together, these data indicate that when a high number of islets are confined to a small space under hypoxia, cell viability and function are significantly impacted. Thus, in order to improve islet survival in this environment during transplantation, oxygenation is of critical importance.