Obésité et diabète. Les variations des acides gras libres circulants sous charge orale en glucose

Résumé L'étude des variations des acides gras libres (AGL) du plasma est entreprise chez 58 sujets obèses et 18 sujets normaux témoins, mis dans des conditions d'exploration identiques. On constate chez les sujets obèses un comportement global des AGL qui est différent de celui des sujets normaux témoins dans la mesure où la dépression initiale de leur taux est plus lente et le maximum de chute est différé aux temps tardifs de l'épreuve. Il en résulte une tendance globale à une absence de réascension secondaire du taux des AGL circulants, à l'inverse de ce qui succède chez le sujet normal, où la valeur moyenne des AGL à la 4^ème h de l'épreuve est plus élevée que le taux moyen de base. Tant chez le sujet normal que chez le sujet obèse, on constate d'importantes variations individuelles. Les anomalies rencontrées chez les obèses sont d'autant plus évidentes que la tolérance glucidique se rapproche des conditions du diabète; cela laisse à penser qu'il existe, chez ces sujets, des relations étroites entre la dégradation de la tolérance glucidique et les anomalies du comportement des AGL circulants. Ce dernier problème est discuté en fonction des relations entre l'obésité et la maladie diabétique.

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Summary The variations of plasma non-esterified fatty acids (NEFA) in 58 obese subjects and 18 normal controls have been studied in identical conditions of investigation. The overall behavior of NEFA in the obese differed from that in the controls in that the initial fall was slower and the maximum depression occurred late in the test. Hence the overall tendency was for the secondary rise in the NEFA level to be missing, which was the reverse of what happened in the normals, in whom the mean NEFA value at the 4th h was above the starting value. Both in normals and in obese subjects there was a considerable individual variation. The anomalies in the obese became more marked as carbohydrate tolerance approached diabetic level; this suggests that there is in these subjects a close connexion between the decline of carbohydrate tolerance and the anomalies of plasma NEFA behavior. The latter is discussed in terms of the relationships between obesity and diabetes.

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Zusammenfassung Bei 58 Fettsüchtigen und 18 Normalpersonen wurden unter identischen Versuchsbedingungen die Variationen der freien Fettsäuren des Plasma (FFA) verfolgt. Bei Fettsüchtigen wurde ein von den Normalpersonen verschiedenes Gesamtverhalten der FFA festgestellt; der Unterschied ist umso grösser je langsamer die anfängliche Senkung des FFA-Spiegels bei den Fettsüchtigen erfolgt und je mehr das Maximum der Abnahme verzögert ist. Daraus ergibt sich eine Gesamttendenz zum Fehlen des sekundären Anstiegs des zirkulierenden FFA-Spiegels, im Gegensatz zu den Verhältnissen bei Normalpersonen, wo der Mittelwert der FFA in der 4. Stunde der Probe höher ist als der mittlere Ausgangswert. Sowohl bei Normalpersonen als auch bei Fettsüchtigen werden erhebliche individuelle Unterschiede beobachtet. Die bei Fettsüchtigen beobachteten Anomalien sind umso ausgesprochener je mehr sich ihre Kohlehydrattoleranz einer diabetischen Stoffwechsellage nähert; das lässt den Verdacht aufkommen, dass bei diesen Individuen eine enge Beziehung zwischen der verminderten Glukosetoleranz und dem abnormen Verhalten der zirkulierenden FFA besteht. Dieses Problem wird im Hinblick auf die Beziehungen zwischen Fettsucht und Diabetes mellitus besprochen.

