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1.
Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease 总被引:3,自引:0,他引:3
C. Couillard P. Mauriège D. Prud'homme A. Nadeau A. Tremblay C. Bouchard J.-P. Després 《Diabetologia》1997,40(10):1178-1184
Summary The cloning of the obese gene and the characterization of its protein product, leptin, has permitted the study of a new hormone potentially involved
in the regulation of adipose tissue mass. The present study examined the gender differences in fasting plasma leptin concentration
and its relationship to body fatness, adipose tissue distribution and the metabolic profile in samples of 91 men (mean age
± SD: 37.3 ± 4.8 years) and 48 women (38.5 ± 6.8 years). Plasma leptin concentrations were strongly associated with body fat
mass measured by underwater weighing [men: r = 0.80, p < 0.0001; women: r = 0.85, p < 0.0001]. In both genders, plasma leptin levels were also strongly correlated with waist girth as well as cross-sectional
areas of abdominal subcutaneous and visceral adipose tissue measured by computed tomography. Women had, on average, plasma
leptin concentrations that were three times higher than men. Furthermore, this gender difference remained significant when
comparing men and women matched for similar levels of body fat mass. The associations between plasma leptin and lipoprotein
concentrations were dependent of adiposity. In both men and women, elevated fasting plasma leptin levels were associated with
higher plasma insulin concentrations, but only in women was the association maintained after correction for fat mass. Thus,
results of the present study show that women have higher plasma leptin levels compared to men, independent of the concomitant
variation in total body fat mass. Furthermore, our results also suggest that, in women, the association between plasma leptin
and insulin concentrations is independent of adiposity, a finding which provides further support to the observation that adipose
tissue leptin secretion may be upregulated by insulin. [Diabetologia (1997) 40: 1178–1184]
Received: 18 February 1997 and in revised form: 28 April 1997 相似文献
2.
A. Marette P. Maurie`ge B. Marcotte C. Atgié C. Bouchard G. Thériault L. J. Bukowiecki P. Marceau S. Biron A. Nadeau J.-P. Després 《Diabetologia》1997,40(5):590-598
Summary Insulin action and GLUT4 expression were examined in adipose tissue of severely obese premenopausal women undergoing gastrointestinal
surgery. Fat samples were taken from three different anatomical regions: the subcutaneous abdominal site, the round ligament
(deep abdominal properitoneal fat), and the greater omentum (deep abdominal intraperitoneal fat). The stimulatory effect of
insulin on glucose transport and the ability of the hormone to inhibit lipolysis were determined in adipocytes isolated from
these three adipose depots. Insulin stimulated glucose transport 2–3 times over basal rates in all adipocytes. However, round
ligament adipose cells showed a significantly greater responsiveness to insulin when compared to subcutaneous and omental
adipocytes. Round ligament fat cells also displayed the greatest sensitivity and maximal antilipolytic response to insulin.
We also investigated whether regional differences in fat cell insulin-stimulated glucose transport were linked to a differential
expression of the GLUT4 glucose transporter. GLUT4 protein content in total membranes was 5 and 2.2 times greater in round
ligament adipose tissue than in subcutaneous and omental fat depots, respectively. Moreover, GLUT4 mRNA levels were 2.1 and
3 times higher in round ligament than in subcutaneous or omental adipose tissues, respectively. Adipose tissue GLUT4 protein
content was strongly and negatively associated (r = –0.79 to –0.89, p < 0.01) with the waist-to-hip ratio but not with total adiposity. In conclusion, these results demonstrate the existence
of site differences in adipose tissue insulin action in morbidly obese women. The greater insulin effect on glucose transport
in round ligament adipocytes was associated with a higher expression of GLUT4 when compared to subcutaneous abdominal and
omental fat cells. Moreover, despite the regional variation in GLUT4 expression, an increased proportion of abdominal fat
was found to be associated with lower levels of GLUT4 in all adipose regions investigated. [Diabetologia (1997) 40: 590–598]
Received: 8 October 1996 and in revised form: 28 January 1997 相似文献
3.
