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ABSTRACT: Aims/hypothesis. Alterations in the regulation of gene expression could be involved in the development of Type II (non-insulin-dependent)
diabetes mellitus.¶Methods. We compared the mRNA concentrations of eight genes encoding proteins involved in insulin action and intermediary metabolism
in skeletal muscle of healthy volunteers and Type II diabetic patients. The in vivo regulation of the expression of these
genes was investigated after 5 days of hypocaloric diet (1045 kJ/day).¶Results. In the basal state, diabetic muscle showed reduced insulin receptor (–38 %), hexokinase II (–73 %), glycogen synthase (–45
%) and lipoprotein lipase (–70 %) mRNA expression. There was no difference in the mRNA abundances of IRS-1, GLUT 4, p85α phosphatidylinositol-3-kinase
(p85αPI3K) or Rad. In both groups, caloric restriction induced weight loss, reduced glycaemia and increased plasma ketone
body concentrations. The diet also increased plasma concentrations of fatty acids and decreased whole-body insulin sensitivity
in control subjects. In control subjects, the diet increased p85αPI3K ( + 146 %), insulin receptor ( + 100 %) and Rad ( +
40 %) mRNA concentrations in muscle. In Type II diabetic patients, the diet increased insulin receptor ( + 41 %) and Rad (
+ 31 %) mRNAs but the expression of p85αPI3K was not modified.¶Conclusion/interpretation. The regulation of the expression of p85αPI3K is altered during caloric restriction in skeletal muscle of Type II diabetic
patients. Because we have shown in an earlier study that there is also a defective regulation of p85αPI3K gene expression
in response to insulin, these data support the hypothesis that alterations in the regulation of gene expression could be involved
in the pathogenesis of Type II diabetes. [Diabetologia (2000) 43: 356–363]
Diabetologia 04/2012; 43(3):356-363. · 6.81 Impact Factor
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ABSTRACT: In the light of recent studies in humans and rodents, AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been described as an integrator of regulatory signals monitoring systemic and cellular energy status. AMP-activated protein kinase (AMPK) has been proposed to function as a 'fuel gauge' to monitor cellular energy status in response to nutritional environmental variations. Recently, it has been proposed that AMPK could provide a link in metabolic defects underlying progression to the metabolic syndrome. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMPK is activated by rising AMP and falling ATP. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta (calmodulin-dependent protein kinase kinase). AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of insulin sensitizing adipokines leptin and adiponectin. AMPK is robustly activated during skeletal muscle contraction and myocardial ischaemia playing a role in glucose transport and fatty acid oxidation. In liver, activation of AMPK results in enhanced fatty acid oxidation as well as decreased glucose production. Moreover, the AMPK system is one of the probable targets for the anti-diabetic drugs biguanides and thiazolidinediones. Thus, the relationship between AMPK activation and beneficial metabolic effects provide the rationale for the development of new therapeutic strategies in metabolic disorders.
Diabetes & Metabolism 01/2008; 33(6):395-402. · 2.41 Impact Factor
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ABSTRACT: The hyperinsulinemic euglycemic glucose clamp method is the gold standard for measuring insulin resistance. However it is complex, and simple indexes have been developed. Some of them are based on formulae that calculate the product or the addition of fasting plasma insulin and glucose values whereas others are based on their ratios. We calculated several simple indexes of insulin resistance and compared them to hyperinsulinemic euglycemic clamp data in 111 subjects with a wide range of insulin resistance. We showed that indexes using insulin and glucose ratios in their formulae are poorly correlated with clamp measurements and give false evaluations, particularly in glucose-intolerant and type 2 diabetic subjects. Thus, whatever the glucose profile of study subjects, we suggest the use of a simple index based on the product or the addition of fasting plasma insulin and glucose values instead of their ratios to obtain insulin resistance evaluations close to the hyperinsulinemic euglycemic clamp technique.
Diabetes & Metabolism 07/2003; 29(3):285-8. · 2.41 Impact Factor
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B Viollet, F Andreelli,
S B Jørgensen,
C Perrin,
D Flamez,
J Mu,
J F P Wojtaszewski,
F C Schuit,
M Birnbaum,
E Richter,
R Burcelin,
S Vaulont
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ABSTRACT: AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To understand better the physiological role of the catalytic AMPK subunit isoforms, we generated two knockout mouse models with the alpha1 (AMPK alpha 1(-/-)) and alpha 2 (AMPK alpha 2(-/-)) catalytic subunit genes deleted. No defect in glucose homoeostasis was observed in AMPK alpha 1(-/-) mice. On the other hand, AMPK alpha 2(-/-) mice presented high plasma glucose levels and low plasma insulin concentrations in the fed period and during the glucose tolerance test. Nevertheless, in isolated AMPK alpha 2(-/-) pancreatic islets, glucose-stimulated insulin secretion was not affected. Surprisingly, AMPK alpha 2(-/-) mice were insulin-resistant and had reduced muscle glycogen synthesis as assessed in vivo by the hyperinsulinaemic euglycaemic clamp procedure. Reduction of insulin sensitivity and glycogen synthesis were not dependent on the lack of AMPK in skeletal muscle, since mice expressing a dominant inhibitory mutant of AMPK in skeletal muscle were not affected and since insulin-stimulated glucose transport in incubated muscles in vitro was normal in AMPK alpha 2(-/-) muscles. Furthermore, AMPK alpha 2(-/-) mice have a higher sympathetic tone, as shown by increased catecholamine urinary excretion. Increased adrenergic tone could explain both decreased insulin secretion and insulin resistance observed in vivo in AMPK alpha 2(-/-) mice. We suggest that the alpha2 catalytic subunit of AMPK plays a major role as a fuel sensor by modulating the activity of the autonomous nervous system in vivo.
Biochemical Society Transactions 03/2003; 31(Pt 1):216-9. · 3.71 Impact Factor
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ABSTRACT: Exercise-induced glucose uptake in skeletal muscle is mediated by an insulin-independent mechanism, but the actual signals to glucose transport in response to muscle contraction have not been identified. The 5'-AMP-activated protein kinase (AMPK) has emerged as a putative mediator of contraction-induced glucose transport, although no conclusive evidence has been provided so far. Recent experiments in AMPK transgenic mice suggest that glucose transport induced by 5-amino-4-imidazolecarboxamide riboside (AICAR) or hypoxia is mediated by AMPK. In contrast, contraction-induced glucose transport in rodent skeletal muscle induced by electrical stimulation in vitro or in situ is not influenced or is only partially reduced by abolishing both or one of the catalytic AMPK subunits. This is compatible with exercise studies done in humans, where no tight correlation is found between AMPK activity and glucose uptake during exercise. Taken together, these results question an essential role of AMPK in exercise-induced glucose uptake and imply that one or more additional pathways are involved in mediating glucose transport in skeletal muscle during exercise.
Biochemical Society Transactions 03/2003; 31(Pt 1):186-90. · 3.71 Impact Factor
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ABSTRACT: Current antidiabetic agents do not suppress insulin resistance, do not reinstate physiological insulin secretion and fail to prevent the gradual loss of B-cell function. Thus, these molecules are unable to maintain long term euglycemia in all type 2 diabetic patients and there is a need for new antidiabetic drugs. Thiazolidinediones (TZD) are a new class of insulin sensitizers recently approved in Europe, in combination therapy with sulfonylureas or/and metformin, for the treatment of type 2 diabetes. TZD show beneficial effects on insulin action, glucose homeostasis and lipid metabolism despite a substantial weight gain. Their potential protective effect on B-cell function and on the development of macrovascular complication is of particular interest. Non TZD PPARgamma agonists are also under clinical trials. Other interesting therapeutic perspectives to treat insulin resistance lie in the development of inhibitors of protein tyrosine phosphatases and in the promotion of non insulin-dependent contraction-like muscle glucose uptake via stimulation of AMP protein kinase (AMPK). As to new insulin secretagogues, the phenylalanine derivative nateglinide is a first phase insulin secretion enhancer primarily intended at controlling post-prandial hyperglycemia. The most promising perspective to improve B-cell function lies in the development of glucagon-like peptide-1 (GLP-1) analogs. Clinical studies show beneficial effects on glucose homeostasis in type 2 diabetics and efficacy in sulfonylurea resistant patients without risk of hypoglycaemia. Animal studies predict beneficial effects on B-cell mass. Finally we will discuss the potential use of gene therapy to treat insulin resistance and B-cell dysfunction.