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Resumen Se emprendió el estudio de las variaciones de los ácidos grasos libres (AGL) del plasma en 58 individuos obesos y 18 testigos normales, puestos en idénticas condiciones de exploración Se constata que en los sujetos obesos un comportamiento global de los AGL es diferente al de los individuos testigos normales en la medida o la depresión de su porcentaje es más lento y el máximo de caída se difiere a los tiempos tardíos de la prueba. Resulta una tendencia global a una ausencia de reascensión secundaria del porcentaje de los AGL circulantes, al contrario de lo que sucede en el individuo normal, en el que el valor medio de los AGL a las cuatro horas de la prueba es más elevado que el porcentaje medio de base. Tanto en el sujeto normal como en el sujeto obeso, se comprueban importantes variaciones individuales. Las anomalías encontradas en los obesos son mucho más evidentes cuando la tolerancia se acerca a las condiciones de la diabetes; esto lleva a pensar que existe, en estos individuos, estrechas relaciones entre la degradación y la tolerancia glucídica y las anomalias del comportamiento de los AGL circulantes. Este último problema se discute en función de las relaciones entre la obesidad y la enfermedad diabética.

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Riassunto Le variazioni dei NEFA plasmatici sono state studiate in 58 pazienti obesi e in 18 individui normali di controllo, posti in condizioni sperimentali identiche. Nei soggetti obesi è stato osservato un comportamento globale dei NEFA diverso da quello degli individui normali di controllo, nel senso che la depressione iniziale è più lenta e la massima caduta si verifica nelle fasi tardive della prova. Ne risulta una tendenza globale all'assenza di risalita secondaria dei NEFA circolanti, contrariamente a quanto avviene nel soggetto normale, in cui il valore medio dei NEFA alla 4^a ora del test è più elevato rispetto al livello medio di base. Sia nel soggetto normale che nell'obeso, si riscontrano importanti variazioni individuali. Le anomalie rilevate negli obesi sono tanto più evidenti quanto più la tolleranza al glucosio si avvicina alle condizioni esistenti nel diabete: ciò induce a ritenere che in questi soggetti esistano stretti rapporti tra la diminuzione della tolleranza al glucosio e le anomalie del comportamento dei NEFA circolanti. Quest'ultimo problema viene discusso alla luce delle relazioni tra obesità e malattia diabetica.

     

Family history of diabetes is associated with enhanced adipose lipolysis: Evidence for the implication of epigenetic factors

Aims

Type 2 diabetes is associated with insulin resistance, adipose hypertrophy and increased lipolysis. The heritability of these traits has been determined by associating them with a family history of diabetes.

Pharmacokinetic aspects and in vitro–in vivo correlation potential for lipid-based formulations

Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.KEY WORDS: Pharmacokinetics, Lipolysis, IVIVC, Efflux transporters, Lymphatic delivery, Food effectAbbreviations: ADME, absorption/distribution/metabolism/elimination; AUC, area under the curve; BCS, biopharmaceutics classification system; BDDCS, biopharmaceutics drug disposition classification system; CACO, human epithelial colorectal adenocarcinoma cells; C_max, maximum plasma concentration; CMC, critical micellar concentration; CYP, cytochrome; DDS, drug delivery systems; FaSSGF, fasted-state simulated gastric fluid; FaSSIF, fasted-state simulated intestinal fluid; FeSSIF, fed-state simulated intestinal fluid; GIT, gastrointestinal tract; IVIVC, in vitro in vivo correlation; LCT, long chain triglyceride; LFCS, lipid formulation classification system; log P, n-octanol/water partition coefficient; MCT, medium chain triglyceride; MDCK, Madin–Darby canine kidney cells; NCE, new chemical entity; P-app, apparent permeability; P-gp, permeability glycoprotein; SCT, short chain triglyceride; SEDDS, self-emulsifying drug delivery system; SIF, simulated intestinal fluid; SMEDDS, self-microemulsifying drug delivery system; SNEDDS, self-nanoemulsifying drug delivery system; Vit E, vitamin E     

Atrial natriuretic peptide inhibits the production of adipokines and cytokines linked to inflammation and insulin resistance in human subcutaneous adipose tissue