Summary The absolute glucose concentrations in subcutaneous adipose tissue and skeletal muscle were determined with microdialysis
in 10 normal-weight, healthy subjects during a standardized hyperinsulinaemic hypoglycaemic clamp. The concentration of tissue
dialysate glucose was measured in 15-min fractions and compared with that in arterialized venous plasma. Insulin (0.15 U ·
kg-1· h−1) was infused i. v. to lower the plasma glucose level to 2.5 mmol/l over 30 min. This level was maintained for 30 min by using
a variable glucose infusion. Thereafter, the insulin infusion was stopped and the plasma glucose level was gradually increased
to baseline levels over 120 min. During a 60-min basal period, the glucose levels in muscle were 0.6 mmol/l lower than those
in plasma (p = 0.002), whereas the levels in adipose tissue and plasma were similar. The glucose nadirs in muscle (1.6 ± 0.1 mmol/l) and
adipose tissue (2.0 ± 0.1 mmol/l) were significantly lower than that in plasma (2.4 ± 0.1 mmol/l) (p = 0.001 and 0.02, respectively), and the time-to-nadir was substantially longer in muscle (69 ± 5 min) and adipose tissue
(57 ± 2 min) than in plasma (39 ± 3 min) (p = 0.0004). When the insulin infusion was stopped, the increases in adipose tissue and muscle glucose concentrations were
delayed by approximately 25 and 45 min, respectively, as compared to the increase in plasma glucose. Thus, it seems that glucose
measurements in adipose tissue and muscle more adequately reflect overall tissue homeostasis than do measurements in blood
and that clinically relevant tissue glucopenia may be overlooked by conventional blood glucose measurements. [Diabetologia
(1997) 40: 1320–1326]
Received: 21 January 1997 and in final revised form: 2 July 1997 相似文献
4.
5.
Lipolysis in skeletal muscle is rapidly regulated by low physiological doses of insulin 总被引:1,自引:1,他引:0
S. Jacob B. Hauer R. Becker S. Artzner P. Grauer K. Löblein M. Nielsen W. Renn K. Rett H.-G. Wahl M. Stumvoll H.-U. Häring 《Diabetologia》1999,42(10):1171-1174
Aims/hypothesis. Both patients with Type II (non-insulin-dependent) diabetes mellitus and normoglycaemic, insulin resistant subjects were
shown to have an increased lipid content in skeletal muscle, which correlates negatively with insulin sensitivity. Recently,
it was shown that during a hyperinsulinaemic euglycaemic clamp interstitial glycerol was reduced not only in adipose tissue
but also in skeletal muscle. To assess whether lipolysis of muscular lipids is also regulated by low physiological concentrations
of insulin, we used the microdialysis technique in combination with a 3-step hyperinsulinaemic glucose clamp. Methods. Nineteen lean, healthy subjects (12 m/7 f) underwent a glucose clamp with various doses of insulin (GC I = 0.1, GC II = 0.25
and GC III = 1.0mU · kg–1· min–1). Two double lumen microdialysis catheters each were inserted in the paraumbilical subcutaneous adipose tissue and in skeletal
muscle (tibialis anterior) to measure interstitial glycerol concentration (index of lipolysis) and ethanol outflow (index
of tissue flow). Results. During the different steps of the glucose clamp, glycerol in adipose tissue was reduced to 81 ± 7 % (GC I), 55 ± 8 % (GC
II) and 25 ± 5 % (GC III), respectively, of basal. In contrast, glycerol in skeletal muscle declined to 73 ± 5 % (GC I) and
to 57 ± 6 % (GC II) but was not further reduced at GC III. Tissue flow was higher in the skeletal muscle and remained unchanged
in both compartments throughout the experiment. Conclusion/interpretation. This study confirms the presence of glycerol release in skeletal muscle. Lipolysis in skeletal muscle and adipose tissue
are suppressed similarly by minute and physiological increases in insulin but differently by supraphysiological increases.
Inadequate suppression of intramuscular lipolysis resulting in increased availability of non-esterified fatty acids, could
represent a potential mechanism involved in the pathogenesis of impaired glucose disposal, i. e. insulin resistance, in muscle.
[Diabetologia (1999) 42: 1171–1174]
Received: 12 March 1999 and in revised form: 21 May 1999 相似文献
6.
Failure of leptin to affect basal and insulin-stimulated glucose metabolism of rat skeletal muscle in vitro 总被引:2,自引:0,他引:2
C. Fürnsinn B. Brunmair R. Furtmüller M. Roden R. Englisch W. Waldhäusl 《Diabetologia》1998,41(5):524-529
Summary Studies on different isolated tissues have provided evidence that leptin may directly modulate cellular glucose handling.
