Aromatic L-Amino Acid Decarboxylase Deficiency Is a Cause of Long-Fasting Hypoglycemia

Objective/Context: Long-fasting hypoglycemia in children may be induced by neurotransmitter disorders. Case Report: A 5-year-old girl with a medical history of chronic diarrhea presented three episodes of severe hypoglycemia (20 mg/dL) between ages 3 and 5 years. She became pale and sweaty with hypothermia (33.5°C), bradycardia (45 bpm), and acidosis and presented a generalized seizure. During the 17-hour fast test performed to determine the etiology of her hypoglycemia, insulin and C-peptide were appropriately low, and human GH, IGF-I, cortisol, amino acids, and acylcarnitines were in the usual range for fasting duration. However, the presence of vanillactic and vanilpyruvic acids in urine led us to investigate the metabolism of dopamine and serotonin in the cerebrospinal fluid. Indeed, these results indicated an aromatic L-amino acid decarboxylase deficiency that impairs the synthesis of serotonin, dopamine, and catecholamines. The diagnosis was confirmed by the low aromatic L-amino acid decarboxylase (AADC) enzyme activity in plasma (5 pmol/min/mL; reference value, 20–130) and the presence of two heterozygous mutations, c.97G>C (p.V33L, inherited from her father) and c.1385G>C (p.R462P, inherited from her mother) in the DCC gene. She was supplemented with pyridoxine and raw cornstarch (1 g/kg) at evening dinner to reduce the night fast. The episodes of hypoglycemia and the chronic diarrhea were suppressed. Conclusion: Here is the first case report of long-fasting hypoglycemia due to a nontypical AADC deficiency. Hypoglycemia was severe, but the other neurological clinical hallmarks present in AADC-deficient patients were mild to moderate. Thus, neurotransmitter disorders should be considered in any patients presenting hypoglycemia with urine excretion of vanillactic acid

Adipocyte pyruvate dehydrogenase kinase 4 expression is associated with augmented PPARγ upregulation in early-life programming of later obesity

We studied adipocytes from 8-week-old control rat offspring (CON) or rat offspring subjected to maternal low (8%) protein (MLP) feeding during pregnancy/lactation, a procedure predisposing to obesity. Acute exposure to isoproterenol or adenosine enhanced PDK4 and PPARc mRNA gene expression in CON and MLP adipocytes. Enhanced adipocyte Pdk4 expression orrelated with increased PPARc expression. Higher evels of PDK4 and PPARc were observed in MLP adipocytes. SCD1 is a PPARc target. Isoproterenol enhanced adipocyte PDK4 and SCD1 gene expression in parallel. This could reflect augmented PPARc expression together with enhanced lipolytic stimulation to supply endogenous PPARc ligands, allowing enhanced adipocyte PDK4 and SCD1 expression via PPARc activation. In contrast, the effect of adenosine to increase PDK4 expression is independent of stimulation of lipolysis and, as SCD1 expression was unaffected by adenosine, unlikely to reflect PPARc activation. Increased adipocyte expression of both PDK4 and SCD1 in the MLP model could participate as components of a ‘‘thrifty’’ phenotype, favouring the development of obesit

Pyruvate Dehydrogenase Kinase 4: Regulation by Thiazolidinediones and Implication in Glyceroneogenesis in Adipose Tissue

OBJECTIVE—Pyruvate dehydrogenase complex (PDC) serves as the metabolic switch between glucose and fatty acid utilization. PDC activity is inhibited by PDC kinase (PDK). PDC shares the same substrate, i.e., pyruvate, as glyceroneogenesis, a pathway controlling fatty acid release from white adipose tissue (WAT). Thiazolidinediones activate glyceroneogenesis. We studied the regulation by rosiglitazone of PDK2 and PDK4 isoforms and tested the hypothesis that glyceroneogenesis could be controlled by PDK

Combined transcriptomic-(1)H NMR metabonomic study reveals yhat monoethylhexyl phthalate stimulates adipogenesis and glyceroneogenesis in human adipocytes

Adipose tissue is a major storage site for lipophilic environmental contaminants. The environmental metabolic disruptor hypothesis postulates that some pollutants can promote obesity or metabolic disorders by activating nuclear receptors involved in the control of energetic homeostasis. In this context, monoethylhexyl phthalate (MEHP) is of particular concern since it was shown to activate the peroxisome proliferator-activated receptor γ (PPARγ) in 3T3-L1 murine preadipocytes. In the present work, we used an untargeted, combined transcriptomic-(1)H NMR-based metabonomic approach to describe the overall effect of MEHP on primary cultures of human subcutaneous adipocytes differentiated in vitro. MEHP stimulated rapidly and selectively the expression of genes involved in glyceroneogenesis, enhanced the expression of the cytosolic phosphoenolpyruvate carboxykinase, and reduced fatty acid release. These results demonstrate that MEHP increased glyceroneogenesis and fatty acid reesterification in human adipocytes. A longer treatment with MEHP induced the expression of genes involved in triglycerides uptake, synthesis, and storage; decreased intracellular lactate, glutamine, and other amino acids; increased aspartate and NAD, and resulted in a global increase in triglycerides. Altogether, these results indicate that MEHP promoted the differentiation of human preadipocytes to adipocytes. These mechanisms might contribute to the suspected obesogenic effect of MEHP

Cannabinoid CB2 Receptor Potentiates Obesity-Associated Inflammation, Insulin Resistance and Hepatic Steatosis

BACKGROUND: Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver. METHODOLOGY: Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 -/-). PRINCIPAL FINDINGS: In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 -/- mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 -/- mice. CONCLUSION/SIGNIFICANCE: These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorder

Role of Pyruvate Dehydrogenase Kinase 4 in Regulation of Blood Glucose Levels

In the well-fed state a relatively high activity of the pyruvate dehydrogenase complex (PDC) reduces blood glucose levels by directing the carbon of pyruvate into the citric acid cycle. In the fasted state a relatively low activity of the PDC helps maintain blood glucose levels by conserving pyruvate and other three carbon compounds for gluconeogenesis. The relative activities of the pyruvate dehydrogenase kinases (PDKs) and the opposing pyruvate dehydrogenase phosphatases determine the activity of PDC in the fed and fasted states. Up regulation of PDK4 is largely responsible for inactivation of PDC in the fasted state. PDK4 knockout mice have lower fasting blood glucose levels than wild type mice, proving that up regulation of PDK4 is important for normal glucose homeostasis. In type 2 diabetes, up regulation of PDK4 also inactivates PDC, which promotes gluconeogenesis and thereby contributes to the hyperglycemia characteristic of this disease. When fed a high fat diet, wild type mice develop fasting hyperglycemia but PDK4 knockout mice remain euglycemic, proving that up regulation of PDK4 contributes to hyperglycemia in diabetes. These finding suggest PDK4 inhibitors might prove useful in the treatment of type 2 diabetes

Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus

Type 2 diabetes is associated with excessive food intake and a sedentary lifestyle. Local inflammation of white adipose tissue induces cytokine-mediated insulin resistance of adipocytes. This results in enhanced lipolysis within these cells. The fatty acids that are released into the cytosol can be removed by mitochondrial β-oxidation. The flux through this pathway is normally limited by the rate of ADP supply, which in turn is determined by the metabolic activity of the adipocyte. It is expected that the latter does not adapt to an increased rate of lipolysis. We propose that elevated fatty acid concentrations in the cytosol of adipocytes induce mitochondrial uncoupling and thereby allow mitochondria to remove much larger amounts of fatty acids. By this, release of fatty acids out of adipocytes into the circulation is prevented. When the rate of fatty acid release into the cytosol exceeds the β-oxidation capacity, cytosolic fatty acid concentrations increase and induce mitochondrial toxicity. This results in a decrease in β-oxidation capacity and the entry of fatty acids into the circulation. Unless these released fatty acids are removed by mitochondrial oxidation in active muscles, these fatty acids result in ectopic triacylglycerol deposits, induction of insulin resistance, beta cell damage and diabetes. Thiazolidinediones improve mitochondrial function within adipocytes and may in this way alleviate the burden imposed by the excessive fat accumulation associated with the metabolic syndrome. Thus, the number and activity of mitochondria within adipocytes contribute to the threshold at which fatty acids are released into the circulation, leading to insulin resistance and type 2 diabetes

Régulation de la glycéronéogenèse du tissu adipeux par les thiazolidinediones et les acides rétinoïques (implications dans le diabète de type 2)

L'obésité est le principal facteur de risque de l'insulino-résistance et du diabète de type 2. Le lien entre l'hypertrophie du tissu adipeux et ces pathologies serait les acides gras non-estérifiés (AGNE) provenant de la lipolyse adipocytaire. Une élévation chronique des AGNE sanguins induirait une résistance à l'insuline. Dans l'adipocyte, une fraction des AGNE issus de la lipolyse est ré-estérifiée en triglycérides. Cette ré-estérification requiert la synthèse de glycérol-3-phosphate qui provient, à jeun, du pyruvate et lactate circulants grâce à une voie métabolique appelée glycéronéogenèse et dont l'enzyme clé est la phosphoénolpyruvate carboxykinase cytosolique (PEPCK-C). Au cours de ce travail, nous avons monté que les thiazolidinediones et les rexinoïdes exercent leurs effets hypolipidémiants et antidiabétiques grâce à une induction rapide et sélective de la transcription du gène PEPCK-C qui conduit à une augmentation de l'activité PEPCK-C et de la glycéronéogenèse.Obesity is a major risk factor for insulin resistance and type 2 diabetes. The link between hypertrophied adipose tissue and this pathology is thought to be non-esterified fatty acids (NEFA) arising from adipocyte lipolysis. Sustained increase in plasma NEFA induces insulin resistance. In adipocytes, a significant part of lipolytic NEFA is re-esterified to triacylglycerol. Re-esterification requires glycerol-3-phosphate which, during fasting, is synthesized from lactate or pyruvate in metabolic pathway named glyceroneogenesis, whose key enzyme is the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). In this study, we give evidence that thiazolidinediones and rexinoids exert their hypolipidemic and antidiabetic effects in adipose tissue at least in part through a rapid and selective induction of PECK-C gene transcription leading to increased PECK-C and glyceroneogenesis. Subsequent fatty acid re-esterification participates in the reduction in blood NEFA and insulin resistance.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Maladies hémorragiques et grossesse (deux années de consultation à l'hôpital Antoine Béclère)

L objectif de ce travail est l étude du suivi de 52 femmes enceintes (82 accouchements) ayant un déficit constitutionnel en un ou plusieurs facteurs de coagulation. Elles ont été suivies par le Dr Boyer-Neumann en consultation d hémostase à l hôpital Antoine Béclère pendant deux ans. Nous avons observé l évolution du taux du facteur déficitaire pendant la grossesse, sa correction ou non pour l indication de l anesthésie péridurale, la prévalence des évènements hémorragiques et la nécessité d utiliser ou non un traitement. Les interruptions précoces de grossesse posent le problème de la non correction du taux du facteur de coagulation déficitaire et donc du risque hémorragique inhérent. Cette étude montre : la difficulté de prise en charge des femmes ayant des déficits modérés, la conduite à tenir devant être discutée au cas par cas ; à l inverse, l existence de recommandations thérapeutiques bien établies pour les formes sévères permettant d éviter toute complication hémorragiqueCHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF