[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES
Ketosis-prone atypical diabetes (KPD) is a subtype of diabetes in which the pathophysiology is yet to be unraveled. The aim of this study was to characterize β- and α-cell functions in Africans with KPD during remission.RESEARCH DESIGN AND METHODS
We characterized β- and α-cell functions in Africans with KPD during remission. The cohort comprised 15 sub-Saharan Africans who had been insulin-free for a median of 6 months. Patients in remission were in good glycemic control (near-normoglycemic) and compared with 15 nondiabetic control subjects matched for age, sex, ethnicity, and BMI. Plasma insulin, C-peptide, and glucagon concentrations were measured in response to oral and intravenous glucose and to combined intravenous arginine and glucose. Early insulin secretion was measured during a 75-g oral glucose tolerance test. Insulin secretion rate and glucagon were assessed in response to intravenous glucose ramping.RESULTSEarly insulin secretion and maximal insulin secretion rate were lower in patients compared with control participants. In response to combined arginine and glucose stimulation, maximal insulin response was reduced. Glucagon suppression was also decreased in response to oral and intravenous glucose, but not in response to arginine and insulin.CONCLUSIONS
Patients with KPD in protracted near-normoglycemic remission have impaired insulin response to oral and intravenous glucose and to arginine, as well as impaired glucagon suppression. Our results suggest that β- and α-cell dysfunctions both contribute to the pathophysiology of KPD.
[Show abstract][Hide abstract] ABSTRACT: Introduction
Nous avons montré précédemment que l’exposition fœtale au diabète maternel est associée chez le descendant adulte à un déficit de l’insulinosécrétion. L’objectif de cette étude est d’évaluer si l’exposition au diabète de type 1 (DT1) in utero est associée à une altération globale de la fonction pancréatique chez le descendant non diabétique et sans marqueurs d’autoimmunité de DT1.
Patients et Méthodes
Nous avons exploré 29 descendants de mères DT1 (groupe exposé) et 29 descendants de pères DT1 (groupe témoin). La réponse précoce de l’insulinosécrétion au glucose oral et la sécrétion d’insuline et de glucagon au cours d’une perfusion de glucose par paliers de 40 min de 4 à 16 mg/kg/min couplée à un test à l’arginine (bolus de 5 g) ont été évaluées. La sensibilité à l’insuline a été mesurée par un clamp euglycémique (80 mUI/m2/min) et la composition corporelle par DEXA. La fonction exocrine pancréatique a été évaluée par une analyse coprologique.
L’âge, le sexe ratio, le pourcentage de masse grasse et la sensibilité à l’insuline étaient similaires chez les exposés et les témoins : 25,9 ± 6,2 vs 26,2 ± 6,1 ans, 55 (F/H) vs 52%, 26,3 ± 8,7 vs 24,5 ± 7,9% de masse grasse et 11,5 ± 2,9 vs 11,7 ± 2,5 mg/kg masse maigre/min respectivement. Deux intolérants au glucose étaient retrouvés dans chaque groupe. L’insulinosécrétion précoce au glucose oral [Δ (insuline/glucose) 0–30 min] était plus faible dans le groupe exposé : 7,8 (médiane) (5,5–10,6 Q1–Q3) vs 11,3 (6,4–17,1) µUI/mmol (p = 0,06). En réponse au glucose IV, et à l’arginine, aucune différence n’était observée entre les 2 groupes sur la sécrétion de l’insuline et les concentrations de glucagon. Cependant, les femmes exposées au diabète maternel avaient une diminution significative des débits sécrétoires d’insuline comparativement à celles du groupe témoin : 12,5 ± 4,5 vs 15,2 ± 5,2 pmol/kg/min (p = 0,03). L’activité chymotrypsique dans les selles était significativement plus basse dans le groupe exposé (p = 0,016).
L’exposition fœtale au DT1 est associée à l’âge adulte à une diminution globale de la fonction pancréatique. Le déficit de l’insulinosécrétion en réponse au glucose IV n’est observé que chez les femmes, ce qui suggère des mécanismes épigénétiques dépendant du sexe.