The present study was performed to elucidate leptin's action on basal and insulin-stimulated glucose metabolism in native
muscle tissue, which under physiological circumstances is the quantitatively most important target tissue of insulin. Isolated
rat soleus muscle strips were incubated for 1 h in the absence or presence of leptin (0, 1, 10, or 100 nmol/l) under basal
or insulin-stimulated conditions (10 nmol/l). No effects of leptin were found on the rates of 3H-2-deoxy-glucose transport (basal: control, 314 ± 14; 1 nmol/l leptin, 320 ± 17; 10 nmol/l leptin, 314 ± 13; 100 nmol/l leptin,
322 ± 16; insulin-stimulated: control, 690 ± 33; 1 nmol/l leptin, 691 ± 29; 10 nmol/l leptin, 665 ± 26; 100 nmol/l leptin,
664 ± 27; cpm · mg–1· h–1; NS vs respective control) and on net glucose incorporation into glycogen (basal: control, 1.75 ± 0.18; 1 nmol/l leptin,
2.01 ± 0.13; 10 nmol/l leptin, 1.92 ± 0.11; 100 nmol/l leptin, 1.81 ± 0.13; insulin-stimulated: control, 5.98 ± 0.40; 1 nmol/l
leptin, 5.93 ± 0.30; 10 nmol/l leptin, 5.46 ± 0.25; 100 nmol/l leptin, 5.85 ± 0.30; μmol · g–1· h–1; NS vs respective control). In parallel, leptin failed to affect rates of aerobic and anaerobic glycolysis as well as muscle
glycogen content. Further experiments revealed that the inability of leptin to directly affect muscle glucose handling prevailed
independently of muscle fiber type (soleus and epitrochlearis muscle), of ambient insulin concentrations (0–30 nmol/l), and
of leptin exposure time (1 h or 6 h). Thus, our findings fail to support speculations about a physiological role of direct
insulin-mimetic or insulin-desensitizing effects of leptin on skeletal muscle tissue. [Diabetologia (1998) 41: 524–529]
Received: 7 October 1997 and in revised form: 23 January 1998 相似文献
7.
Abstract.
Obesity is often accompanied by hyperleptinemia, hyperinsulinemia, and an increased parasympathetic tone. Obese-hyperglycemic mice (Umeå ob/ob) have functional leptin receptors and a raised parasympathetic tone. We studied insulin release in islets isolated from 9-monthold severely obese ob/ob mice. Leptin (0.5–18 nM) did not affect insulin release together with 2.8–20 mM glucose. Leptin (18 µM) had no effect in the presence of low glucose (2.8–5.5 mM), but increased insulin secretion in islets challenged with 11.1 or 16.7 mM glucose. Leptin at 18 µM increased insulin secretion stimulated by the parasympathetic neurotransmitters acetylcholine (ACh; 10 µM) or vasoactive intestinal peptide (VIP; 10 nM), and by 5 mM theophylline or 2.5 µM forskolin. Overnight culture increased the effect of 18 µM leptin, but no effects were observed with 18 nM leptin. Pretreatment of islets with phorbol 12-myristate 13-acetate (PMA) did not suggest any involvement of protein kinase C. In summary, a high concentration of leptin stimulates insulin release in the presence of stimulatory concentrations of glucose alone and with parasympathetic neurotransmitters. Hyperleptinemia and increased parasympathetic stimulation may in part cause the hyperinsulinemia observed in obesity. This may aggravate insulin resistance and the abnormal metabolism in diabetes mellitus. 相似文献
8.
9.
R. Vettor C. Pagano M. Granzotto P. Englaro P. Angeli W. F. Blum G. Federspil F. Rohner-Jeanrenaud B. Jeanrenaud 《Diabetologia》1998,41(11):1361-1367
Summary Intracerebroventricular administration of neuropeptide Y to normal rats induces a syndrome characterised by obesity, hyperinsulinaemia,
insulin resistance and over expression of the adipose tissue ob gene. Little is known about the effect of circulating neuropeptide Y on glucose metabolism, insulin secretion and leptin.
