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The effects of nefopam and ketamine on pain control and rehabilitation after total knee replacement were compared in a prospective, double blinded study. Seventy-five patients were randomly assigned to receive a 0.2mg kg(-1) bolus of nefopam or ketamine, followed by a 120microg kg(-1) h(-1) continuous infusion until the end of surgery, and 60microg kg(-1) h(-1) until the second postoperative day, or an equal volume of saline considered as placebo. Pain scores measured on a visual analog scale at rest and on mobilization, and patient-controlled intravenous morphine consumption, were assessed during 48h. We measured the maximal knee flexion on the third postoperative day, and the delay to obtain a 90 degrees flexion. Ketamine and nefopam reduced morphine consumption (p

Mesenchymal stem cells (MSCs) are multipotent non-haematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases. Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. While insulin replacement represents the current therapy for type 1 diabetes, its metabolic control remains difficult, as exogenous insulin cannot exactly mimic the physiology of insulin secretion. Pancreatic or islet transplantation can provide exogenous insulin independence, but is limited by its intrinsic complications and the scarcity of organ donors. In this context, stem cell therapy, based on the generation of insulin-producing cells (IPCs) derived from MSCs, represents an attractive possibility. In this review, we provide a brief characterization of MSC immunomodulatory effects, and present the current experimental evidence for the potential therapeutic efficacy of MSC transplantation in diabetes.

L’exercice physique regulier associe a une alimentation equilibree est considere depuis longtemps comme la pierre angulaire du traitement du diabete de type 2. Nous disposons maintenant de cinq etudes prospectives qui confirment le role majeur de l’activite physique dans la prevention du diabete dans les populations a risque. Malgre le nombre important de revue et de consensus publie dans la litterature internationale, peu d’etudes ont evalue l’efficacite de l’activite physique sur le controle glycemique de maniere rigoureuse. Les meta-analyses recentes, et en particulier celle publiee par la Cochrane Collaboration , confirment un effet propre, modere, de l’activite physique reguliere sur la baisse du taux d’Hb1Ac qui est de l’ordre de 0,6 % et qui ne s’accompagne pas d’une perte de poids significative malgre des effets favorables sur la composition corporelle. Bien que les programmes d’entrainement evalues ne soient pas homogenes, l’adjonction d’efforts musculaires de resistance aux activites aerobies semble donner des resultats superieurs.

OBJECTIVE— ATP-sensitive K+ channels (KATP channels) link glucose metabolism to the electrical activity of the pancreatic β-cell to regulate insulin secretion. Mutations in either the Kir6.2 or sulfonylurea receptor (SUR) 1 subunit of the channel have previously been shown to cause neonatal diabetes. We describe here an activating mutation in the ABCC8 gene, encoding SUR1, that is associated with the development of type 2 diabetes only in adults. RESEARCH DESIGN AND METHODS— Recombinant KATP channel subunits were expressed using pIRES2-based vectors in human embryonic kidney (HEK) 293 or INS1(832/13) cells and the subcellular distribution of c-myc–tagged SUR1 channels analyzed by confocal microscopy. KATP channel activity was measured in inside-out patches and plasma membrane potential in perforated whole-cell patches. Cytoplasmic [Ca2+] was imaged using Fura-Red. RESULTS— A mutation in ABCC8/SUR1, leading to a Y356C substitution in the seventh membrane-spanning α-helix, was observed in a patient diagnosed with hyperglycemia at age 39 years and in two adult offspring with impaired insulin secretion. Single KATP channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP (IC50 = 24 and 95 μmol/l for wild-type and mutant channels, respectively). Similar effects were observed in the absence of Mg2+, suggesting an allosteric effect via associated Kir6.2 subunits. Overexpression of SUR1-Y356C in INS1(832/13) cells impaired glucose-induced cell depolarization and increased in intracellular free Ca2+ concentration, albeit more weakly than neonatal diabetes–associated SUR1 mutants. CONCLUSIONS— An ABCC8/SUR1 mutation with relatively minor effects on KATP channel activity and β-cell glucose sensing causes diabetes in adulthood. These data suggest a close correlation between altered SUR1 properties and clinical phenotype.

OBJECTIVE—To characterize insulin action in Africans with ketosis-prone diabetes (KPD) during remission. RESEARCH DESIGN AND METHODS—At Saint-Louis Hospital, Paris, France, 15 African patients with KPD with an average 10.5-month insulin-free near-normoglycemic remission period (mean A1C 6.2%) were compared with 17 control subjects matched for age, sex, BMI, and geographical origin. Insulin stimulation of glucose disposal, and insulin suppression of endogenous glucose production (EGP) and nonesterified fatty acids (NEFAs), was studied using a 200-min two-step (10 mU · m−2 body surface · min−1 and 80 mU · m−2 · min −1 insulin infusion rates) euglycemic clamp with [6,6-2H2]glucose as the tracer. Early-phase insulin secretion was determined during an oral glucose tolerance test. RESULTS—The total glucose disposal was reduced in patients compared with control subjects (7.5 ± 0.8 [mean ± SE] vs. 10.5 ± 0.9 mg · kg−1 · min−1; P = 0.018). EGP rate was higher in patients than control subjects at baseline (4.0 ± 0.3 vs. 3.0 ± 0.1 mg · kg−1 · min−1; P = 0.001) and after 200-min insulin infusion (10 mU · m−2 · min−1: 1.6 ± 0.2 vs. 0.6 ± 0.1, P = 0.004; 80 mU · m−2 · min−1: 0.3 ± 0.1 vs. 0 mg · kg−1 · min−1, P = 0.007). Basal plasma NEFA concentrations were also higher in patients (1,936.7 ± 161.4 vs. 1,230.0 ± 174.1 μmol/l; P = 0.002) and remained higher after 100-min 10 mU · m−2 · min−1 insulin infusion (706.6 ± 96.5 vs. 381.6 ± 55.9 μmol/l; P = 0.015). CONCLUSIONS—The triad hepatic, adipose tissue, and skeletal muscle insulin resistance is observed in patients with KPD during near-normoglycemic remission, suggesting that KPD is a form of type 2 diabetes.