[Show abstract][Hide abstract] ABSTRACT: We evaluated short-term changes in serum amino-terminal procollagen propeptide (P1NP) and cross-linked C-terminal telopeptide (betaCTX) of type I collagen after parathyroidectomy (PTX) in 41 postmenopausal women with primary hyperparathyroidism (PHPT). Serum levels of 25-hydroxyvitamin D, intact PTH, calcium, phosphate, albumin, creatinine, P1NP, and betaCTX were measured before and 2 days after PTX. Their P1NP and betaCTX levels were compared with those measured in 41 normally menstruating and 30 postmenopausal controls. Fifteen of these 41 women had both pre-surgery P1NP and betaCTX concentrations above the upper limit noted in our postmenopausal controls [high turnover (HT) subgroup], while betaCTX levels were solely above the upper limit lastly mentioned in 11 women [high bone resorption (HBR) subgroup]. In addition, these two markers were within the postmenopausal control range in 12 of them [normal turnover (NT) subgroup]. A more significant decrease in postoperative betaCTX levels was observed in the 15 HT compared with the 12 NT PHPT women. The significant postoperative increase in P1NP levels observed in the 15 HT as well as in the 11 HBR was no longer significant in the 12 NT women. In conclusion, higher pre-surgery P1NP and betaCTX levels in post-menopausal PHPT women are associated with a preferential activation of bone formation over bone resorption after PTX.
Journal of Bone and Mineral Metabolism 02/2009; 27(2):240-6. · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ketosis prone type 2 diabetes (KPD) is an atypical form of diabetes described mainly in people of sub-Saharan African origin. Its pathogenesis is unknown, although we have previously described a high prevalence of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in patients with KPD. However, 50% of these deficient patients lacked the G6PD gene mutation. The isoforms of the transcription factor sterol regulatory element binding protein 1 (SREBP-1) are known to stimulate G6PD gene expression, and some polymorphisms in the SREBP-1 gene (SREBF-1) have been described only in Africans. We investigated one of these, the Arg585Gln polymorphism, in a candidate gene approach for KPD.
We examined the presence of the Arg585Gln polymorphism in SREBF-1 in 217 consecutive unrelated Africans [73 patients with KPD, 80 with classical type 2 diabetes (T2D) and 64 nondiabetic subjects]. Patients underwent clinical and biochemical evaluations, and were assessed for G6PD activity and insulin secretion (glucagon test).
There were no differences in frequency of the Arg585Gln polymorphism and the 585Gln allele among the three groups (allele frequency: KPD: 0.089, T2D: 0.031, nondiabetic group: 0.070; P=0.1). When the 585Gln allele frequency was compared separately between patients with KPD and those with T2D, it was significantly higher in the former (P=0.032). There was no difference between carriers and noncarriers of the 585Gln allele regarding G6PD activity and insulin secretion.
The results of this exploratory study show that the polymorphism Arg585Gln in SREBF-1 is not associated with the KPD phenotype. Further studies in larger populations are needed to confirm our findings.
[Show abstract][Hide abstract] ABSTRACT: To characterize insulin action in Africans with ketosis-prone diabetes (KPD) during remission.
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 x m(-2) body surface x min(-1) and 80 mU x m(-2) x min (-1) insulin infusion rates) euglycemic clamp with [6,6-(2)H(2)]glucose as the tracer. Early-phase insulin secretion was determined during an oral glucose tolerance test.
The total glucose disposal was reduced in patients compared with control subjects (7.5 +/- 0.8 [mean +/- SE] vs. 10.5 +/- 0.9 mg x kg(-1) x 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 x kg(-1) x min(-1); P = 0.001) and after 200-min insulin infusion (10 mU x m(-2) x min(-1): 1.6 +/- 0.2 vs. 0.6 +/- 0.1, P = 0.004; 80 mU x m(-2) x min(-1): 0.3 +/- 0.1 vs. 0 mg x kg(-1) x 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 micromol/l; P = 0.002) and remained higher after 100-min 10 mU x m(-2) x min(-1) insulin infusion (706.6 +/- 96.5 vs. 381.6 +/- 55.9 micromol/l; P = 0.015).
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.
Diabetes care 10/2008; 31(12):2332-7. · 7.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate two-site non competitive insulin immunoassays [BI-INSULIN assay (IRMA) and an electro-chemiluminescent immunoassay (ECLIA)] in routine practice.