We therefore aimed to evaluate the effect of an intravenous infusion of neuropeptide Y on glucose disposal, endogenous glucose
production, whole body glycolytic flux, and glucose storage as assessed during euglycaemic hyperinsulinaemic clamp. In addition,
the insulin-stimulated glucose utilisation index in individual tissues was measured by the 2-deoxy-[1-3H]-glucose technique. The effect of neuropeptide Y on insulin secretion was evaluated by hyperglycaemic clamp. Infusion did
not induce any change in endogenous glucose production during basal conditions or at the end of the clamp. Glucose disposal
was significantly increased in the rats given neuropeptide Y compared with controls (27.8 ± 1.3 vs 24.3 ± 1.6 mg · min–1· kg–1; p < 0.05) as was the glycolytic flux (18.9 ± 1.6 vs 14.4 ± 0.8 mg · min–1· kg–1; p < 0.05), while glucose storage was comparable in the two groups. In skeletal muscle, the glucose utilisation index was increased
significantly in rats given neuropeptide Y. The glucose utilisation index in subcutaneous and epididimal adipose tissue was
not significantly different between the two groups. Plasma leptin was significantly increased by hyperinsulinaemia, but was
not affected by neuropeptide Y infusion. Both the early and late phase of the insulin response to hyperglycaemia were significantly
reduced by neuropeptide Y. In conclusion neuropeptide Y infusion may increase insulin-induced glucose disposal in normal rats,
accelerating its utilisation through the glycolytic pathway. Neuropeptide Y reduces both phases of the insulin response to
hyperglycaemia. [Diabetologia (1998) 41: 1361–1367]
Received: 4 March 1998 and in revised form: 27 May 1998 相似文献
10.
New insights into sympathetic regulation of glucose and fat metabolism 总被引:10,自引:2,他引:10
Nonogaki K 《Diabetologia》2000,43(5):533-549
The autonomic nervous system modulates glucose and fat metabolism through both direct neural effects and hormonal effects.
This review presents recent concepts on the sympathetic regulation of glucose and fat metabolism. Focally released norepinephrine
from sympathetic nerves is likely to increase glucose uptake in skeletal muscle and adipose tissues independent of insulin
but norepinephrine does not contribute so much as epinephrine to hepatic glucose production. Epinephrine increases hepatic
glucose production and inhibits insulin secretion and the glucose uptake by tissues that is induced by insulin. Additionally,
catecholamines can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores.
It is likely that β-(β3)-adrenergic receptors mediate these responses. Alterations of central neurotransmission and environmental factors can change
the relative contribution of sympathetic outflow to the pancreas, liver, adrenal medulla and adipose tissues, leading to the
modulation of glucose and fat metabolism. Recent studies have proposed that leptin, an adipocyte hormone, affects the central
nervous system to increase sympathetic outflow independent of feeding. The effects of leptin on glucose and fat metabolism
could be in part mediated by the sympathetic nervous system. Studies using mice with a genetic disruption of serotonin 5-HT2 c receptor indicate that central neural mechanisms in the regulation of sympathetic outflow and satiety could be dissociated.
Abnormalities of sympathetic effects, including disturbances of leptin and β3-adrenergic receptor signalling, are likely to cause obesity and impaired glucose tolerance in rodents and humans. These
findings indicate that dysfunction of the sympathetic nervous system could predispose to obesity and Type II (non-insulin-dependent)
diabetes mellitus. [Diabetologia (2000) 43: 533–549] 相似文献
11.
Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a PI3-kinase mediated effect 总被引:4,自引:0,他引:4
Summary It was recently shown that leptin impairs insulin signalling, i. e. insulin receptor autophosphorylation and insulin-receptor
substrate (IRS)-1 phosphorylation in rat-1 fibroblasts, NIH3T3 cells and HepG2 cells. To evaluate whether leptin might impair
the effects of insulin in muscle tissue we studied the interaction of insulin and leptin in a muscle cell system, i. e. C2C12 myotubes. Preincubation of C2C12 cells with leptin (1–500 ng/ml) did not significantly affect insulin stimulated glucose transport and glycogen synthesis
(1.8 to 2 fold stimulation); however, leptin by itself (1 ng/ml) was able to mimic approximately 80–90 % of the insulin effect
on glucose transport and glycogen synthesis. Both glucose transport as well as glycogen synthesis were inhibited by the phosphatidylinositol-3
(PI3)-kinase inhibitor wortmannin and the protein kinase C inhibitor H7 while no effect was observed with the S6-kinase inhibitor
rapamycin. We determined whether the effect of leptin occurs through activation of IRS-1 and PI3-kinase. Leptin did not stimulate
PI3-kinase activity in IRS-1 immunoprecipitates; however, PI3-kinase activation could be demonstrated in p85α immunoprecipitates
(3.04 ± 1.5 fold of basal). In summary the data provide the first evidence for a positive crosstalk between the signalling
chain of the insulin receptor and the leptin receptor. Leptin mimics in C2C12 myotubes insulin effects on glucose transport and glycogen synthesis most likely through activation of PI3-kinase. This effect
of leptin occurs independently of IRS-1 activation in C2C12 cells. [Diabetologia (1997) 40: 606–609]
Received: 24 January 1997 and in revised form: 3 March 1997 相似文献
12.