Diabetes & Metabolism 10/2001; 27(4 Pt 1):415-23. · 2.41 Impact Factor
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ABSTRACT: Defective regulation of gene expression may be involved in the pathogenesis of type 2 diabetes. We have characterized the concerted regulation by insulin (3-h hyperinsulinemic clamp) of the expression of 10 genes related to insulin action in skeletal muscle and in subcutaneous adipose tissue, and we have verified whether a defective regulation of some of them could be specifically encountered in tissues of type 2 diabetic patients. Basal mRNA levels (determined by reverse transcriptase-competitive polymerase chain reaction) of insulin receptor, insulin receptor substrate-1, p85alpha phosphatidylinositol 3-kinase (PI3K), p110alphaPI3K, p110betaPI3K, GLUT4, glycogen synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) were similar in muscle of control (n = 17), type 2 diabetic (n = 9), type 1 diabetic (n = 9), and nondiabetic obese (n = 9) subjects. In muscle, the expression of hexokinase II was decreased in type 2 diabetic patients (P < 0.01). In adipose tissue, SREBP-1c (P < 0.01) mRNA expression was reduced in obese (nondiabetic and type 2 diabetic) subjects and was negatively correlated with the BMI of the subjects (r = -0.63, P = 0.02). Insulin (+/-1,000 pmol/l) induced a two- to threefold increase (P < 0.05) in hexokinase II, p85alphaPI3K, and SREBP-1c mRNA levels in muscle and in adipose tissue in control subjects, in insulin-resistant nondiabetic obese patients, and in hyperglycemic type 1 diabetic subjects. Upregulation of these genes was completely blunted in type 2 diabetic patients. This study thus provides evidence for a specific defect in the regulation of a group of important genes in response to insulin in peripheral tissues of type 2 diabetic patients.
Diabetes 05/2001; 50(5):1134-42. · 8.29 Impact Factor
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ABSTRACT: Fatty acid transporter protein (FATP)-1 mRNA expression was investigated in skeletal muscle and in subcutaneous abdominal adipose tissue of 17 healthy lean, 13 nondiabetic obese, and 16 obese type 2 diabetic subjects. In muscle, FATP-1 mRNA levels were higher in lean women than in lean men (2.2 +/- 0.1 vs. 0.6 +/- 0.2 amol/microg total RNA, P < 0.01). FATP-1 mRNA expression was decreased in skeletal muscle in obese women both in nondiabetic and in type 2 diabetic patients (P < 0.02 vs. lean women in both groups), and in all women there was a negative correlation with basal FATP-1 mRNA level and body mass index (r = -0.74, P < 0.02). In men, FATP-1 mRNA was expressed at similar levels in the three groups both in skeletal muscle (0.6 +/- 0.2, 0.6 +/- 0.2, and 0.8 +/- 0.2 amol/microg total RNA in lean, obese, and type 2 diabetic male subjects) and in adipose tissue (0.9 +/- 0.2 amol/microg total RNA in the 3 groups). Insulin infusion (3 h) reduced FATP-1 mRNA levels in muscle in lean women but not in lean men. Insulin did not affect FATP-1 mRNA expression in skeletal muscle in obese nondiabetic or in type 2 diabetic subjects nor in subcutaneous adipose tissue in any of the three groups. These data show a gender-related difference in the expression of the fatty acid transporter FATP-1 in skeletal muscle of lean individuals and suggest that changes in FATP-1 expression may not contribute to a large extent to the alterations in fatty acid uptake in obesity and/or type 2 diabetes.
AJP Endocrinology and Metabolism 12/2000; 279(5):E1072-9. · 4.75 Impact Factor
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ABSTRACT: Secondary failure to dietary and maximal oral treatment leads to insulin therapy in type 2 diabetic patients. However, weight gain is a frequent side effect of insulin therapy in these patients. Mechanisms for this weight gain are complex. Insulin 1) reduces glycosuria and its caloric expenditure; 2) stimulates the stockage of fatty acids into triglycerides in adipose tissue, thus favoring an increase in adipose mass; 3) yields a positive nitrogen balance through an inhibition of muscle proteolysis, thus favoring an increase in lean mass. Most studies report an average 6 kg weight gain during the first year following the initiation of insulin therapy in type 2 diabetic patients. Analysing body composition variations shows that weight gain results both from an increase in fat mass (mean 63%) and an increase in lean mass (mean 37%). Preexisting obesity does not influence this weight gain. Finally, the 10 year-follow up of UKPDS showed a beneficial effect of insulin therapy on microangiopathy prevention, without increasing cardiovascular mortality as compared with type 2 diabetic patients on oral treatment. Thus, while weight gain seems mandatory, it should not refrain from initiating insulin therapy in poorly controlled type 2 diabetic patients, as its expected beneficial effects on the prevention of microangiopathy seem well established.
Diabetes & Metabolism 07/2000; 26 Suppl 3:42-5. · 2.41 Impact Factor
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ABSTRACT: Type 1 diabetes mellitus is considered as an autoimmune disease against beta cells. Diabetes recurrence after pancreas transplantation is well known in HLA-identical twins while it is rarely reported in recipients of cadaveric pancreatic grafts. In the present case report, diabetes recurrence occurred in a recipient who underwent cadaveric combined pancreas kidney transplantation. Seven years after transplantation the patient exhibited progressive hyperglycemia needing insulin therapy while the renal graft was well functioning. The diagnosis of recurrent disease was obtained on the histological features such as selective loss of beta cells without clear signs of insulitis and on the presence of markers (GAD 65 and IA-2) for humoral autoimmunity. It is intriguing that, at the time of recurrence of type 1 diabetes, the patient had stopped steroids and azathioprine, while only cyclosporine was maintained as immunosuppressive treatment. Our case report underlines the relevance of studying the humoral autoimmune response directed to islet autoantigens in cadaveric pancreas allograft recipients. Furthermore, it suggests that an efficient immunosuppressive treatment after transplantation may be able to reduce the autoimmune response against the pancreatic allograft.
Diabetes & Metabolism 06/2000; 26(3):215-8. · 2.41 Impact Factor
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ABSTRACT: Alterations in the regulation of gene expression could be involved in the development of Type II (non-insulin-dependent) diabetes mellitus.
We compared the mRNA concentrations of eight genes encoding proteins involved in insulin action and intermediary metabolism in skeletal muscle of healthy volunteers and Type II diabetic patients. The in vivo regulation of the expression of these genes was investigated after 5 days of hypocaloric diet (1045 kJ/day).
In the basal state, diabetic muscle showed reduced insulin receptor (-38%), hexokinase II (-73%), glycogen synthase (-45%) and lipoprotein lipase (-70%) mRNA expression. There was no difference in the mRNA abundances of IRS-1, GLUT 4, p85 alpha phosphatidylinositol-3-kinase (p85 alpha PI3K) or Rad. In both groups, caloric restriction induced weight loss, reduced glycaemia and increased plasma ketone body concentrations. The diet also increased plasma concentrations of fatty acids and decreased whole-body insulin sensitivity in control subjects. In control subjects, the diet increased p85 alpha PI3K (+146%), insulin receptor (+100%) and Rad (+40%) mRNA concentrations in muscle. In Type II diabetic patients, the diet increased insulin receptor (+41%) and Rad (+31%) mRNAs but the expression of p85 alpha PI3K was not modified.
The regulation of the expression of p85 alpha PI3K is altered during caloric restriction in skeletal muscle of Type II diabetic patients. Because we have shown in an earlier study that there is also a defective regulation of p85 alpha PI3K gene expression in response to insulin, these data support the hypothesis that alterations in the regulation of gene expression could be involved in the pathogenesis of Type II diabetes.