We studied 145 consecutive patients attending our Endocrine Department for general endocrine explorations and metabolic status investigations.
The ECLIA yielded higher results than IRMA in all but six patients treated by glargine.
Insulin levels measured by Elecsys in patients treated by glargine are directly related to glargine biotransformation into detectable metabolite (M1).
[Show abstract][Hide abstract] ABSTRACT: Introduction
Le diabète cétonurique (ketosis-prone diabetes -KPD) se caractérise par des épisodes de cétose ou d’acidocétose nécessitant une insulinothérapie le plus souvent transitoire. Il survient principalement chez des sujets originaires d’Afrique sub-Saharienne et sa physiopathologie n’est pas connue. Le glucagon étant la principale hormone cétogène, nous avons évalué la fonction alpha insulaire in vivo chez des patients KPD à distance d’une décompensation cétosique.
Matériels et méthodes
Nous avons exploré 19 patients KPD en rémission (HbA1c ≤ 6,5 % depuis au moins 3 mois en l’absence d’insuline) comparativement à 19 sujets témoins normo-glycémiques appariés pour l’âge (44,5 ± 2,4 (sem) vs 43,7 ± 1,9 ans respectivement), le sexe et l’origine ethnique. Nous avons mesuré les concentrations de glucagon en réponse à l’insuline (clamp euglycémique hyperinsulinémique), au glucose oral (75 g), au glucose IV (perfusion de glucose par paliers de 40 min de 2 à 10 mg.kg−1.min−1), et à l’arginine (5 g IV). Le produit glucagon x glucose (10−3 pg.mmol.ml−2) a été utilisé comme indice de résistance à la suppression par le glucose de la sécrétion du glucagon.
Au cours de l’HGPO, l’indice de résistance était de 881,4 ± 105,5 vs 614,5 ± 48,7 (p = 0,03) de base, 1576,9 ± 138,7 vs 1188,4 ± 130,2 (p = 0,04) à 30 min, et 1680,8 ± 147,2 vs 652,6 ± 39,9 (p < 0,001) à 120 min chez les patients et les témoins respectivement. Au cours du clamp euglycémique, la baisse des concentrations de glucagon était similaire dans les 2 groupes (patients : 119,9 ± 10,7 à 81,3 ± 7,1pg/ml ; témoins : 124,4 ± 9,3 à 89,0 ± 8,2 pg/ml). Au cours la perfusion de glucose par palier, chaque augmentation d’un mmol/l de glycémie faisait chuter les concentrations moyennes de glucagon de 1,75 % chez les patients contre 4,6 % chez les témoins (p < 0,04). En réponse à l’arginine, aucune différence n’était observée entre les deux groupes.
Les patients KPD en rémission présentent une altération de la suppression de la sécrétion de glucagon en réponse au glucose oral et intraveineux, comme cela a été décrit chez les patients diabétiques de type 2. Ces données plaident en faveur du KPD comme forme de diabète de type 2.
[Show abstract][Hide abstract] ABSTRACT: Because of previously reported ethnic differences in determinants and markers of obesity and related metabolic disorders, we sought to investigate circulating levels of adiponectin and their correlates in a sub-Saharan African (sSA) population.
We studied 70 non-diabetic volunteers (33M/37F) living in Yaoundé, Cameroon, aged 24-69 yr, with BMI 20-42 kg/m2. In all participants we measured waist circumference and total body fat by bioimpedance, and obtained a fasting venous blood sample for measurement of plasma glucose, serum insulin and adiponectin concentrations. We performed a euglycaemic hyperinsulinaemic clamp in 1/4 subjects, and HOMAIR was used as surrogate of fasting insulin sensitivity index since it best correlates to clamp measurements.