Resume Le GLP-1 est une incretine jouant un role majeur dans le controle de l’homeostasie glucidique en situation physiologique. Au cours du DT2, sa secretion est diminuee alors que son action est conservee, ce qui en a fait une molecule de choix innovante comme traitement antidiabetique. Cependant, les limites pharmacocinetiques du GLP-1 liees a sa degradation enzymatique par la DPP-IV ont pousse au developpement de medicaments comprenant les analogues injectables du GLP-1 resistant a cette enzyme, et les inhibiteurs de la DPP-IV administres par voie orale. Les donnees de la litterature confirment le caractere prometteur de ces deux classes therapeutiques avec un avantage substantiel des analogues sur le controle ponderal, alors que les inhibiteurs ont un meilleur profil de tolerance. En outre, leur association aux medicaments antidiabetiques existants, meme en situation d’echec de ces derniers, semble tres avantageuse. Cependant des questions relatives a l’efficacite et surtout la securite au long cours de ces medicaments sont encore posees, et il reste a mieux definir leur role dans la strategie therapeutique du diabete de type 2.

AIMS Epidemiological and experimental data suggest that activation of the oestrogen receptor pathway limits the incidence and the progression of diabetic nephropathy. We tested the hypothesis that raloxifene protects against increasing urinary albumin excretion in post-menopausal women with Type 2 diabetes in a randomized pilot clinical trial. METHODS We included 39 post-menopausal women with Type 2 diabetes and micro- or macro-albuminuria in a 6-month, double-blind, placebo-controlled trial: 20 received placebo and 19 received 60 mg raloxifene per day. The albumin : creatinine ratio (ACR) in urine was determined on three consecutive days during the week before randomization and during the week before the final visit. RESULTS One patient in each group dropped out in the first 3 weeks, leaving 37 patients for the analysis (19 on placebo and 18 on raloxifene). From randomization to the final visit, mean ACR was unchanged in the placebo group {277 microg/mg (67; 651) [median (interquartile range)] vs. 284 microg/mg (79; 1508)} but decreased slightly in the raloxifene group [376 microg/mg (67; 615) vs. 243 microg/mg (103; 549)]. This corresponds to a change of +24 (-37; +517) for the placebo group vs. -10 microg/mg (-36; +16) for the raloxifene group (P = 0.11). In multivariate analysis, raloxifene treatment (P(adjusted) = 0.013), baseline low-density lipoprotein (LDL) cholesterol (P(adjusted) = 0.023) and change in LDL cholesterol (P(adjusted) = 0.008) were related to the absolute change in ACR. Adverse effects were similar in the two groups. CONCLUSIONS These results suggest that raloxifene may limit the progression of albuminuria in post-menopausal women with diabetes; further studies in a larger population are warranted.

Background Fetal exposure to hyperglycemia impacts negatively kidney development and function. Objective Our objective was to determine whether fetal exposure to moderate hyperglycemia is associated with epigenetic alterations in DNA methylation in peripheral blood cells and whether those alterations are related to impaired kidney function in adult offspring. Design Twenty nine adult, non-diabetic offspring of mothers with type 1 diabetes (T1D) (case group) were matched with 28 offspring of T1D fathers (control group) for the study of their leukocyte genome-wide DNA methylation profile (27,578 CpG sites, Human Methylation 27 BeadChip, Illumina Infinium). In a subset of 19 cases and 18 controls, we assessed renal vascular development by measuring Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) at baseline and during vasodilatation produced by amino acid infusion. Results Globally, DNA was under-methylated in cases vs. controls. Among the 87 CpG sites differently methylated, 74 sites were less methylated and 13 sites more methylated in cases vs. controls. None of these CpG sites were located on a gene known to be directly involved in kidney development and/or function. However, the gene encoding DNA methyltransferase 1 (DNMT1)—a key enzyme involved in gene expression during early development–was under-methylated in cases. The average methylation of the 74 under-methylated sites differently correlated with GFR in cases and controls. Conclusion Alterations in methylation profile imprinted by the hyperglycemic milieu of T1D mothers during fetal development may impact kidney function in adult offspring. The involved pathways seem to be a nonspecific imprinting process rather than specific to kidney development or function.

Hand washing before glucose and ketone fingerprick testing prevents false results in users of skin lightening cosmetics

International audience; Background : Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily that inhibits bone resorption, has been suggested as a potential marker of cardiovascular risk. This study aimed to assess the relationship between insulin resistance, lipid profile and OPG levels in obese and non-obese sub-Saharan African women.Methods :Sixty obese (44) and non-obese (16) volunteer women aged 18 to 40 years were recruited in this cross-sectional study. Their clinical (age, height, weight, waist circumference, systolic and diastolic blood pressures) and biochemical parameters (fasting blood glucose, total cholesterol, high density lipoprotein-cholesterol (HDL-C)) were measured using standard methods. Insulin levels were measured using an electrochemiluminescence immunoassay, while OPG levels were measured using the ELISA technique. Low density lipoprotein-cholesterol (LDL-C), body mass index (BMI) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were calculated using standard methods. Abdominal obesity was defined as a waist circumference ≥ 80 cm.Results : OPG levels were higher in obese than in normal subjects, though the difference was not significant (p = 0.9). BMI, waist circumference, percent body fat and systolic blood pressure were significantly higher in obese than in non-obese subjects (p

Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin. AGL is associated with high risk for lymphoma, especially PTCL. Autoimmunity likely contributes to this risk. Lymphoma developed with or without metreleptin, suggesting metreleptin does not directly cause lymphoma development; a theoretical role of metreleptin in lymphoma progression remains possible. For most patients with AGL and severe metabolic complications, the proven benefits of metreleptin on metabolic disease will likely outweigh theoretical risks of metreleptin in lymphoma development or progression.