Diabetologia 04/2000; 43(3):356-63. · 6.81 Impact Factor
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H A Koistinen,
J P Bastard,
E Dusserre,
P Ebeling,
N Zegari, F Andreelli,
C Jardel,
M Donner,
L Meyer,
P Moulin,
B Hainque,
J P Riou,
M Laville,
V A Koivisto,
H Vidal
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ABSTRACT: An association with subcutaneous adipose tissue TNFalpha expression and insulin resistance has been suggested in obesity/type-2 diabetes, but this has not been examined directly. In the first part of the study we investigated whether this association is present in 7 lean, 10 obese nondiabetic and 9 type-2 diabetic men. In the second part of the study we examined the relationship between adipose tissue TNFalpha mRNA levels and BMI in 81 nondiabetic subjects spanning a wide range of BMIs.
Subcutaneous adipose tissue TNFalpha mRNA levels and insulin sensitivity were determined with quantitative RT-competitive PCR and hyperinsulinaemic clamp, respectively.
Subcutaneous adipose tissue TNFalpha mRNA levels were similar in 7 lean and 10 obese nondiabetic and 9 type-2 diabetic men (P = 0.68), and did not change in response to 240-min hyperinsulinaemia. TNFalpha mRNA levels and insulin sensitivity were not correlated. Unexpectedly, no correlation between TNFalpha mRNA and BMI was found. The relationship between adipose tissue TNFalpha mRNA and BMI was examined further in 31 male and 50 female nondiabetic subjects. The subcutaneous adipose tissue TNFalpha mRNA level correlated with BMI in all subjects (rS = 0.32, P < 0.01), and in a subgroup analysis in men (rS = 0.55, P < 0.01) but not in women (rS = - 0.08). The correlation in men was dependent on a fourfold higher TNFalpha mRNA level in 5 morbidly obese men while there was no difference in TNFalpha mRNA levels in lean or obese men.
Subcutaneous adipose tissue TNFalpha expression does not correlate with insulin sensitivity in nondiabetic or type-2 diabetic men; is not regulated by acute hyperinsulinaemia; and is increased only in morbidly obese men.
European Journal of Clinical Investigation 04/2000; 30(4):302-10. · 3.02 Impact Factor
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ABSTRACT: To further examine the relationships between leptin and female reproductive axis, we conducted hormonal studies in two patients with lipoatropic diabetes that occurred before puberty. Despite complete atrophy of sc and visceral adipose tissue, menarche occurred in these two patients between 11-12 yr of age, followed by regular menstrual cycles. One patient had been pregnant three times, giving birth to children who did not develop the disease. In our two patients, repeated analysis revealed leptin levels below 1 ng/mL (normal range for 20 insulin-treated diabetic women, 2-23 ng/mL for body mass index of 14-39 kg/m2; personal data). We measured peripheral levels of estradiol, progesterone, FSH, LH, free testosterone, and androstenedione within the first 5 days of the menstrual cycle, and we tested the reactivity of pituitary after iv injection of 100 microg GnRH. The variation in body temperature in the morning before arising was also analyzed. We showed that 1) all measured levels of hormones were in the normal range for both patients; and 2) low levels of leptin did not impair the development of reproductive function in one patient and was associated with normal gonadal function in both patients. We conclude that puberty and fertility can occur despite chronic low serum levels of leptin. This suggests that leptin is not fundamental to the maintenance of normal reproductive function in humans.
Journal of Clinical Endocrinology & Metabolism 03/2000; 85(2):715-9. · 6.50 Impact Factor
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ABSTRACT: To determine human PPARgamma coactivator-1 (PGC-1) amino acid sequence and to study PGC-1 mRNA tissue distribution. PGC-1 is a novel transcriptional coactivator of nuclear receptors that may play a role in the control of thermogenesis.
Subcutaneous adipose tissue was obtained from six obese and five lean male subjects. Vastus lateralis skeletal muscle was obtained from seven lean and six obese subjects undergoing a 5-day severe calorie restriction. Other tissue biopsies were from nonobese nondiabetic subjects.