Males had lower adiponectin levels than females (8.8 +/- 4.3 vs. 11.8 +/- 5.5 microg/L). There was no significant correlation between adiponectin and total body fat (rs = -0.03; NS), whereas adiponectin was inversely correlated with waist circumference (rs = -0.39; p = 0.001). Adiponectin correlated negatively with insulin resistance (rs = -0.35; p = 0.01). In a regression analysis using fasting adiponectin concentration as the dependent variable, and age, HOMAIR, waist circumference, and fat mass as predictors, waist circumference (beta = -3.30; p = 0.002), fat mass (beta = -2.68; p = 0.01), and insulin resistance (beta = -2.38; p = 0.02) but not age (beta = 1.11; p = 0.27) were independent predictors of adiponectin. When considering gender, these relations persisted with the exception of waist circumference in females.
Adiponectin correlates in this study population are comparable to those observed in Caucasians with the exception of waist circumference in women. The metabolic significance of waist circumference is therefore questioned in sSA women.
[Show abstract][Hide abstract] ABSTRACT: Diagnosis of adrenal insufficiency in critically ill patients has relied on random or cosyntropin-stimulated cortisol levels, and has not been corroborated by a more accurate diagnostic standard.
We used the overnight metyrapone stimulation test to investigate the diagnostic value of the standard cosyntropin stimulation test, and the prevalence of sepsis-associated adrenal insufficiency.
This was an inception cohort study.
In two consecutive septic cohorts (n = 61 and n = 40), in 44 patients without sepsis and in 32 healthy volunteers, we measured (1) serum cortisol before and after cosyntropin stimulation, albumin, and corticosteroid-binding globulin levels, and (2) serum corticotropin, cortisol, and 11beta-deoxycortisol levels before and after an overnight metyrapone stimulation. Adrenal insufficiency was defined by postmetyrapone serum 11beta-deoxycortisol levels below 7 microg/dl. More patients with sepsis (31/61 [59% of original cohort with sepsis] and 24/40 [60% of validation cohort with sepsis]) met criteria for adrenal insufficiency than patients without sepsis (3/44; 7%) (p < 0.001 for both comparisons). Baseline cortisol (< 10 microg/dl), Delta cortisol (< 9 microg/dl), and free cortisol (< 2 microg/dl) had a positive likelihood ratio equal to infinity, 8.46 (95% confidence interval, 1.19-60.25), and 9.50 (95% confidence interval, 1.05-9.54), respectively. The best predictor of adrenal insufficiency (as defined by metyrapone testing) was baseline cortisol of 10 microg/dl or less or Delta cortisol of less than 9 microg/dl. The best predictors of normal adrenal response were cosyntropin-stimulated cortisol of 44 microg/dl or greater and Delta cortisol of 16.8 microg/dl or greater.
In sepsis, adrenal insufficiency is likely when baseline cortisol levels are less than 10 microg/dl or delta cortisol is less than 9 microg/dl, and unlikely when cosyntropin-stimulated cortisol level is 44 microg/dl or greater or Delta cortisol is 16.8 microg/dl or greater.
American Journal of Respiratory and Critical Care Medicine 01/2007; 174(12):1319-26. · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vitamin D is essential for bone mineralization, and its deficiency may be the cause of skeletal fractures and osteomalacia. Geographical or ethnic factors may modulate the cutaneous synthesis of vitamin D. We hypothesized that major changes in keratinization may similarly alter the cutaneous synthesis of vitamin D.
To explore calciotrophic hormones, parameters of bone remodelling and bone mineral density (BMD) in nine patients with non-bullous congenital ichthyosis.
Six patients were European, three were North African. Four had received acitretin over a long period of time. A complete biological investigation, including serum and urinary calcium and phosphorus, calciotrophic hormones [intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-(OH)D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D)], bone formation and resorption markers, was performed on all patients during the winter season and repeated among four patients after summer. BMD was measured in all patients.
All patients had a marked 25-(OH)D deficiency, clearly below the deficiency threshold of 25 nmol/L. Patients from North Africa had a greater deficiency than European patients, perhaps because of the difference in skin pigmentation. iPTH remained normal in European patients but was elevated among the North Africans. After sun exposure, an improvement in vitamin status was visible in only one patient. Bone formation and resorption markers remained normal. Femoral neck osteodensitometry indicated values near the osteopaenic threshold in two young North African females. No deleterious effect of retinoids on vitamin D metabolism was observed.
Patients, and in particular pigmented patients, with congenital ichthyosis present a severe deficiency in vitamin D. Care provided to protect the skeletal future of these patients involves measuring BMD and prescribing supplementation.
