Switching the optical and electrical properties of carbon nanotube hybrid films using a photoresponsive dispersant as a dopant.

The light-induced switching of the optical and electrical properties of single-walled carbon nanotubes (SWCNTs) was demonstrated following hybridisation with an azobenzene-based photoresponsive dispersant in solid film. The resultant SWCNT/photoresponsive dispersant hybrid film showed switching of absorbance in the near-infrared region by the irradiation of UV and visible lights, which was caused by the change of the doping ability of the dispersant to SWCNT. In addition, the switching of the electrical properties of the SWCNT hybrid film was also observed.

Visceral, subcutaneous abdominal adiposity and liver fat content distribution in normal glucose tolerance, impaired fasting glucose and/or impaired glucose tolerance.

OBJECTIVES: To examine the specific distribution of liver fat content, visceral and subcutaneous adiposity in normal glucose tolerance (NGT/NGT), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined conditions (IFG+IGT), as well as with newly diagnosed type 2 diabetes (nT2D). DESIGN: Multicenter, international observational study: cross-sectional analysis. SUBJECTS: Two thousand five hundred and fifteen patients (50.0% women, 54.5% non-Caucasian) without previously known diabetes were recruited from 29 countries. Abdominal fat distribution was measured by computed tomography (CT). Liver fat was estimated using the CT-liver mean attenuation. RESULTS: Compared with NGT/NGT patients, increased visceral adiposity was found in iIFG, iIGT, IFG+IGT and nT2D; estimated liver fat progressively increased across these conditions. A one-s.d. increase in visceral adiposity was associated with an increased risk of having iIFG (men: odds ratio (OR) 1.41 (95% confidence interval (CI) 1.15-1.74), women: OR 1.62 (1.29-2.04)), iIGT (men: OR 1.59 (1.15-2.01), women: OR 1.30 (0.96-1.76)), IFG+IGT (men: OR 1.64 (1.27-2.13), women: OR 1.83 (1.36-2.48)) and nT2D (men: OR 1.80 (1.35-2.42), women: OR 1.73 (1.25-2.41)). A one-s.d. increase in estimated liver fat was associated with iIGT (men: OR 1.46 (1.12-1.90), women: OR 1.81 (1.41-2.35)), IFG+IGT (men: OR 1.42 (1.14-1.77), women: OR 1.74 (1.35-2.26)) and nT2D (men: OR 1.77 (1.40-2.27), women: OR 2.38 (1.81-3.18)). Subcutaneous abdominal adipose tissue showed an inverse relationship with nT2D in women (OR 0.63 (0.45-0.88)). CONCLUSIONS: Liver fat was associated with iIGT but not with iIFG, whereas visceral adiposity was associated with both. Liver fat and visceral adiposity were associated with nT2D, whereas subcutaneous adiposity showed an inverse relationship with nT2D in women.

Assessment of cardiometabolic risk and prevalence of meeting treatment guidelines among patients with type 2 diabetes stratified according to their use of insulin and/or other diabetic medications: results from INSPIRE ME IAA.

AIM: Visceral adipose tissue (VAT) and liver fat (LF) are strongly associated with type 2 diabetes. It is not known, however, how diabetes treatment and/or risk factor management modulates the association between VAT, LF and diabetes. The aim was to determine the level of VAT and LF in patients with type 2 diabetes according to their treatment status and achievement of the American Diabetes Association's (ADA) diabetes management goals. METHODS: We performed a cross-sectional analysis of the baseline data of the International Study of the Prediction of Intra-Abdominal Adiposity and its Relationship with Cardiometabolic risk/Intra-Abdominal Adiposity (INSPIRE ME IAA), a 3-year prospective cardiometabolic imaging study conducted in 29 countries. Patients (n = 3991) were divided into four groups: (i) those without type 2 diabetes (noT2D n = 1003 men, n = 1027 women); (ii) those with type 2 diabetes but not treated with diabetes medications (T2Dnomeds n = 248 men, n = 198 women); (iii) those with type 2 diabetes and treated with diabetes medications but not yet using insulin (T2Dmeds-ins n = 591 men, n = 484 women) and (iv) those with type 2 diabetes and treated with insulin (T2Dmeds+ins n = 233 men, n = 207 women). Abdominal and liver adiposity were measured by computed tomography. RESULTS: Fewer patients with high VAT or LF achieved the ADA's goals for high-density lipoprotein cholesterol (HDL-C) or triglycerides compared to patients with low VAT or LF. Visceral adiposity (p = 0.02 men, p = 0.003 women) and LF (p = 0.0002 men, p = 0.0004 women) increased among patients who met fewer of the ADA treatment criteria, regardless of type 2 diabetes treatment. CONCLUSION: Residual cardiometabolic risk exists among patients with type 2 diabetes characterized by elevated VAT and LF.