Aim We investigated the association of HLA DRB1 and DQB1 alleles, haplotypes and genotypes with unprovoked antibody-negative ketosis-prone atypical diabetes (A − KPD) in comparison to type 2 diabetes (T2D). Methods A − KPD and T2D sub-Saharan African patients aged 19–63 years were consecutively recruited. Patients positive for cytoplasmic islet cell, insulin, glutamic acid decarboxylase or islet antigen-2 autoantibodies were excluded. Odds ratios were obtained via logistic regression after considering alleles with a minimum frequency of 5% in the study population. Bonferroni correction was used in the case of multiple comparisons. Results Among the 130 participants, 35 (27%) were women and 57 (44%) were A − KPD. DRB1 and DQB1 allele frequencies were similar for both A − KPD and T2D patients; they did not confer any substantial risk even after considering type 1 diabetes susceptibility and resistance alleles. We found no association between A − KPD and the derived DRB1*07-DQB1*02:02 (OR: 0.55 [95%CI: 0.17–1.85], P = 0.336); DRB1*11-DQB1*03:01 (OR: 2.42 [95%CI: 0.79–7.42], P = 0.123); DRB1*15-DQB1*06:02 (OR: 0.87 [95%CI: 0.39–1.95], P = 0.731) and DRB1*03:01-DQB1*02:01 (OR: 1.48 [95%CI: 0.55–3.96], P = 0.437) haplotypes. Overall, we did not find any evidence of susceptibility to ketosis associated with DRB1 and DQB1 genotypes (all P > 0.05) in A − KPD compared to T2D. Similar results were obtained after adjusting the analysis for age and sex. Conclusion Factors other than DRB1 and DQB1 genotype could explain the propensity to ketosis in A − KPD. These results need to be confirmed in a larger population with the perspective of improving the classification and understanding of the pathophysiology of A − KPD.

Transient elastometry is a noninvasive procedure used to measure fibrosis when patients are diagnosed with liver disease; it might be used to monitor changes over time. We investigated whether there are short-term variations in stiffness measurements that are not attributable to changes in fibrosis by studying patients with stable liver disease.We performed a retrospective analysis of 531 paired liver stiffness measurements made by Fibroscan when the study began (LSM1) and at follow-up (LSM2), more than 1 day and less than 1 year apart, from 432 stable (for body mass index, waist circumference, and alcohol consumption), untreated, immunocompetent patients with chronic liver disease (from January 2006 through March 2009). Variations between the first and follow-up measurements were expressed as absolute (LSM2-LSM1, kPa) or relative ([LSM2-LSM1]/LSM1*100) or as changes in fibrosis stage.There was20% variation in 49.7%,30% in 34.3%, and50% in 12.2% of paired measurements; this variation was constant across the spectrum of LSM1 values. The variations produced a 1-fibrosis stage difference in 31.5% of pairs and a ≥ 2-stage difference in 9.8% of pairs. Patients with LSM17 kPa had increased probability of having a different stage of fibrosis at LSM2, compared with patients with LSM17 kPa. Factors associated with variation included measurements made by 2 different operators or at least 1 non-senior operator, ratios of interquartile range:median values, significant fibrosis (≥ 7 kPa) at LSM1, baseline body mass index, or a 2-fold difference in level of alanine aminotransferase between measurements. When the analyses were restricted to measurements made by the same operator, the variation was slightly reduced; fibrosis stage differed between measurements for only 34.3% of cases.Operator-related and patient-related factors produce significant variations in liver stiffness measurements made by transient elastometry, limiting its use in monitoring patients. These variations are unrelated to disease progression. The lowest levels of variation occur in measurements made in patients with no or early-stage fibrosis or by a single experienced operator.

Resume Objectifs Nous avons compare le dosage semi-quantitatif d’acetoacetate par bandelette urinaire avec le dosage capillaire quantitatif du principal corps cetonique, le 3-beta-hydroxybutyrate (3-HB), pour le diagnostic d’acidocetose aux urgences. Methodes Etude retrospective sur un an des patients qui presentaient lors du triage une hyperglycemie ≥ 250 mg/l. Nous avons compare sensibilite, specificite, valeurs predictives (VP) et rapports de vraisemblance (RV) de la cetonurie et de la cetonemie pour le diagnostic d’acidocetose (cetonurie ou cetonemie, bicarbonates sanguins 16 meq/l) sur l’echantillon de patients pour lesquels la cetonurie, la cetonemie et l’ionogramme etaient disponibles. Resultats Nous avons etudie 355 patients hyperglycemiques. La mediane du delai d’obtention de la cetonurie (77 % des malades) etait de 21 min. Ce delai etait superieur a 2 heures dans plus de 10 % des cas. La comparaison entre cetonurie et cetonemie etait possible pour 173 patients (dont 6 % en acidocetose). Une cetonurie egale a une croix ou moins, ou une cetonemie inferieure a 3 mmol/l permettaient d’exclure l’acidocetose (VP negative 100 %). Au seuil de deux croix de cetonurie et de 3 mmol/l de cetonemie, les deux tests avaient la meme sensibilite (100 %), mais la specificite du 3-HB (94 %) etait significativement plus elevee (p Conclusion Le dosage capillaire du 3-HB est plus rapide a obtenir et plus performant que la cetonurie pour detecter une acidocetose a l’accueil des urgences.

Context: Ketosis-prone diabetes (KPD) is mostly observed in males of West African descent and is characterized by phasic or permanent insulin dependence without apparent autoimmune process. Objective: KPD subjects display a propensity to hyperglycemia-induced acute insulin deficiency, suggesting that they exhibit a propensity to oxidative stress in β-cells. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a defense mechanism against oxidative stress, and G6PD deficiency, an X-linked genetic disorder with male predominance, is frequent in West Africans. We hypothesized that mutations in the G6PD gene could predispose to KPD. Design: We studied G6PD erythrocyte enzyme activity and the insulin secretory reserve (glucagon-stimulated C peptide) in a cohort of hospitalized West Africans with KPD (n = 59) or type 2 diabetes (T2DM; n = 59) and in normoglycemic controls (n = 55). We also studied the G6PD gene in an extended population of KPD patients (n = 100), T2DM patients (n = 59), and controls (n = 85). ...

Summary A new method is now available to measure capillary levels of 3hydroxybutyrate (3HB), one of the three ketone bodies. It is a quantitative and enzymatic test that uses the same equipment as for home capillary blood glucose determination but with specific strips. In comparison to urine ketone test, there is no false negative or false positive results, it is highly correlate to standard automate assays and patients find it more acceptable. Clinical implementations of this new test begin to be reported. Some studies showed an advantage of ketonemia versus ketonuria measurement to detect and to treat diabetic ketoacidosis in the emergency room. In diabetic patients treated with continuous subcutaneous insulin infusion, ketonemia seems to be more relevant to detect lack of insulin. In the current care of patient with type 1 diabetes and especially in children blood ketone test is more effective than urine ketone test to prevent hospitalisation during sick days. For other situations such as diabetic pregnancy or type 2 diabetes, more data are needed to determine if capillary measurement of 3HB is really useful. This new test is easier and less unpleasant than doing urinary test but it is still far more expensive. Further clinical studies are needed to define whether self 3HB monitoring should substitute urinary test in outpatient care.