Human PGC-1 was cloned from a skeletal muscle cDNA library. A reverse transcription-competitive polymerase chain reaction assay was developed to determine PGC-1 mRNA levels in human tissues.
The human amino acid sequence showed 95% identity with mouse PGC-1. PGC-1 mRNA was expressed at very low levels in the small and large intestines and white adipose tissue. Heart, kidney, liver and skeletal muscle showed higher mRNA levels. The degree of obesity did not affect PGC-1 mRNA levels in adipose tissue while lean subjects expressed more PGC-1 mRNA than obese subjects in skeletal muscle. A 5-day severe calorie restriction induced PGC-1 mRNA expression in skeletal muscle of obese but not of lean subjects.
PGC-1 shows a restricted tissue expression that suggests a tissue-specific role in the control of gene transcription and possible interaction with various members of the PPAR family. The lower expression of skeletal muscle PGC-1 in obesity could contribute to an alteration of mitochondrial gene expression.
International Journal of Obesity 01/2000; 23(12):1327-32. · 4.69 Impact Factor
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ABSTRACT: Skeletal muscle uncoupling protein 2 and 3 (UCP-2 and UCP-3) mRNA levels are increased during calorie restriction in lean and nondiabetic obese subjects. In this work, we have investigated the effect of a 5-day hypocaloric diet (1,045 kJ/day) on UCP-2 and UCP-3 gene expression in the skeletal muscle of type-2 diabetic obese patients. Before the diet, UCP-2 and UCP-3 mRNA levels were more abundant in diabetic than in nondiabetic subjects. The long (UCP-3(L)) and short (UCP-3(S)) forms of UCP-3 transcripts were expressed at similar levels in nondiabetic subjects, but UCP-3(S) transcripts were twofold more abundant than UCP-3(L) transcripts in the muscle of diabetic patients. Calorie restriction induced a two- to threefold increase in UCP-2 and UCP-3 mRNA levels in nondiabetic patients. No change was observed in type-2 diabetic patients. Variations in plasma nonesterified fatty acid level were positively correlated with changes in skeletal muscle UCP-3(L) (r = 0.6, P < 0.05) and adipose tissue hormone-sensitive lipase (r = 0.9, P < 0.001) mRNA levels. Lack of increase in plasma nonesterified fatty acid level and in hormone-sensitive lipase upregulation in diabetic patients during the diet strengthens the hypothesis that fatty acids are associated with the upregulation of uncoupling proteins during calorie restriction.
The American journal of physiology 11/1999; 277(5 Pt 1):E830-7.
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Diabetes Obesity and Metabolism 10/1999; 1(5):297-8. · 3.38 Impact Factor
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ABSTRACT: We report the case of a 26 year-old woman, with an uncomplicated type 1 IDDM of 17 yr duration followed for her first pregnancy. At conception, HbA1c (measured by HPLC) was 6.5% and fructosamine was 280 u.mol.l (normal range below 285). During the follow-up, 15-days-interval frutosamine never exceeded the normal range and HbA1c values were under 6.5% excepted in the third trimester (7.0 +/- 0.8%) coinciding with a bad control of the 2 hours post-prandial blood glucose. A fetal macrosomy was discovered at 34 weeks of gestation and a heavy-for-date 4680 g baby was delivered by caesarean section at 38 weeks of gestation. Our case report outlines again the need to achieve the recommended target of metabolic control for the diabetic pregnant woman (blood preprandial glucose: 3.9-5.6 mM; post-prandial 2 h < 6.7 mM) specially during the third trimester of pregnancy. The use of computer databases might be helpful for precise monitoring during this narrow window period.