Serum adiponectin level is not only decreased in metabolic syndrome but also in borderline metabolic abnormalities.

OBJECTIVE: Along with the increasing prevalence of obesity and related diseases, particularly atherosclerotic diseases, metabolic syndrome (MetS) is now a common and major public health issue in many countries around the world. Adiponectin, a protein secreted by the adipose tissue, has become recognized as a key player in the development of MetS. These days, not only MetS but also borderline metabolic/physiological abnormalities, such as impaired fasting glucose, high normal blood pressure and high normal plasma cholesterol, have been reported to be risk factors for atherosclerotic disease. Therefore, we undertook this study to determine the relationship between adiponectin and borderline metabolic/physiological abnormalities, as well as MetS. DESIGN: A cross-sectional study performed from April 2007 to November 2009. SUBJECTS: In 16 892 Japanese adults (10 008 men and 6884 women), we examined the relationship between the serum adiponectin concentration and borderline metabolic/physiological abnormalities or MetS by a questionnaire survey about medical treatment, body size measurement and measurement of laboratory parameters including the serum adiponectin concentration. RESULTS: Adiponectin showed a significant negative correlation with the number of MetS components. In subjects without overt diabetes mellitus, hypertension or dyslipidemia, the adiponectin concentration also showed a significant negative correlation with the number of borderline metabolic abnormalities. CONCLUSION: The decrease of circulating adiponectin may start before the development of diabetes mellitus, hypertension, dyslipidemia or MetS. Adiponectin is an important biomarker for reflecting the adverse influence of visceral fat in persons with MetS, and also in these subclinical states.

The role of fat topology in the risk of disease.

Clustering of multiple risk factors such as impaired glucose metabolism, lipid disorders and hypertension has been shown to be the major background of atherosclerotic diseases, and disease entities such as the metabolic syndrome represent a highly atherogenic state. Although these common risks may generally co-exist by accident in one individual, clustering of multiple risk factors in the metabolic syndrome does not occur by accident, and there should be a key player for the syndrome. In 1983, we reported the method for fat analysis using computed tomography scan, which enables us to analyze intra-abdominal visceral adiposity as well as subcutaneous fat. Visceral fat accumulation has been shown to cause impaired glucose metabolism, lipid disorders, and hypertension, and therefore it is considered to be a key player in the metabolic syndrome. To clarify the mechanism by which visceral fat accumulation causes a variety of metabolic and vascular diseases, we studied the molecular characteristics of adipose tissue and adipocytes by investigating expressed genes in visceral and subcutaneous adipocytes and revealed that adipocytes, especially visceral adipocytes, secrete a variety of bioactive substances, the so-called adipocytokines. We showed that visceral fat accumulation causes abnormalities in adipocytokine secretion, such as hypersecretion of plasminogen activator inhibitor 1, which is related to thrombogenic vascular diseases. More importantly, we discovered an important benign adipocytokine named adiponectin, which protects against the development of diabetes mellitus, hypertension, inflammation, and atherosclerotic vascular diseases. Plasma levels of adiponectin decreased in individuals with visceral fat accumulation, and hypoadiponectinemia caused by visceral fat accumulation might be one of the major causes of metabolic syndrome.

A trilogy of primary prevention statin trials. Panel discussion.

Presented is a report of a panel discussion held as part of the ISA 2006 Sankyo Forum titled "A Trilogy of Primary Prevention Statin Trials--The Impact of These Landmark Studies on Clinical Practice," Rome, Italy, June 2006. The themes of the panel discussion were the design features of three trials, WOSCOPS, AFCAPS/TexCAPS, and Japan's MEGA Study; comparison of their primary endpoints; and the implications of their results. Among the topics discussed by the panel of experts from Japan, USA, and UK were observations on the benefits associated with pravastatin at low dose as demonstrated in the MEGA Study as well as that study's implications for women, who represented the majority of subjects. Several suggestions were put forth to explain how the low dose used in MEGA elicited similar LDL-C reductions to those observed in WOSCOPS and AFCAPS/TexCAPS at higher doses including the body size hypothesis, genetic variation, and statin-diet interaction. It was felt that in Japan, the current guidelines are adequate; there seemed no merit in radically reducing LDL-C levels since in the Japanese population the risk is generally low. Japanese physicians tend to use small doses of statin and believe that these are effective in lowering cholesterol sufficiently with few side effects and encourage good compliance.

Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-alpha in patients with recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: Type 1A diabetes results from autoimmune destruction of pancreatic beta cells. We examined the involvement of TNF-alpha and IL-1beta, as well as of T cells, macrophages and dendritic cells, in the destruction of beta cells in patients with recent-onset type 1 diabetes. MATERIALS AND METHODS: We obtained pancreatic biopsy specimens from six patients with recent-onset type 1 diabetes and analysed these by immunohistochemistry. RESULTS: T cell infiltration was less common in islets without beta cells (12.5 [0-33.3]%) than in those with beta cells (46.0 [17.4-83.3]%), while macrophages and dendritic cells showed a similar extent of infiltration into islets both with or without beta cells. TNF-alpha was detected in 25.0 (4.3-46.9)% of macrophages and 11.8 (0-40.0)% of dendritic cells infiltrating the islets in samples from each patient, but not at all in T cells. IL-1beta was detected in 1.8 (0-11.3)% of T cells infiltrating the islets with beta cells, while it was found in 19.2 (0-35.3)% of macrophages or 10.7 (0-31.3)% of dendritic cells infiltrating the islets in samples from each patient (all values median [range]). CONCLUSIONS/INTERPRETATION: Macrophages and dendritic cells infiltrate the islets and produce inflammatory cytokines (TNF-alpha and IL-1beta) during the development of type 1A diabetes.

Changes in adiponectin receptor expression in muscle and adipose tissue of type 2 diabetic patients during rosiglitazone therapy.

AIMS/HYPOTHESIS: Adiponectin is important in the regulation of insulin sensitivity in man. Its receptors, adipoR1 and R2, have recently been identified, but their expression in adipose tissue and their regulation in response to insulin sensitisation of diabetic patients have never been assessed. We therefore explored the regulation of adipoR1/R2 and adiponectin expression in adipose tissue and skeletal muscle, and of adiponectin plasma concentrations in response to insulin sensitisation by rosiglitazone. METHODS: Patients with type 2 diabetes were studied in a double-blind, placebo-controlled crossover study, using in vivo arteriovenous techniques of measuring adipose tissue and muscle blood flow, combined with measurement of adipose tissue and skeletal muscle gene expression. RESULTS: Rosiglitazone treatment increased adiponectin concentrations by 69%. Skeletal muscle adipoR1 expression was down-regulated from 109.0 (70.1-165.7) (median [interquartile range]) to 82.8 (63.6-89.3) relative units (p=0.04), but adipose tissue adipoR1 expression was up-regulated from 5.3 (4.4-9.4) to 11.2 (4.8-15.3) relative units (p=0.02) by rosiglitazone. In contrast to adipoR1 expression, adipoR2 expression was not altered by rosiglitazone in either of the tissues. The increase in adipose tissue adipoR1 expression with rosiglitazone was associated with increased postprandial triglyceride clearance (r=0.67, p=0.05), and increased fasting fatty acid output (r=0.78, p=0.01) measured in subcutaneous adipose tissue. CONCLUSIONS/INTERPRETATION: AdipoR1 expression is up-regulated in adipose tissue but down-regulated in skeletal muscle by rosiglitazone. These data suggest that adipoR1 plays a role in mediating the effects of adiponectin in specific tissues in relation to insulin sensitisation.

Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment.

AIMS/HYPOTHESIS: We have previously reported that fulminant type 1 diabetes is characterised by an absence of diabetes-related antibodies and a remarkably abrupt onset. However, little is known about the mechanism of beta cell destruction in this diabetes subtype, and to obtain insights into the aetiology of the disease, we investigated residual endocrine cells and the expression of Fas and Fas ligand in fulminant type 1 diabetes. METHODS: Residual beta and alpha cells were morphologically assessed in pancreatic tissue obtained by biopsy from five patients with recent-onset fulminant type 1 diabetes and five patients with recent-onset typical autoimmune type 1 diabetes. In addition, the expression of Fas and Fas ligand was evaluated by immunohistochemistry. RESULTS: In fulminant type 1 diabetes, beta and alpha cell areas were decreased significantly, compared with autoimmune type 1 diabetes and control subjects. In contrast, the alpha cell area was not decreased significantly in autoimmune type 1 diabetes, compared with that in control subjects. No Fas expression in islets and Fas ligand expression in CD3(+) cells in the exocrine pancreas were found in the fulminant type 1 diabetic patients who underwent this evaluation. CONCLUSIONS/INTERPRETATION: Our study showed that beta and alpha cells are damaged in fulminant type 1 diabetes. In addition to the lack of Fas and Fas ligand expression, the results suggest that the mechanism of beta cell destruction in fulminant type 1 diabetes is different from that in autoimmune type 1 diabetes.

Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn's disease.

BACKGROUND AND AIMS: A characteristic feature of Crohn's disease (CD) is mesenteric adipose tissue hypertrophy. Mesenteric adipocytes or specific proteins secreted by them may play a role in the pathogenesis of CD. We recently identified adiponectin as an adipocyte specific protein with anti-inflammatory properties. Here we report on expression of adiponectin in mesenteric adipose tissue of CD patients. METHODS AND RESULTS: Mesenteric adipose tissue specimens were obtained from patients with CD (n = 22), ulcerative colitis (UC) (n = 8) and, for controls, colon carcinoma patients (n = 28) who underwent intestinal resection. Adiponectin concentrations were determined by enzyme linked immunosorbent assay, and adiponectin mRNA levels were determined by real time quantitative reverse transcription-polymerase chain reaction. Tissue concentrations and release of adiponectin were significantly increased in hypertrophied mesenteric adipose tissue of CD patients compared with normal mesenteric adipose tissue of CD patients (p = 0.002, p = 0.040, respectively), UC patients (p = 0.002, p = 0.003), and controls (p<0.0001, p<0.0001). Adiponectin mRNA levels were significantly higher in hypertrophied mesenteric adipose tissue of CD patients than in paired normal mesenteric adipose tissue from the same subjects (p = 0.024). Adiponectin concentrations in hypertrophied mesenteric adipose tissue of CD patients with an internal fistula were significantly lower than those of CD patients without an internal fistula (p = 0.003). CONCLUSIONS: Our results suggest that adipocytes in hypertrophied mesenteric adipose tissue produce and secrete significant amounts of adiponectin, which could be involved in the regulation of intestinal inflammation associated with CD.

Plasma adiponectin levels in women with anorexia nervosa.

Adiponectin is a plasma protein exclusively secreted by adipose tissue, which plays a role in modulating lipid and glucose metabolism. The plasma adiponectin concentration shows an inverse correlation with the body mass index in normal and obese individuals, but it has not been investigated in subjects with an extremely low body weight and undernutrition such as anorexia nervosa patients. We investigated plasma adiponectin levels in 21 females with anorexia nervosa. Nineteen healthy females served as the lean control group. The subjects with anorexia nervosa had a significantly lower weight and showed a tendency towards higher adiponectin levels than the control group. No correlation between adiponectin and BMI was found in patients with anorexia nervosa, while a linear negative correlation was seen in lean controls. The patient who showed the lowest adiponectin level reached a life-threatening state and required intravenous feeding in hospital. In association with improved nutrition and weight gain, the adiponectin level increased gradually until the body mass index was about 16 and then decreased subsequently as would be expected in lean normal subjects. These observations suggest that adipose tissue secretes less adiponectin and the adiponectin levels do not show an inverse correlation simply with body mass index in some subjects with severe undernutrition.

Plasma adiponectin concentration before and after successful kidney transplantation.

BACKGROUND: Adiponectin, a protein secreted exclusively by adipocytes, is presumed to be involved in the pathogenesis of atherosclerosis and insulin resistance. An elevated plasma adiponectin concentration was found in ESRD patients on hemodialysis (HD). However, the role of kidneys in adiponectin biodegradation/elimination is unknown. Therefore, we assessed plasma adiponectin concentrations in ESRD patients before and after successful kidney transplantation. METHODS: Among 44 hemodialyzed patients (29 men, 15 women; mean age 39 +/- 11 years; mean body mass index [BMI] 23.6 +/- 3.5 kg/m(2); mean duration of HD treatment before kidney transplantation 27 +/- 26 months), plasma adiponectin concentrations and insulin resistance indices (HOMA-R) were measured twice: immediately before kidney transplantation (Tx) and 1-2 days before patient discharge from the hospital with stable kidney transplant function (mean serum creatinine level 191 +/- 105 micromol/L). The control group consisted of 22 normotensive healthy subjects (12 men, 10 women). RESULTS: Among uremic patients, before Tx, plasma adiponectin concentrations were significantly higher than in healthy subjects (20.8 +/- 8.3 vs 8.7 +/- 4.8 microg/mL; P <.001) After successful Tx, plasma adiponectin concentrations decreased significantly (20.8 +/- 8.3 vs 15.7 +/- 7.0 microg/mL before and after Tx, respectively; P <.001). Simultaneously, after successful kidney transplantation, an increase in HOMA-R was observed (1.01 +/- 0.61 vs 1.43 +/- 0.83; P =.002). However, changes in adiponectinemia did not significantly correlate with serum creatinine or HOMA-R. CONCLUSION: The kidneys seem to play an important role in adiponectin biodegradation and/or elimination.