We compared the semiquantitative measurement of acetoacetate using urinary dipsticks with the bedside quantitative fingerprick measurement of the principal ketone bodies 3-beta-hydroxybutyrate, for the diagnosis of ketoacidosis.This is a one year retrospective study of patients who presented with hyperglycemia levels of 250 mg/l or greater in the Emergency Department setting. We compared the sensitivity, specificity, and predictive value of ketonuria and ketonemia for the diagnosis of ketoacidosis (urine or blood ketone bodies, blood bicarbonates20 mmol/l, anion gap16 meq/l) in a sample of patients for whom the levels of ketone bodies in the blood and urine as well as serum electrolytes were available.We studied 355 hyperglycemic patients. The median time between arrival and dipstick testing was 21 min, and was greater than 2 h in more than 10% of cases. Comparison between ketonuria and ketonemia was performed in 173 patients (6% with diabetic ketoacidosis). Ketonuria equal to or less than one cross or a 3-beta-hydroxybutyrate value lower than 3 mmol/l enabled ketoacidosis to be excluded (negative predictive value 100%). At two-cross cutoff points for ketonuria and at the 3 mmol/l cutoff point for ketonemia, the two tests had the same sensitivity (100%), but the specificity of 3-beta-hydroxybutyrate (94%) was significantly higher (P0.0001) than that of ketonuria (77%). The best positive predictive value for ketonemia was obtained at the 5 mmol/l cutoff point (100%) and for ketonuria at the three-cross cutoff point (26%). At the three-cross cutoff point for ketonuria and at the 5 mmol/l cutoff point for ketonemia, the two tests had the same negative likelihood ratio (0.1), but the positive likelihood ratio of 3-beta-hydroxybutyrate (infinite) was higher than that of ketonuria.The measurement of 3-beta-hydroxybutyrate in capillary blood is faster and more effective than the use of dipsticks in the urine to detect ketoacidosis in the Emergency Department setting.

BACKGROUND This study aimed to assess the association between lifetime exposure to urban environment (EU) and obesity, diabetes, and hypertension in an adult population of Sub-Saharan Africa. METHODS We studied 999 women and 727 men aged > or =25 years. They represent all the adults aged > or =25 years living in households randomly selected from a rural and an urban community of Cameroon with a 98% and 96% participation rate respectively. Height, weight, blood pressure, and fasting blood glucose were measured in all subjects. Current levels of physical activity (in metabolic equivalents [MET]) were evaluated through the Sub-Saharan African Activity Questionnaire. Chronological data on lifetime migration were collected retrospectively and expressed as the total (EUt) or percentage (EU%) of lifetime exposure to urban environment. RESULTS Lifetime EUt was associated with body mass index (BMI) (r = 0.42; P < 0.0001), fasting glycaemia (r = 0.23; P < 0.0001), and blood pressure (r = 0.17; P < 0.0001) but not with age. The subjects who recently settled in a city (< or =2 years) had higher BMI (+2.9 kg/m(2); P < 0.001), fasting glycaemia (+0.8 mmol/l; P < 0.001), systolic (+23 mmHg; P < 0.001) and diastolic (+9 mmHg; P = 0.001) blood pressure than rural dwellers with a history of 2 years EU. EU during the first 5 years of life was not, on its own, associated with glycaemia or BMI. However, both lifetime EUt and current residence were independently associated with obesity and diabetes. The association between lifetime EUt and hypertension was not independent of current residence and current level of physical activity. CONCLUSIONS This study suggests that for the study of obesity and diabetes, in addition to current residence, both lifetime exposure to an urban environment and recent migration history should be investigated.

Nonautoimmune ketosis-prone diabetic syndromes are increasingly frequent in nonwhite populations. We have characterized a cohort of patients of sub-Saharan African origin who had ketosis-prone type 2 diabetes (n = 111), type 1 diabetes (n = 21), and type 2 diabetes (n = 88) and were admitted to a hospital for management of uncontrolled diabetes. We compared epidemiological, clinical, and metabolic features at diabetes onset and measured insulin secretion (glucagon-stimulated C-peptide) and insulin action (short intravenous insulin tolerance test) during a 10-year follow-up. Ketosis-prone type 2 diabetes shows a strong male predominance, stronger family history, higher age and BMI, and more severe metabolic decompensation than type 1 diabetes. In ketosis-prone type 2 diabetes, discontinuation of insulin therapy with development of remission of insulin dependence is achieved in 76% of patients (non-insulin dependent), whereas only 24% of patients remain insulin dependent. During evolution, ketosis-prone type 2 diabetes exhibit specific beta-cell dysfunction features that distinguish it from type 1 and type 2 diabetes. The clinical course of non-insulin-dependent ketosis-prone type 2 diabetes is characterized by ketotic relapses followed or not by a new remission. Progressive hyperglycemia precedes and is a strong risk factor for ketotic relapses (hazard ratio 38). The probability for non-insulin-dependent ketosis-prone type 2 diabetes to relapse is 90% within 10 years, of whom approximately 50% will become definitively insulin dependent. Insulin sensitivity is decreased in equal proportion in both ketosis-prone type 2 diabetes and type 2 diabetes, but improves significantly in non-insulin-dependent ketosis-prone type 2 diabetes, only after correction of hyperglycemia. In conclusion, ketosis-prone type 2 diabetes can be distinguished from type 1 diabetes and classical type 2 diabetes by specific features of clinical pathophysiology and also by the natural history of beta-cell dysfunction and insulin resistance reflecting a propensity to glucose toxicity.

Aim Previously, we described patients with ketosis-prone type 2 diabetes (KPD) and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but no mutation of the G6PD gene. Our present study used two complementary approaches to test whether hyperglycaemia might inhibit G6PD activity: (1) effect of acute hyperglycaemia induced by glucose ramping; and (2) effect of chronic hyperglycaemia using correlation between G6PD activity and HbA 1c levels. Methods In the first substudy, 16 KPD patients were compared with 11 healthy, non-diabetic control subjects of the same geographical background. Erythrocyte G6PD activity and plasma glucose were assessed at baseline and every 40min during intravenous glucose ramping that allowed maintaining hyperglycaemia for more than 3h. In the second substudy, erythrocyte G6PD activity and HbA 1c levels were evaluated in 108 consecutive African patients with either type 2 diabetes or KPD, and a potential correlation sought between the two variables. Results The maximum plasma glucose level after 200min of glucose perfusion was 20.9±3.7mmol/L for patients and 10.7±2.3mmol/L for controls. There was no difference between baseline and repeated G6PD activity levels during acute hyperglycaemia in either KPD patients ( P =0.94) or controls ( P =0.57), nor was there any significant correlation between residual erythrocyte G6PD activity and HbA 1c levels ( r =−0.085, P =0.38). Conclusion Neither acute nor chronic hyperglycaemia affects erythrocyte G6PD activity. Thus, hyperglycaemia alone does not explain cases of G6PD deficiency in the absence of gene mutation as described earlier.

Despite a well-recognized clinical benefit of the 2(nd)-generation tyrosine kinase inhibitor nilotinib in patients with imatinib-resistant/-intolerant or newly diagnosed chronic myeloid leukemia, recent evidence suggests that nilotinib has a propensity to increase the risk of occlusive arterial events, especially in patients with pre-existing cardiovascular risk factors. Given the key role of lipids in cardiovascular diseases, we studied the plasma lipid profile and global cardiovascular risk prior to and during nilotinib therapy in a series of 27 patients in the setting of a prospective single center study. Data from a minimum 1-year follow up showed that nilotinib significantly increased total, low- and high-density lipoprotein cholesterol within three months. Consequently, the proportion of patients with non-optimal low-density lipoprotein cholesterol increased from 48.1% to 88.9% by 12 months, leading to cholesterol-lowering drug intervention in 22.2% of patients. The proportion of patients with low levels of high-density lipoprotein cholesterol decreased from 40.7% to 7.4% by 12 months. In contrast, a significant decrease in triglycerides was observed. Global cardiovascular risk worsened in 11.1% of patients due to diabetes or occlusive arterial events. Whether hypercholesterolemia was the main driver of occlusive arterial events was uncertain: a longer follow up is necessary to ask whether nilotinib-induced hypercholesterolemia increases long-term risk of atherosclerotic diseases. Nevertheless, given key atherogenic properties of low-density lipoprotein cholesterol, we conclude that when prescribing nilotinib, commitment to detect lipid disorders at baseline and during follow up is mandatory given their frequency, requirement for changes in lifestyle or drug intervention, and potential for long-term cardiovascular complications.

OBJECTIVE: To investigate the effect of an exercise training program on lipid profile in correlation with DHEA level and body weight and body composition in type 2 diabetic men. DESIGN: Longitudinal, controlled clinical intervention study with exercise training consisting of an 8 week supervised program of aerobic exercise (75% VO2 peak, 45 min), twice a week and intermittent exercise, once a week, on a bicyle ergometer. SUBJECTS: Sixteen men (age 45.4±7.2 y (mean±s.d.), HbA1c 8.15±1.7%, body mass index (BMI) 29.6±4.6 kg/m2) were randomly divided into two groups: trained group (n=8) and control group (n=8). MEASUREMENTS: Lipid, apo- and lipoprotein and DHEA concentrations. Cross-sectional areas of subcutaneous and visceral adipose tissue and mid-thigh muscle by magnetic resonance imaging. RESULTS: Training decreased visceral (153.25±38.55 vs 84.20±21.30 cm2, P

Is the Informal Sector Involved in a Form of Tax Evasion ? An econometric analysis of small-scale enterprises' tax compliance. This paper assesses whether a model of tax evasion can provide an explanation for the existence of the informal sector in LDCs. A tax evasion model based on the «principal-agent» approach is presented as a framework for empirical analysis. Based on data from a survey undertaken in Antananarivo, the empirical results indicate that the probability of a firm belonging to the informal sector is indeed related to tax evasion., Dans cet article, nous essayons de déterminer dans quelle mesure la fiscalité influence le dualisme formel-informel. Un modèle de fraude fiscale appliqué aux micro-entreprises et à la fiscalité malgache est construit, puis testé à partir des données de l'enquête sur le secteur informel à Antananarivo. Il ressort de nos estimations que la propension d'une entreprise à devenir formelle peut être expliquée de manière pertinente par un modèle de fraude fiscale., Gautier Jean-François. L'informel est-il une forme de fraude fiscale ? Une analyse micro-économétrique de la fraude fiscale des micro-entreprises . In: Revue d'économie du développement, 9e année N°3, 2001. pp. 25-50.

Knowledge of how the brain contributes to the regulation of food intake in humans is limited. We used positron emission tomography and measures of regional cerebral blood flow (rCBF) (a marker of neuronal activity) to describe the functional anatomy of satiation (i.e., the response to a liquid meal) in the context of extreme hunger (36-h fast) in 11 obese (BMI > or =35 kg/m2, age 27+/-5 years, weight 115+/-11 kg, 38+/-7% body fat; mean +/- SD) and 11 lean (BMI < or =25 kg/m2, age 35+/-8 years, weight 73+/-9 kg, 19+/-6% body fat) men. As in lean men, satiation in obese men produced significant increases in rCBF in the vicinity of the ventromedial and dorsolateral prefrontal cortex and significant decreases in rCBF in the vicinity of the limbic/paralimbic areas (i.e., hippocampal formation, temporal pole), striatum (i.e., caudate, putamen), precuneus, and cerebellum. However, rCBF increases in the prefrontal cortex were significantly greater in obese men than in lean men (P < 0.005). rCBF decreases in limbic/paralimbic areas, temporal and occipital cortex, and cerebellum were also significantly greater in obese men than in lean men (P < 0.005), whereas rCBF decreases in the hypothalamus and thalamus were attenuated in obese men compared with lean men (P < 0.05). This study raises the possibility that the brain responses to a meal in the prefrontal areas (which may be involved in the inhibition of inappropriate response tendencies) and limbic/paralimbic areas (commonly associated with the regulation of emotion) may be different in obese and lean men. Additional studies are required to investigate how these differential responses are related to the pathophysiology of obesity.

The central role of the hypothalamus in the origination and/or processing of feeding-related stimuli may be modulated by the activity of other functional areas of the brain including the insular cortex (involved in enteroceptive monitoring) and the prefrontal cortex (involved in the inhibition of inappropriate response tendencies). Regional cerebral blood flow (rCBF), a marker of neuronal activity, was measured in 11 healthy, normal-weight men by using positron emission tomography in a state of hunger (after 36-h fast) and a state of satiation (after a liquid meal). Hunger was associated with significantly increased rCBF in the vicinity of the hypothalamus and insular cortex and in additional paralimbic and limbic areas (orbitofrontal cortex, anterior cingulate cortex, and parahippocampal and hippocampal formation), thalamus, caudate, precuneus, putamen, and cerebellum. Satiation was associated with increased rCBF in the vicinity of the ventromedial prefrontal cortex, dorsolateral prefrontal cortex, and inferior parietal lobule. Changes in plasma insulin concentrations in response to the meal were negatively correlated with changes in rCBF in the insular and orbitofrontal cortex. Changes in plasma free fatty acid concentrations in response to the meal were negatively correlated with changes in rCBF in the anterior cingulate and positively correlated with changes in rCBF in the dorsolateral prefrontal cortex. In conclusion, these findings raise the possibility that several regions of the brain participate in the regulation of hunger and satiation and that insulin and free fatty acids may be metabolic modulators of postprandial brain neuronal events. Although exploratory, the present study provides a foundation for investigating the human brain regions and cognitive operations that respond to nutritional stimuli.

Cet article illustre les difficultes de l'application d'une TVA et les paradoxes auxquels celle-ci peut mener, dans le cadre d'un programme de reformes fiscales dans un ped. L'analyse des donnees d'une enquete sur le secteur industriel formel a Madagascar a permis de quantifier l'impact de certaines regles de gestion de la TVA (systeme d'exemption et montant butoir au remboursement des credits de TVA, communes aux systemes de TVA dans les ped) sur les recettes fiscales et l'activite des entreprises. Ces regles, ainsi que l'importance du secteur informel, intro duisent des distorsions importantes aussi bien au niveau de l'origine des recettes fiscales (sur taxation des produits de premiere necessite) qu 'au niveau des incitations economiques (remanence de la TVA pour les entre prises exportatrices, biais dans la concurrence). Ces resultats empiriques remettent en cause les qualites theoriques de neutralite de l'impot, ainsi que la modelisation qui en est faite.

Accumulation of visceral adipose tissue is associated with metabolic complications such as noninsulin-dependent diabetes mellitus. The aim of this study was to evaluate the effect of abdominal adipose tissue on insulin sensitivity in subjects with noninsulin-dependent diabetes mellitus (NIDDM). Areas of abdominal fat were calculated from axial magnetic resonance images obtained at the level of the umbilicus in 21 men with NIDDM [age, 45.6 +/- 8.3 (+/-SD) yr; body mass index, 29.3 +/- 4.5 kg/m(-2); total body fat (skinfold thickness), 26.8 +/- 5.4%; waist to hip ratio, 0.97 +/- 0.07; duration of diabetes, 59 +/- 47 months; hemoglobin A1c, 8.1 +/- 1.5%]. Insulin sensitivity was evaluated by an insulin tolerance test. The areas of deep abdominal fat and sc abdominal fat were, respectively, 135.3 +/- 55.1 and 211.8 +/- 99.1 cm2. The blood glucose disappearance rate was 2.11 +/- 0.87%/min and was negatively related to deep abdominal fat (r = 0.72; P = 0.0025). In contrast, areas of sc abdominal fat, total body fat, body mass index, and waist to hip ratio were not related to the blood glucose disappearance rate. Plasma triglyceride concentrations averaged 1.8 +/- 0.8 mmol/L and were positively related to deep abdominal fat (r = 0.69; P = 0.0018). We conclude that insulin sensitivity is strongly related to visceral adipose tissue accumulation in NIDDM.

This study investigated the ability of two models to represent glucose kinetics in the basal steady state and during an intravenous glucose tolerance test (IVGTT). Six young nonobese male subjects were studied after an overnight fast. Two bolus injections of [U-13C]glucose were given 150 min apart, the first without and the second together with concomitant injection of unlabeled glucose. [3-3H]glucose was constantly infused throughout the study and served to provide an independent means for evaluation of system responses. A linear time-invariant three-compartmental model and the two-compartment time-variant model proposed by Caumo and Cobelli were used to interpret measured time courses of [U-13C]glucose and to reconstruct endogenous glucose production and glucose removal. The ability of the two models to describe the glucose tracer time course was comparable. Simulation studies showed that the two-compartmental time-variant system better predicted measured [3-3H]glucose concentration profiles than did the three-compartmental time-invariant model. However, endogenous glucose production and the integral of excess glucose removal over basal during the IVGTT derived from the two models were almost identical.

OBJECTIVE To evaluate the effects of an intense physical training program on abdominal fat distribution, glycemic control, and insulin sensitivity in patients with NIDDM and to determine whether branched-chain amino acid (BCAA) supplements influence these effects. RESEARCH DESIGN AND METHODS Twenty-four patients (ages 45 ± 2 [mean ± SE] years, BMI 30.2 ± 0.9 kg/m2, HbA1c 7.9 ± 0.3%) were randomly assigned to four groups: training plus BCAA supplement (n = 6), training plus placebo (n = 6), sedentary plus BCAA supplement (n = 6), and sedentary plus placebo (n = 6). Physical training consisted of a supervised 45-min cycling exercise at 75% of their oxygen uptake peak (VO2 peak) two times per week and an intermittent exercise one time per week for 2 months. RESULTS Patients who exercised increased their VO2 peak by 41% and their insulin sensitivity by 46%. Physical training significantly decreased abdominal fat evaluated by magnetic resonance imaging (umbilicus), with a greater loss of visceral adipose tissue (VAT) (48%) in comparison with the loss of subcutaneous adipose tissue (18%), but did not significantly affect body weight. The change in visceral abdominal fat was associated with the improvement in insulin sensitivity (r = 0.84, P = 0.001). BCAA supplementation had no effect on abdominal fat and glucose metabolism. CONCLUSIONS Physical training resulted in an improvement in insulin sensitivity with concomitant loss of VAT and should be included in the treatment program for patients with NIDDM.