Aims/hypothesis Increased adipose tissue secretion of adipokines and cytokines has been implicated in the chronic low-grade inflammation state and insulin resistance associated with obesity. We tested here whether the cardiovascular and metabolic hormone atrial natriuretic peptide (ANP) was able to modulate adipose tissue secretion of several adipokines (derived from adipocytes) and cytokines (derived from adipose tissue macrophages). Subjects and methods We used protein array to measure the secretion of adipokines and cytokines after a 24-h culture of human subcutaneous adipose tissue pieces treated or not with a physiological concentration of ANP. The effect of ANP on protein secretion was also directly studied on isolated adipocytes and macrophages. Gene expression was measured by real-time RT-quantitative PCR. Results ANP decreased the secretion of the pro-inflammatory cytokines IL-6 and TNF-α, of several chemokines, and of the adipokines leptin and retinol-binding protein-4 (RBP-4). The secretion of the anti-inflammatory molecules IL-10 and adiponectin remained unaffected. The cytokines were mainly expressed in macrophages that expressed all components of the ANP-dependent signalling pathway. The adipokines, leptin, adiponectin and RBP-4 were specifically expressed in mature adipocytes. ANP directly inhibited the secretion of IL-6 and monocyte chemoattractant protein-1 by macrophages. The inhibitory effects of ANP on leptin and growth-related oncogene-α secretions were not seen under selective hormone-sensitive lipase inhibition. Conclusions/interpretation We suggest that ANP, either by direct action on adipocytes and macrophages or through activation of adipocyte hormone-sensitive lipase, inhibits the secretion of factors involved in inflammation and insulin resistance.     

Polymorphisms in PNLIP, encoding pancreatic lipase, and associations with metabolic traits

Pancreatic lipase (EC 3.1.1.3) is an exocrine secretion that hydrolyzes dietary triglycerides in the small intestine. We developed genomic amplification primers to sequence the 13 exons of PNLIP, which encodes pancreatic lipase, in order to screen for possible mutations in cell lines of four children with pancreatic lipase deficiency (OMIM 246600). We found no missense or nonsense mutations in these samples, but we found three silent single-nucleotide polymorphisms (SNPs), namely, 96A/C in exon 3, 486C/T in exon 6, and 1359C/T in exon 13. In 50 normolipidemic Caucasians, the PNLIP 96C and 486T alleles had frequencies of 0.083 and 0.150, respectively. The PNLIP 1359T allele was absent from Caucasian, Chinese, South Asian, and North American aboriginal samples, but had a frequency of 0.085 in an African sample, suggesting that it is a population-specific variant. In an association analysis of 185 African neonates, the PNLIP 1359C/T SNP genotype was significantly associated with concentrations of plasma lipoproteins. These associations were most likely due to linkage disequilibrium with another functional variant at or near PNLIP. Thus, we report three new SNPs for the PNLIP, which may serve as markers for association analyses and for pharmacogenetic studies of pancreatic lipase inhibitors. Received: January 18, 2001 / Accepted: February 19, 2001     

Studies on the antilipolytic effect of adenosine and related compounds in isolated fat cells

Summary Basal lipolysis in isolated fat cells of rats was increased by adenosine in a dose-dependent manner. Low concentrations of this nucleoside (1–10 M) inhibited noradrenaline-induced glycerol production by about 50% and completely blocked the effect of theophylline on fat cells. Glycerol release, induced by dibutyryl cyclic AMP, was increased by 5 M adenosine. Inosine, hypoxanthine, and xanthine had weaker antilipolytic properties, whereas adenine was virtually without effect.Although dipyridamole (20 M) strongly decreased the uptake of adenosine into fat cells, it did not counteract the antilipolytic action of this nucleoside. Low concentrations of adenosine (0.1 M), which by themselves were without any effect, greatly enhanced the effect of insulin on lipolysis. It is tentatively suggested that adenosine may be involved in the physiological control of lipolysis and that this nucleoside has its site of action on the cell membrane.Recipient of a Deutsche Forschungsgemeinschaft scholarship     

Neurochemical phenotype of sympathetic nervous system outflow from brain to white fat