L. Frittitta J. F. Youngren P. Sbraccia M. D'Adamo A. Buongiorno R. Vigneri I. D. Goldfine V. Trischitta 《Diabetologia》1997,40(3):282-289
Summary In the present study we measured PC-1 content, tumour necrosis factor (TNF)-α gene expression, and insulin stimulation of
insulin receptor tyrosine-kinase activity in adipose tissue from non-obese, non-diabetic subjects. These parameters were correlated
with in vivo insulin action as measured by the intravenous insulin tolerance test (Kitt values). PC-1 content was negatively correlated with Kitt values (r = –0.5, p = 0.04) and positively with plasma insulin levels both fasting (r = 0.58, p = 0.009) and after 120 min during oral glucose tolerance test (OGTT) (r = 0.67, p = 0.002). Moreover, adipose tissue PC-1 content was higher in relatively insulin-resistant subjects (Kitt values lower than 6) than in relatively insulin-sensitive subjects (Kitt values higher than 6) (525 ± 49 ng/mg protein vs 336 ± 45, respectively, p = 0.012). Adipose tissue insulin receptor tyrosine-kinase activity in response to insulin was significantly lower at all
insulin concentrations tested (p = 0.017, by two-way analysis of variance test) in insulin-resistant than in insulin-sensitive subjects (Kitt values lower or higher than 6, respectively). In contrast to PC-1, no significant correlation was observed between adipose
tissue TNF-α mRNA content and Kitt values, and plasma insulin levels, both fasting and at after 120 min during OGTT. Also, no difference was observed in TNF-α
mRNA content between subjects with Kitt values higher or lower than 6. These studies in adipose tissue, together with our previous studies in skeletal muscle raise
the possibility that PC-1, by regulating insulin receptor function, may play a role in the degree of insulin sensitivity in
non-obese, non-diabetic subjects. [Diabetologia (1997) 40: 282–289]
Received: 2 August 1996 and in revised form: 16 October 1996 相似文献
13.
Summary Hyperinsulinaemia in the fasting state and a blunted insulin secretory response to acute glucose stimulation are commonly
observed in obesity associated non-insulin-dependent diabetes mellitus. Hyperlipidaemia is a hallmark of obesity and may play
a role in the pathogenesis of this beta-cell dysfunction because glucose metabolism in pancreatic beta cells may be altered
by the increased lipid load. We tested this hypothesis by assessing the chronic effect of oleic acid on glucose metabolism
and its relationship with glucose-induced insulin release in βHC9 cells in tissue culture. Our results show: (1) A 4-day treatment with oleic acid caused an enhancement of insulin release
at 0–5 mmol/l glucose concentrations while a significant decrease in insulin release occurred when the glucose level was greater
than 15 nmol/l; (2) Hexokinase activity was increased and a corresponding left shift of the dose-dependency curve of glucose
usage was observed associated with inhibition of glucose oxidation in oleic acid treated βHC9 cells, yet the presumed glucose-related ATP generation did not parallel the change in insulin release due to glucose;
(3) The rate of cellular respiration was markedly increased in oleic acid treated βHC9 cells both in the absence of glucose and at all glucose concentrations tested. This enhanced oxidative metabolism may
explain the increased insulin release at a low glucose level but is clearly dissociated from the blunted insulin secretion
at high glucose concentrations. We conclude that a reduction of oxidative metabolism in pancreatic beta cells is unlikely
to be the cause of the dramatic effect that high levels of non-esterified fatty acids have on glucose-induced insulin release.
[Diabetologia (1997) 40: 1018–1027]
Received: 18 February 1997 and in revised form: 22 April 1997 相似文献
14.
The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes 总被引:1,自引:1,他引:0
M. Poggi J. Jager O. Paulmyer-Lacroix F. Peiretti T. Gremeaux M. Verdier M. Grino A. Stepanian S. Msika R. Burcelin D. de Prost J. F. Tanti M. C. Alessi 《Diabetologia》2009,52(6):1152-1163
Aims/hypothesis Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand
(CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human
adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation.
Methods
CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western
blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and
neutralising antibodies in lymphocyte/adipocyte co-culture.
Results
CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal–vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein
kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport
in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and
were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation
of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement
of a cell–cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes.
Conclusions/interpretation Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine
production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40. 相似文献
15.
Berndt J Kovacs P Ruschke K Klöting N Fasshauer M Schön MR Körner A Stumvoll M Blüher M 《Diabetologia》2007,50(7):1472-1480
Aims/hypothesis Increased expression and activity of the lipogenic pathways in adipose tissue may contribute to the development of obesity.
As a central enzyme in lipogenesis, the gene encoding fatty acid synthase (FASN) was identified as a candidate gene for determining body fat. In the present study we tested the hypothesis that increased
FASN expression links metabolic alterations of excess energy intake, including hyperinsulinaemia, dyslipidaemia and altered adipokine
profile to increased body fat mass.
Subjects and methods In paired samples of visceral and subcutaneous adipose tissue from 196 participants (lean or obese), we investigated whether
FASN mRNA expression (assessed by PCR) in adipose tissue is increased in obesity and related to visceral fat accumulation, measures
of insulin sensitivity (euglycaemic–hyperinsulinaemic clamp) and glucose metabolism.
Results
FASN mRNA expression was increased by 1.7-fold in visceral vs subcutaneous fat. Visceral adipose tissue FASN expression was correlated with FASN protein levels, subcutaneous FASN expression, visceral fat area, fasting plasma insulin, serum concentrations of IL-6, leptin and retinol-binding protein 4
(RBP4), and inversely with measures of insulin sensitivity, independently of age, sex and BMI. Moreover, we found significant
correlations between FASN expression and markers of renal function, including serum creatinine and urinary albumin excretion.
Conclusions/interpretation Increased FASN gene expression in adipose tissue is linked to visceral fat accumulation, impaired insulin sensitivity, increased circulating
fasting insulin, IL-6, leptin and RBP4, suggesting an important role of lipogenic pathways in the causal relationship between
consequences of excess energy intake and the development of obesity and type 2 diabetes. 相似文献
16.
Leptin is suppressed during infusion of recombinant human insulin-like growth factor I (rhIGF I) in normal rats 总被引:2,自引:0,他引:2
Summary To examine whether insulin-like growth factor I (IGF I) or growth hormone (GH) influences leptin in vivo we measured leptin
mRNA in epididymal fat pads and serum leptin of normal rats infused subcutaneously for 6 days with recombinant human (rh)IGF
I (1 mg/day), rhGH (200 mU/day), or vehicle. In addition, we determined fat pad weight and food consumption as well as IGF
I, insulin, glucose, non-esterified fatty acid (NEFA), glycerol, β-hydroxybutyrate and triglyceride (TG) serum concentrations. Food intake was identical during all three treatments. RhIGF
I but not rhGH raised IGF I serum concentrations, reduced fat pad weight (60.3 ± 7.4 % of control rats, p = 0.019), and suppressed leptin mRNA (38.8 ± 11.9 % of control rats, p = 0.002), serum leptin (51.6 ± 10.5 % of control rats, p = 0.0028) and serum triglycerides (39.3 ± 8.0 % of control rats, p = 2.6 × 10–6). Both rhIGF I and rhGH reduced non-esterified fatty acids (NEFA) (p = 0.00 001 and 0.0007, respectively), whereas serum glycerol, β-OH butyrate and glucose concentrations remained unchanged. Serum insulin concentrations during rhIGF I were lower than during
rhGH infusion and correlated with leptin mRNA (r = 0.589, p = 0.016) and fat pad weight (r = 0.643, p = 0.007). Reduction of adipose tissue mass and suppression of leptin by IGF I appear to be due to reduced circulating insulin
leading to enhanced fat mobilization and NEFA oxidation as well as to increased gluconeogenesis from glycerol. In contrast,
decreased NEFA concentrations during rhGH in the presence of unchanged fat pad weight, serum glycerol and triglycerides might
result from more efficient re-esterification of released fatty acids within the triglyceride-fatty acid cycle. The results
also show that exogenously infused IGF I and GH act on lipid metabolism by different mechanisms and suggest an IGF-independent,
probably direct, metabolic effect of GH. Finally, in agreement with previous studies in GH-infused hypophysectomized rats,
it appears unlikely that GH regulates leptin in the rat. [Diabetologia (1999) 42: 160–166]
Received: 21 July 1998 and in revised form: 5 October 1998 相似文献
17.