International audience; Adult beta-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of beta-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1 alpha represses genes important for beta-cell development and function. More precisely, PGC-1 alpha inhibited the expression of the key beta-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1 alpha complex to the Pdx1 promoter. To explore PGC-1 alpha function, we generated mice with inducible beta-cell PGC-1 alpha overexpression. Mice overexpressing PGC-1 alpha exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased beta-cell mass, and beta-cell hypotrophy. Interestingly, PGC-1 alpha expression in fetal life only was sufficient to impair adult beta-cell function whereas beta-cell PGC-1 alpha overexpression from adult age had no consequence on beta-cell function. Altogether, our results demonstrate that the GR and PGC-1 alpha participate in the fetal programming of adult beta-cell function through inhibition of Pdx1 expression. Diabetes 62:1206-1216, 2013

International audience; Although regular physical activity is an integral part of T2D management, few diabetic patients have a sufficient level of physical activity. However over the past decade or so, the beneficial effects of regular physical activity have been well demonstrated, both in T2D prevention (50% reduction in the incidence of T2D in subjects with high metabolic risk) as well as T2D management for the improvement of glycaemic control (mean 0.7% improvement of HbA(1c)) and the reduction of T2D-related comorbidities (improvement in blood pressure values and lipid profile, decrease in insulin resistance). Physical activity has both acute effects (effects of one exercise session) and more prolonged effects of exercise when it is repeated on a regular basis (training effect). In addition, the physical activity recommendations have been extended to a wide range of physical activities (by combining both endurance and muscle strengthening exercises), thus varying the physical activity practiced according to the patient's available time, practice sites, preferences and interests. Following a pathophysiology review, the effects of physical activity will be discussed and presented in terms of evidence-based medicine. The recommendations will be defined and practical prescribing information will be suggested, while taking into account that clinicians are concerned with answering questions regarding how, where and with whom: how can patients be motivated to practice a physical activity over the long-term? And how can qualified exercise trainers and appropriate practice settings be found? (C) 2013 Elsevier Masson SAS. All rights reserved.

Patients with Type 2 diabetes (T2D) are highly susceptible to infection and have an increased incidence of some tumors, possibly due to immune system dysfunction. In the innate cellular immune system, Natural Killer (NK) lymphocytes are important effectors responsible for controlling infections and combating tumor development. We analyzed NK cell subsets in 51 patients with long-standing T2D. Compared with healthy blood donors, diabetic patients showed a profound decrease in both NKG2D-positive NK cells (44% vs. 55.5%, P

Fig 4 and its caption appear incorrectly in the published article. Please see the correct Fig 4 and its caption here. Fig 4 GCs inhibit liraglutide-induced increase of serotonin contents in vivo.

International audience; Recombinant methionyl human leptin (r-metHuLeptin) was first used as a replacement therapy in patients bearing inactivating mutations in the leptin gene. In this indication, it was shown since 1999 to be very efficient in inducing a dramatic weight loss in rare children and adults with severe obesity due to the lack of leptin. These first clinical trials clearly showed that r-metHuLeptin acted centrally to reduce food intake, inducing loss of fat mass, and to correct metabolic alterations, immune and neuroendocrine defects. A few years later, r-metHuLeptin was also shown to reverse the metabolic complications associated with lipodystrophic syndromes, due to primary defects in fat storage, which induce leptin deficiency. The beneficial effects, which could be mediated by central and/or peripheral mechanisms, are thought to mainly involve the lowering effects of leptin on ectopic lipid storage, in particular in liver and muscles, reducing insulin resistance. Interestingly, r-metHuLeptin therapy also reversed the hypothalamic-pituitary-gonadal axis dysfunctions associated with hypothalamic amenorrhea. However, if r-metHuLeptin treatment has been shown to be dramatically efficient in leptin-deficient states, its very limited effect in inducing weight loss in common obese patients revealed that, in patients with adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance prevent r-metHuLeptin from inducing any additional effects. This review will present the current data about the effects of r-metHuLeptin therapy in humans, and discuss the recent perspectives of this therapy in new indications.

Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism.Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushing's syndrome.Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital.High-dose therapy combining mitotane (3.0-5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 μg/24 h) was monitored.Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 μg/24 h (range 853-22,605) at baseline to 50 μg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 μg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively).When surgical treatment for severe ACTH-dependent Cushing's syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.

Saxagliptin, a dipeptidyl peptidase-4 inhibitor, has been the focus of a large clinical development programme, including Phase 3 randomized vs placebo-controlled clinical trials as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control using initial monotherapy (metformin, glibenclamide, thiazolidinedione). This clinical programme has shown saxagliptin to be effective in the control of fasting and postprandial glycemic parameters, in addition to a good overall safety profile. The present paper aims at reviewing the overall short-term and long-term efficacy of saxagliptin in its Phase 3 development program and tries to pinpoint some factors that may be more predictive of treatment response in clinical practice. In individual and pooled analyses of the three pivotal add-on to monotherapy trials, saxagliptin (5mg once daily) led to significant reductions in HbA(1c) from baseline to 24 weeks. Additional analyses showed that reductions in HbA(1c) were maintained in the long-term, notably for 102 weeks, in combination with metformin. Data have also shown that the absolute reduction in HbA(1c) seen with saxagliptine from baseline to Week 24 was numerically greater with an elevated baseline HbA(1c). In these recently published pooled analyses, clinically pertinent reductions in HbA(1c) were also obtained with saxagliptin across a wide range of subgroups of T2D patients when examined either by specific baseline demographic characteristics or by β-cell function indices such as the HOMA-β.

OBJECTIVE In animal studies, hyperglycemia during fetal development reduces nephron numbers. We tested whether this observation translates into renal dysfunction in humans by studying renal functional reserve in adult offspring exposed in utero to maternal type 1 diabetes. RESEARCH DESIGN AND METHODS We compared 19 nondiabetic offspring of type 1 diabetic mothers with 18 offspring of type 1 diabetic fathers (control subjects). Glomerular filtration rate (51Cr-EDTA clearance), effective renal plasma flow (123I-hippurate clearance), mean arterial pressure, and renal vascular resistances were measured at baseline and during amino acid infusion, which mobilizes renal functional reserve. RESULTS Offspring of type 1 diabetic mothers were similar to control subjects for age (median 27, range 18–41, years), sex, BMI (23.1 ± 3.7 kg/m2), and birth weight (3,288 ± 550 vs. 3,440 ± 489 g). During amino acid infusion, glomerular filtration rate and effective renal plasma flow increased less in offspring of type 1 diabetic mothers than in control subjects: from 103 ± 14 to 111 ± 17 ml/min (8 ± 13%) vs. from 108 ± 17 to 128 ± 23 ml/min (19 ± 7%, P = 0.009) and from 509 ± 58 to 536 ± 80 ml/min (5 ± 9%) vs. from 536 ± 114 to 620 ± 140 ml/min (16 ± 11%, P = 0.0035). Mean arterial pressure and renal vascular resistances declined less than in control subjects: 2 ± 5 vs. −2 ± 3% (P = 0.019) and 3 ± 9 vs. −14 ± 8% (P = 0.001). CONCLUSIONS Reduced functional reserve may reflect a reduced number of nephrons undergoing individual hyperfiltration. If so, offspring of type 1 diabetic mothers may be predisposed to glomerular and vascular diseases.