The sympathetic innervation of white adipose tissue (WAT) appears to be a dominant mechanism triggering lipolysis. The purpose of this study was to determine the neurochemical phenotype of neurons comprising the sympathetic outflow from brain to WAT. This was accomplished by injecting Siberian hamster WAT with a viral retrograde transneuronal tract tracer, the pseudorabies virus (PRV), in combination with immunocytochemical characterization of several neurotransmitters or their synthetic enzymes in the brain. Catecholaminergic (tyrosine hydroxylase [TH] and dopamine-beta-hydroxylase [DBH] immunoreactivity) and peptidergic (arginine vasopressin [AVP] and oxytocin [OXY] immunoreactivity) neurons were part of this outflow, but the percentage of double-labeled cells was small, consistent with previous studies. Brainstem PRV + TH- or PRV + DBH-labeled cells were in previously identified noradrenergic areas (A5, A6, and subcoeruleus, rostroventrolateral medulla [RVL], some reticular nuclei). Forebrain double labeling was greatest in the paraventricular (TH, AVP, OXY) and suprachiasmatic (AVP) nuclei, both implicated in the central control of lipolysis. Differences between the PRV double labeling reported here for WAT versus that of other sympathetic peripheral targets were PRV + DBH in A5 and RVL, and PRV + TH in RVL and in the lateral paragigantocellular and lateral reticular nuclei. Collectively, these results begin to identify the neurochemical identity of the sympathetic outflow from brain to WAT.     

Electrical stimulation of the ventromedial hypothalamus enhances both fat utilization and metabolic rate that precede and parallel the inhibition of feeding behavior

The effects of ventromedial hypothalamic (VMH) stimulation on various metabolic parameters in freely moving animals were measured using a specific indirect calorimetric chamber associated with a quantitative measurement of locomotor activity, which allows the separate measurement of locomotor energy expenditure from that of background metabolism, BM (free from expenses due to locomotion). To obtain circumscribed VMH stimulation, a slight-intensity (20-25 microA) bipolar, constant current was applied for 15 min at the beginning of the dark phase on ad libitum fed rats. The VMH stimulation suppressed feeding for 40 min, then animals progressively recovered within the subsequent 60 min as shown by comparison with the control group. On different days, the same stimulation parameters were applied while food was unavailable, and metabolic parameters were recorded. An increase in BM lasting 30 min was observed. This increase in metabolic rate was sustained by means of a recruitment of lipid stores as indicated by a concomitant drop in respiratory quotient. These observations indicate that the VMH is part of the sympathetic nervous system, capable of inducing lipolysis. The sequence of metabolic and feeding events may then in part be due to VMH-induced lipolysis that provides more fuel to the metabolic economy, raising the BM, which in turn decreases hunger.     

Substrate metabolism during exercise in the spinal cord injured

The primary aim of the study was to examine substrate metabolism during combined passive and active exercise in individuals with spinal cord injury (SCI). Nine men and women with SCI (mean age 40.6 ± 3.4 years) completed two trials of submaximal exercise 1 week apart. Two maintained a complete injury and seven had an incomplete injury. Level of injury ranged from thoracic (T4–T6 and T10) to cervical (four C5–C6 and three C6–C7 injuries). During two bouts separated by 1 week, subjects completed two 30 min sessions of active lower-body and passive upper-body exercise, during which heart rate (HR) and gas exchange data were continuously assessed. One-way analysis of variance with repeated measures was used to examine differences in all variables over time. Results demonstrated significant increases (P < 0.05) in HR and oxygen uptake (VO₂) from rest to exercise. Respiratory exchange ratio (RER) significantly increased (P < 0.05) during exercise from 0.85 ± 0.02 at rest to 0.95 ± 0.01 at the highest cadence, reflecting increasing reliance on carbohydrate from 50.0 to 83.0% of energy metabolism. Data demonstrate a large reliance on carbohydrate utilization during 30 min of exercise in persons with SCI, with reduced contribution of lipid as exercise intensity was increased. Strategies to reduce carbohydrate utilization and increase lipid oxidation in this population should be addressed.