Seongjoon Park Toshimitsu Komatsu Hiroko Hayashi Haruyoshi Yamaza Takuya Chiba Yoshikazu Higami Kazunao Kuramoto Isao Shimokawa 《Age (Dordrecht, Netherlands)》2008,30(4):293-302
Calorie restriction (CR) may exert an anti-aging effect through a metabolic adaptation to limited energy intake. The present
study investigated the effect of CR on insulin signaling in response to glucose load in the epididymal adipose tissue of male
F344 rats at 7 and 22 months of age. Young and middle-aged rats were fed ad libitum (AL) or 30% CR diets for 4 months, underwent
glucose tolerance tests and were sacrificed 15 min after an intraperitoneal glucose or saline injection to evaluate glucose-stimulated
insulin response and subsequent activation of insulin signaling molecules in the adipose tissue. In the 7- and 22- month AL
groups, glucose administration increased serum insulin levels and also increased phosphorylated (p) levels of the insulin
receptor (IR), v-akt murine thymoma viral oncogene homolog (Akt), protein kinase C (PKC) ζ/λ and the membrane fraction of
glucose transporter 4 (mGlut4). In contrast, in the 7-month CR group, p-Akt, p-PKCζ/λ and mGlut4 levels were upregulated without
glucose stimulation; the glucose load augmented the p-IR level but there was no additional activation of the downstream molecules.
In the 22-month CR group, these unexpected findings were not observed. In summary, basal levels of insulin signaling molecules
such as p-Akt, p-PKCζ/λ, and mGlut4 were significantly increased with a low insulin response in the 7-month CR group. The
present results suggest the presence of an age-specific insulin-independent mechanism that is induced by CR to regulate energy
metabolism in white adipose tissue.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
18.
Summary The adrenergic regulation of adipose tissue lipolysis in response to insulin-induced hypoglycaemia (intravenous infusion
of soluble insulin 0.10 IU · kg body weight−1· h−1 until the arterial plasma glucose fell below 2.8 mmol/l) was investigated directly in vivo in 11 insulin-dependent diabetic
(IDDM) patients and 12 control subjects, using microdialysis of the extracellular space of abdominal subcutaneous adipose
tissue. The tissue glycerol level (lipolysis index) and the escape of ethanol from the perfusion medium (blood flow index)
were continuously monitored. During insulin infusion the arterial glucose level was reduced in parallel and the hypoglycaemic
nadir was almost identical in the two groups (diabetic patients 2.2 ± 0.1 and control subjects 2.3 ± 0.1 mmol/l). While the
maximum response of plasma epinephrine to hypoglycaemia was 30 % lower in diabetic patients than in the control subjects (p < 0.05), the glycerol levels in adipose tissue and in plasma, as well as in serum non-esterified fatty acids, increased twice
as much in the former as in the latter group following hypoglycaemia (p < 0.01). Addition of the beta-adrenoceptor blocker propranolol (10−4 mol/l) to the tissue perfusate almost completely prevented the hypoglycaemia-induced increase in the adipose tissue glycerol
level in both groups, whereas in situ perfusion with 10−4 mol/l of the alpha-adrenoceptor blocker phentolamine resulted in an additional increase in the tissue glycerol levels; during
alpha-blockade, the glycerol response to hypoglycaemia remained enhanced by threefold in the diabetic patients (p < 0.01). In both groups local adipose tissue blood flow increased transiently in a similar way after hypoglycaemia; the increase
being inhibited by in situ beta-adrenoceptor blockade. We conclude that both alpha- and beta-adrenergic mechanisms regulate
adipose tissue lipolysis in response to hypoglycaemia. In IDDM, lipolysis is markedly enhanced following hypoglycaemia, despite
a reduced catecholamine secretory response, because of increased beta-adrenoceptor action in adipose tissue. [Diabetologia
(1996) 39: 845–853]
Received: 5 July 1995 and in final revised form: 4 March 1996 相似文献
19.