Journal of the European Academy of Dermatology and Venereology 10/2006; 20(8):947-52. · 2.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe the first case of a 36 year-old male patient with a somatotropin and thyreotropin secreting pituitary adenoma, co-treated by a long-acting releasing somatostatin analog (Octreotide) and a GH receptor antagonist (Pegvisomant). The patient normalized his biological disease activity reflected by hormone levels but his tumor size remained unchanged as measured by MRI. The co-treatment was well tolerated and induced a synergic effect on IGF1 levels that allowed us to use low doses of both therapies.
Annales d Endocrinologie 07/2006; 67(3):249-52. · 1.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since the demonstration that vitamin D status might influence the clinical and biological expression of primary hyperparathyroidism (PHPT), a serum 25-hydroxy vitamin D (25-OHD) concentration of 50 nmol/l has been considered by an expert panel as the minimum level to be maintained in asymptomatic PHPT patients. Two yr after this recommendation, we aimed to evaluate the frequency of serum 25-OHD concentrations below this threshold in PHPT patients. In the present study, serum 25-OHD, second- and third-generation PTH, calcium, phosphate, magnesium, albumin and creatinine were measured in 72 out 145 consecutive PHPT patients operated on in our Endocrine Surgery Department, in whom blood samples were available before as well as two days after surgical intervention. Before surgery, the frequency of serum 25-OHD levels <50 nmol/l ranged from 91.5 to 100% whatever the classification used to identify patients: whole group, symptomatic vs asymptomatic, patients with calcium levels >3 vs <3 mmol/l. 25-OHD concentrations correlated negatively with the weight of adenoma, PTH levels, and total calcium concentrations measured before surgery. Pre-operative PTH levels, whatever the assay used, and total calcium concentrations were positively and significantly correlated. Two days post-surgery, 13 patients were moderately hypocalcemic. Neither pre-surgery 25-OHD nor PTH, calcium or phosphorus level or adenoma weight were predictive of post-operative hypocalcemia. The dramatic frequency of low 25-OHD concentrations in our PHPT patients demonstrates that the above-mentioned recommendation is far from being applied in France despite evidence of worsening expression of PHPT with decreasing 25-OHD serum levels.
Journal of endocrinological investigation 06/2006; 29(6):511-5. · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Third-generation parathyroid hormone (PTH) assays have been reported to measure only intact PTH(1-84), in contrast to second-generation assays, which also detect PTH(7-84) fragments. Higher PTH measurements were observed with third- than with second-generation PTH assays in a few patients with either severe primary hyperparathyroidism or parathyroid carcinoma.
We analyzed biological data [second- and third-generation PTH assays, 25-hydroxyvitamin D (25-OHD), calcium, and phosphate concentrations] obtained before and after surgery for 2 groups of patients selected from a large series of consecutive patients with primary hyperparathyroidism (PHPT): 7 female patients with surgically and histologically confirmed PHPT (group 1) and a matched group (group 2).
For group 1 but not group 2, PTH concentrations measured by third-generation PTH assays before surgery were higher than those measured by the second-generation assays. Circulating 25-OHD, calcium, and phosphate concentrations were similar in both groups. In addition, PTH values measured with the third-generation PTH assays in group 1 decreased after surgery.
Our results confirm that third-generation PTH assays do not measure only PTH(1-84). The frequency of this unexpected finding of markedly lower PTH concentrations than previously reported was approximately 5% in patients with PHPT without malignancy. We do not know whether the presence of this unexpected profile is predictive of malignancy.
[Show abstract][Hide abstract] ABSTRACT: This study was conducted in order to evaluate the effect of glucose-insulin homeostasis on adrenal steroids and was designed to separate the effects of hyperglycaemia from those of insulin.
Eight healthy men aged 22.6 +/- 3.4 (SD) underwent an 80 mU/m2/min hyperinsulinaemic euglycaemic 100-min clamp, a 200-min graded glucose infusion at 2-16 mg/kg/min and a measurement of fat mass.
Circulating glucose, insulin and adrenal steroid levels including dehydroepiandrosterone (DHEA) were determined before and during both infusion tests. Steroid variations in relation to insulinaemia and glycaemia were analysed using univariate, multivariate tests and nonlinear mixed models.
Hyperinsulinaemia induced no significant modification of adrenal steroid levels. By contrast, hyperglycaemia decreased all adrenal steroids except DHEA-sulphate by 47-66%. The drop occurred early, averaging 51% for 17OH pregnenolone and 57% for DHEA at the 80th minute of glucose infusion, whereas blood glucose was 7.1 +/- 1.2 mmol/1. This effect was independent of insulinaemia, fat mass and waist circumference. Thus, we estimated models that could best predict steroid variations according to blood glucose. At thresholds defining impaired fasting glycaemia and diabetes, the estimated decrease in DHEA was 40% and 45%, respectively, culminating at 60% at 9.3 mmol/1 glycaemia, with no detectable further decrease.
Our data suggest that hyperglycaemia dramatically decreases adrenal androgen levels in men, possibly by acting at early steps of synthesis, independently of insulinaemia and fat mass.
[Show abstract][Hide abstract] ABSTRACT: Since the demonstration that the second-generation PTH assays, also called intact PTH assays, recognize a non-1-84 PTH fragment in addition to the intact 1-84 PTH, new PTH assays defined as third-generation assays have been commercialized. Two previous studies aimed at evaluating whether these third-generation PTH assays improved the diagnostic sensitivity for primary hyperparathyroidism (PHPT), but they yielded opposite results.
In the present study we compared two second-generation PTH assays (the total intact PTH assay from Scantibodies Laboratory, Inc., and the intact PTH assay from Nichols Institute Diagnostics) with two third-generation assays (the cyclase-activating PTH assay also from Scantibodies Laboratory and the bio-intact PTH assay from Nichols Institute) in a series of 145 consecutive PHPT patients operated in our endocrine surgery department over a 10-month period. A group of 74 healthy subjects served as controls.
The diagnostic sensitivities for PHPT of the total intact, the intact, the cyclase-activating, and the bio-intact assays were 93.8%, 97.3%, 84.2%, and 89.0%, respectively, with 95% confidence intervals in the control groups of 10-46, 11-60, 8.4-34, and 9-41 ng/liter, respectively.
Our findings demonstrate that the diagnostic sensitivities of second- and third-generation PTH assays are similar. Third-generation PTH assays do not therefore improve the diagnosis of elevated serum PTH levels in PHPT, although there are numerical differences among the values.
[Show abstract][Hide abstract] ABSTRACT: White adipose tissue (WAT) plays a critical role in the development of insulin resistance via secretion of free fatty acids (FFA) and adipocytokines. Muscle-specific insulin receptor knockout (MIRKO) mice do not develop insulin resistance or diabetes under physiological conditions despite a marked increase in adiposity and plasma FFA. On the contrary, WAT of MIRKO is sensitized to insulin action during a euglycemic clamp, and WAT glucose utilization is dramatically increased. To get insight into the potential antidiabetic role of MIRKO adiposity, we have studied insulin action in WAT during a euglycemic, hyperinsulinemic clamp, and we have characterized the morphology and biology of WAT. During the clamp, there is no alteration in the expression or activation in the insulin signaling molecules involved in glucose transport through the phosphoinositide 3-kinase/Akt and CAP/Cbl pathways in WAT from MIRKO. The 53% increase in WAT mass results from a 48% increase in adipocyte number (P < 0.05) without alteration in cell size and contemporary to a 300% increase in mRNA levels of the adipogenic transcription factor CCAAT enhancer binding protein-alpha (C/EBP-alpha) (P < 0.05). There is a 39.5% increase in serum adiponectin (P < 0.01) without modification in serum leptin, resistin, and TNF-alpha. In conclusion, the MIRKO mouse displays muscle insulin resistance, visceral obesity, and dyslipidemia but does not develop hyperinsulinemia or diabetes. There is an accelerated differentiation of small insulin sensitive adipocytes, an increased secretion of the insulin sensitizer adiponectin, and maintenance of leptin sensitivity. The MIRKO mouse confirms the importance of WAT plasticity in the maintenance of whole body insulin sensitivity and represents an interesting model to search for new secreted molecules that positively alter adipose tissue biology.