Diabetes & Metabolism 09/1999; 25(4):341-3. · 2.41 Impact Factor
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ABSTRACT: Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) are mitochondrial proteins that may play a role in the control of energy expenditure by uncoupling respiration from ATP synthesis. The present review focuses on data obtained in humans. UCP2 is widely expressed in the body, whereas UCP3 expression is restricted to skeletal muscle. Positive correlations have been reported between UCP2 mRNA concentrations in adipose tissue, UCP3 mRNA concentrations in skeletal muscle, and components of the metabolic rate. Fasting induces an up-regulation of UCP2 and UCP3 mRNA expression. In vivo and in vitro studies suggest that fatty acids could modulate uncoupling protein gene expression. The putative relationship between obesity, energy expenditure and uncoupling protein expression, and the unexpected rise in UCP2 and UCP3 mRNA concentrations during short-term fasting, are discussed in view of the recent data obtained in rodents and cell lines.
International Journal of Obesity 07/1999; 23 Suppl 6:S64-7. · 4.69 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-gamma is one of the key actors of adipocyte differentiation. This study demonstrates 1) that PPAR-gamma mRNA expression is not altered in subcutaneous adipose tissue (n = 44) or in skeletal muscle (n = 19) of subjects spanning a wide range of BMIs (20-53 kg/m2) and 2) that insulin acutely increases PPAR-gamma mRNA expression in human adipocytes both in vivo and in vitro. The effect of insulin was investigated in abdominal subcutaneous biopsies obtained before and at the end of a 3-h euglycemic-hyperinsulinemic clamp. Insulin significantly increased PPAR-gamma mRNA levels in lean subjects (88 +/- 17%, n = 6), in type 2 diabetic patients (100 +/- 19%, n = 6), and in nondiabetic obese patients (91 +/- 20%, n = 6). Both PPAR-gamma1 and PPAR-gamma2 mRNA variants were increased (P < 0.05) after insulin infusion. In isolated human adipocytes, insulin induced the two PPAR-gamma mRNAs in a dose-dependent manner, with half-maximal stimulation at a concentration of approximately 1-5 nmol/l. However, PPAR-gamma2 mRNA was rapidly (2 h) and transiently increased, whereas a slow and more progressive induction of PPAR-gamma1 was observed during the 6 h of incubation. In explants of human adipose tissue, PPAR-gamma protein levels were significantly increased (42 +/- 3%, P < 0.05) after 12 h of incubation with insulin. These data demonstrate that PPAR-gamma belongs to the list of the insulin-regulated genes and that obesity and type 2 diabetes are not associated with alteration in the expression of this nuclear receptor in adipose tissue.
Diabetes 05/1999; 48(4):699-705. · 8.29 Impact Factor
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ABSTRACT: We investigated the regulation of the mRNA expression of the insulin receptor, insulin receptor substrate-1 (IRS-1) and p85alpha-phosphatidylinositol-3-kinase (PI-3K), three major actors of insulin action, in skeletal muscle from 10 healthy lean volunteers, 13 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 7 non-diabetic obese subjects. The in vivo regulation by insulin was studied using a 3-h euglycaemic, hyperinsulinaemic clamp. There were no differences in the basal concentrations of the three mRNAs in skeletal muscle between groups. Insulin infusion produced a twofold reduction in insulin receptor substrate-1 mRNA expression in the three groups (p<0.02). In contrast, insulin increased p85alpha-phosphatidylinositol-3-kinase mRNA expression in muscle from non-diabetic subjects (+98+/-22% in lean and +127+/-16% in obese, p<0.02) but this effect was totally impaired in Type II diabetic patients (+5+/-12%, NS). A similar defect in insulin action on p85alpha-phosphatidylinositol-3-kinase mRNA expression was observed in abdominal subcutaneous adipose tissue (+138+/-25%, p<0.01 in lean and +46+/-14%, p<0.02 in obese and +29+/-11%, NS in Type II diabetic patients). The lack of action of insulin on p85alpha-phosphatidylinositol-3-kinase mRNA in diabetic subjects was probably not due to a deleterious effect of hyperglycaemia since improvement of the glycaemic control for 10 days did not restore the response in muscle or in adipose tissue. This study provides evidence for a defect in the regulation by insulin of PI-3K gene expression in Type II diabetic patients, thus reinforcing the concept that alterations at the gene expression might be involved in the pathogeny of Type II diabetes.
Diabetologia 04/1999; 42(3):358-64. · 6.81 Impact Factor