C. Drewes M. A. Nauck R. Horn J. Holst W. Schmiegel G. Brabant 《Acta diabetologica》1997,34(3):230-234
Glucagon-like peptide 1 [7–36 amide] (GLP-1) and the obese gene product (leptin) are thought to be involved in the central regulation of feeding. Both may act from the peripheral circulation
to influence brain function. To study potential interactions, GLP-1 ([7–36 amide]: 0.4, 0.8 pmol kg–1 min–1 or placebo on separate occasions) was infused intravenously (from –30 to 240 min) into nine healthy volunteers [age 26±3
years, body mass index: 22.9±1.6 kg/m2, glycated haemoglobin HbA1c: 5.0%± 0.2% (normal: 4.0%–6.2%), creatinine: 1.1±0.1 mg/dl], and (at 0 min) a liquid test meal (50 g sucrose in 400 ml 8%
amino acid, total amino acids 80 g/l) was administered via a nasogastric tube. Plasma leptin (radioimmunoassay, RIA), glucose,
insulin (microparticle enzyme immunoassay), C-peptide (enzyme-linked immunosorbent assay) and GLP-1 (RIA) were measured, and
statistical analysis was done with repeated-measures ANOVA and Student's t-test. Plasma leptin concentrations were 31±6 pmol/l in the basal state. They did not change within 240 min after meal ingestion
nor in response to the infusion of exogenous GLP-1 [7–36 amide] (P=0.99 for the interaction of experiment and time) leading to GLP-1 mean plasma levels of 25±2 and 36±3 (basal 6±1) pmol/l.
On the other hand, glucose (from basal 4.7±0.1 to 6.0±0.2 mmol/l at 15 min, P<0.05) and insulin (from basal 28±2 to 325±78 pmol/l at 45 min, P<0.05) increased clearly after the meal with placebo. In conclusion, (1) plasma leptin levels in normal human subjects show
no short-term changes after feeding a liquid mixed meal and (2) do not appear to be directly influenced by physiological and
pharmacological elevations in plasma GLP-1 [7–36 amide] concentrations. This does not exclude interactions at the cerebral
(hypothalamic) level or on more long-term temporal scales.
Received: 5 February 1997 / Accepted in revised form: 18 June 1997 相似文献
20.
Summary It is not clear how circadian lipolysis and circulating concentrations of non-esterified fatty acids (NEFA) are altered in
intensively treated insulin-dependent diabetic (IDDM) patients. Ten IDDM patients on an intensive insulin regimen and eight
healthy control subjects were investigated under ordinary living conditions for 27 h by microdialysis of subcutaneous adipose
tissue. The true tissue glycerol concentration and adipose blood flow changes were monitored as an index of lipolysis. A circadian
pattern in adipose tissue lipolysis was observed in both groups, decreasing during the day and increasing during evening-night.
The daytime decrease was normal, but the evening-night rise was elevated in IDDM (p = 0.03). Circulating NEFA decreased during the day and increased at night. The latter increase was enhanced threefold in
IDDM (p = 0.003) and correlated with fasting glucose levels (r = 0.77). Nocturnal growth hormone (GH) was increased fivefold in IDDM and correlated to nocturnal lipolysis (r = 0.83). Adipose tissue blood flow increased during the night in a similar fashion in both groups. Near-normalization of
glucose for 24 h in IDDM did not affect the nocturnal increases in NEFA, GH and lipolysis. In conclusion, a circadian rhythm
in lipolysis was found. Increased lipolytic rates during evening-night may at least in part raise nocturnal circulating NEFA.
Nocturnal NEFA and lipolysis are further enhanced in IDDM, maybe due to elevated GH, but not to insulinopenia or hyperglycaemia.
[Diabetologia (1997) 40: 1070–1078]
Received: 27 February 1997 and in revised form: 28 April 1997 相似文献