Identification of a novel variant in the phosphoenolpyruvate carboxykinase gene promoter in Japanese patients with type 2 diabetes.

Phospho enolpyruvate carboxykinase (PEPCK) plays an important role in gluconeogenesis and hepatic glucose production. To test the hypothesis that mutations of the PEPCK gene promoter contribute to the increased hepatic glucose production that leads to diabetes, we screened for polymorphisms of the PEPCK promoter region in 252 Japanese type 2 diabetic patients and 188 non-diabetic control subjects. A novel variant at position - 232 (C to G) was found at a similar frequency in type 2 diabetes patients (32 %) and control subjects (35 %) (p = 0.26). However, patients with the - 232 G/G genotype had an earlier age of onset than those with the - 232 C/C or - 232 C/G genotypes (p = 0.028). As the variant might well otherwise influence hormonal action, we transfected PEPCK-luciferase fusion gene constructs with the variant into human hepatoma cells and examined the response to dexamethasone, insulin, and cAMP. The reporter assay showed no significant difference in hormonal responses with the fusion gene containing the variant. Accordingly, the single-base variant at position - 232 of the PEPCK gene promoter is most probably not a major contributor to the pathogenesis of type 2 diabetes. However, this variation may be useful as a genetic marker for other metabolic disorders, especially in Japanese.

Successful second allogeneic peripheral blood stem cell transplantation and donor lymphocyte infusion in patients with relapsed acute leukemia using the same donors as for the initial allogeneic bone marrow transplantation.

We report the successful treatment of two acute lympho- blastic leukemia (ALL) patients who relapsed following allogeneic bone marrow transplantation (allo-BMT) with allogeneic peripheral blood sem cell transplantation(allo-PBSCT) and donor lymphocyte infusion (DLI) from the same HLA-identical related donors as those used for the first allo-BMT. The patients relapsed on days 154 and 351 from the initial allo-BMT, respectively. Since conventional reinduction chemotherapy failed, allo-PBSCT was undertaken while the patients were still myelosuppressed immediately after reinduction chemotherapy. To induce and/or enhance GVL effects following allo-PBSCT, we performed rapid tapering of CsA and added DLI. After allo-PBSCT and DLI, the patients maintained their complete remission at 55 and 48 months post allo-PBSCT, respectively. From these findings, allo-PBSCT and DLI may be a useful treatment strategy for acute leukemia relapsing after allo-BMT.

Gastrin activates nuclear factor kappaB (NFkappaB) through a protein kinase C dependent pathway involving NFkappaB inducing kinase, inhibitor kappaB (IkappaB) kinase, and tumour necrosis factor receptor associated factor 6 (TRAF6) in MKN-28 cells transfected with gastrin receptor.

BACKGROUND: We previously reported that gastrin induces expression of CXC chemokines through activation of nuclear factor kappaB (NFkappaB) in gastric epithelial cells that express gastrin receptor. AIMS: To clarify gastrin receptor mediated signals leading to activation of NFkappaB. METHODS: MKGR26 cells were created by transfecting gastrin receptor cDNA into MKN-28 cells. Degradation of inhibitor kappaB (IkappaB) and phosphorylation of protein kinase C (PKC)-delta were both detected by western blot analysis. NFkappaB activation was determined by luciferase assay and electrophoretic mobility shift analysis. RESULTS: Gastrin induced degradation of IkappaB-alpha and activation of NFkappaB, which was abolished by the selective gastrin receptor antagonist L-740,093 and the general PKC inhibitor GF109203X. Gastrin induced phosphorylation of PKC-delta, and its inhibitor rottlerin partially suppressed NFkappaB activation. However, the mitogen activated protein kinase (MAPK) kinase inhibitor PD98059, p38 MAPK inhibitor SB203580, and tyrphostin AG1478 had no effect on NFkappaB activation. Introduction of the dominant negative mutant of IkappaB kinase, of NFkappaB inducing kinase, and of tumour necrosis factor receptor associated factor 6 (TRAF6), but not that of TRAF2, inhibited gastrin induced activation of NFkappaB. CONCLUSIONS: Gastrin activates NFkappaB via a PKC dependent pathway which involves IkappaB kinase, NFkappaB inducing kinase, and TRAF6.