In rodent adipocytes, activated AMP-activated protein kinase reduces the lipolytic rate. As the hypoglycaemic drugs metformin and thiazolidinediones activate this enzyme in rodents, we tested the hypothesis that in addition to their known actions they could have an anti-lipolytic effect in human adipocytes.Adipose tissue was obtained from individuals undergoing plastic surgery. Adipocytes were isolated and incubated with lipolytic agents (isoprenaline, atrial natriuretic peptide) and biguanides or thiazolidinediones. Lipolysis was quantified by the glycerol released in the medium. AMP-activated protein kinase activity and phosphorylation state were determined using standard procedures.In human adipocytes, isoprenaline and atrial natriuretic peptide stimulated the lipolytic rate three- to fourfold. Biguanides and thiazolidinediones activated AMP-activated protein kinase and inhibited lipolysis by 30-40%, at least in part by inhibiting hormone-sensitive lipase translocation to the lipid droplet. Inhibition of AMP-activated protein kinase by compound C precluded this inhibitory effect on lipolysis. Stimulation of lipolysis also induced an activation of AMP-activated protein kinase concomitant with a drop in ATP concentration.We show for the first time in human adipocytes that biguanides and thiazolidinediones activate AMP-activated protein kinase, thus counteracting lipolysis induced by lipolytic agents. In addition, beta-agonist- or ANP-stimulated lipolysis increases AMP-activated protein kinase activity. This is because of an increase in the AMP/ATP ratio, linked to activation of some of the released fatty acids into acyl-CoA. AMP-activated protein kinase activation could represent a physiological means of avoiding a deleterious drain of energy during lipolysis but could be used to restrain pharmacological release of fatty acids.

OBJECTIVE Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved. RESEARCH DESIGN AND METHODS The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at RESULTS A novel coding mutation, L30M, potentially affecting insulin multimerization, was identified in five diabetic individuals (diabetes onset 17–36 years) in a single family. L30M preproinsulin-GFP fluorescence largely associated with the endoplasmic reticulum (ER) in MIN6 β-cells, and ER exit was inhibited by ∼50%. Two additional mutants, R55C (at the B/C junction) and R6H (in the signal peptide), were normally targeted to secretory granules, but nonetheless caused substantial ER stress. CONCLUSIONS We describe three INS mutations cosegregating with early-onset diabetes whose clinical presentation is compatible with MODY. These led to the production of (pre)proinsulin molecules with markedly different trafficking properties and effects on ER stress, demonstrating a range of molecular defects in the β-cell.

Caveolins form plasmalemnal invaginated caveolae. They also locate around intracellular lipid droplets but their role in this location remains unclear. By studying primary adipocytes that highly express caveolin-1, we characterized the impact of caveolin-1 deficiency on lipid droplet proteome and lipidome. We identified several missing proteins on the lipid droplet surface of caveolin-deficient adipocytes and showed that the caveolin-1 lipid droplet pool is organized as multi-protein complexes containing cavin-1, with similar dynamics as those found in caveolae. On the lipid side, caveolin deficiency did not qualitatively alter neutral lipids in lipid droplet, but significantly reduced the relative abundance of surface phospholipid species: phosphatidylserine and lysophospholipids. Caveolin-deficient adipocytes can form only small lipid droplets, suggesting that the caveolin-lipid droplet pool might be involved in lipid droplet size regulation. Accordingly, we show that caveolin-1 concentration on adipocyte lipid droplets positively correlated with lipid droplet size in obese rodent models and human adipocytes. Moreover, rescue experiments by caveolin- green fluorescent protein in caveolin-deficient cells exposed to fatty acid overload demonstrated that caveolin-coated lipid droplets were able to grow larger than caveolin-devoid lipid droplets. Altogether, these data demonstrate that the lipid droplet-caveolin pool impacts on phospholipid and protein surface composition of lipid droplets and suggest a functional role on lipid droplet expandability.

Background: To assess the pattern of metabolic profile associated with first stroke episode in a hospital setting in Cameroon. Methods: All patients admitted for firstever-in-lifetime stroke over a 6-month period were eligible for inclusion in the study. The 84% participation rate yielded 57 of 68 patients between 16 and 85 years of age. Fifty-seven control subjects were selected to match patients included for age range, sex, and known hypertension and diabetes. We measured fasting serum glucose, insulin, and lipids in controls and in patients between days 3 and 7 after admission.Results: Total cholesterol was comparable in patients and controls (172.6 6 39.5 v 175.4 6 49.7 mg/dL; P 5.75), as were triglycerides (129.4 6 56.1 v 122.4 6 60.7 mg/dL; P 5.53). high-density lipoprotein cholesterol (HDL-C) levels were lower in patients than in controls (37.4 6 20.6 v 50.2 6 18.0 mg/dL; P 5.001), with comparable levels of lowdensity lipoprotein cholesterol (LDL-C; 109.4 6 43.0 v 100.7 6 48.8 mg/dL; P 5 .32). The LDL-C/HDL-C ratio was higher in patients compared to controls (4.0 6 3.0 v 2.3 6 1.7; P 5.0001), as was the total cholesterol/HDL-C ratio (5.9 6 3.5 v 3.9 6 1.8; P 5.0001). Compared to controls, stroke patients had higher fasting insulin levels (5.9 6 5.4 v 2.3 6 3.2 IU/mL; P , .001) and higher insulin resistance as measured by the homeostatic model assessment of insulin resistance (1.9 6 2.2 v 0.7 6 1.0; P 5 .001). Conclusions: Stroke is associated with markers of insulin resistance, low serum levels of HDL, and high total cholesterol/HDL ratio in this African population. Studies with a larger sample size and cohort designs are warranted to explore the causal pathways, persistence of these abnormalities, and population-specific cut