T130I mutation in HNF-4alpha gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects.

AIMS/HYPOTHESIS: Mutations in hepatocyte nuclear factor (HNF)-4alpha gene cause a form of maturity-onset diabetes of the young (MODY1). The T130I mutation is a rare missense mutation, which affects a conserved amino acid in a DNA binding domain. This mutation can be found in the general population, so this variant alone does not cause MODY. However, its significance in the development of late-onset Type 2 diabetes is not known. METHODS: We screened 423 unrelated Japanese patients with late-onset Type 2 diabetes and 354 unrelated non-diabetic control subjects for the T130I mutation in the HNF-4alpha gene. The transactivation ability of T130I-HNF-4alpha was assessed using reporter gene assay. RESULTS: The frequency of the T130I mutation was higher in Type 2 diabetic patients ( p=0.015, odds ratio 4.3, 95%CI 1.24-14.98) than control subjects. The serum HDL-cholesterol concentration was lower in Type 2 diabetic patients with the T130I mutation compared with those without this mutation ( p=0.006). Reporter gene analysis showed that T130I-HNF-4alpha transcriptional activity was not impaired compared with wild-type HNF-4alpha in Hela and MIN6 cells, but it was reduced in HepG2 and primary cultured mouse hepatocytes (27-78% of wild type, p<0.05). CONCLUSION/INTERPRETATION: Our findings suggest that T130I-HNF-4alpha is a loss-of-function mutation in hepatocytes and that this mutation is associated with late-onset Type 2 diabetes in Japanese subjects. The T130I mutation in the HNF-4alpha gene might be involved in the development of Type 2 diabetes in the Japanese population.

Circulating adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients.

Adiponectin, one of the most abundant gene transcript proteins in human fat cells, has been shown to improve insulin action and is also suggested to exert antiatherogenic effects. We measured circulating adiponectin levels and risk factors for atherosclerosis in 45 healthy first-degree relatives of type 2 diabetic subjects (FDR) as well as 40 healthy control subjects (CON) without a known family history of diabetes. Insulin sensitivity (S(i)) was studied with the minimal model, and measurements of adiponectin, metabolic variables, inflammatory markers, and endothelial injury markers, as well as lipoprotein concentrations, were performed. FDR were insulin resistant (3.3 +/- 2.4 vs. 4.5 +/- 2.6 x 10(-4) x min(-1) per microU/ml [mean +/- SD], P < 0.01), and their circulating plasma adiponectin levels (6.6 +/- 1.8 vs. 8.1 +/- 3.0 microg/ml, P < 0.03) were decreased. After adjustments for age in FDR, adiponectin levels were negatively correlated with fasting proinsulin (r -0.64, P < 0.001), plasminogen activator inhibitor (PAI)-1 activity (r -0.56, P < 0.001), fasting insulin (r -0.55, P < 0.001), and acute insulin response (r -0.40, P < 0.05); they were positively related to HDL cholesterol (r 0.48, P < 0.01) and S(i) (r 0.41, P < 0.01). Furthermore, when adjusted for age, waist, and S(i), adiponectin was associated with HDL cholesterol and proinsulin, which explained 51% of the variation in adiponectin in multiple regression analyses in that group. In conclusion, circulating plasma adiponectin levels were decreased in nonobese but insulin-resistant FDR and, in addition, related to several facets of the insulin resistance syndrome (IRS). Thus, hypoadiponectinemia may be an important component of the association between cardiovascular disease and IRS.

Novel LPL mutation (L303F) found in a patient associated with coronary artery disease and severe systemic atherosclerosis.

BACKGROUND: Patients with lipoprotein lipase (LPL) deficiency had been generally thought to be spared accelerated atherosclerosis in spite of a marked elevation of plasma triglyceride levels. However, it has been recently reported that some heterozygous and homozygous LPL-deficient patients are associated with premature atherosclerosis. In this paper, we report a 55-year-old type I hyperlipidaemic patient with a novel missense mutation in the LPL gene. PATIENT AND RESULTS: The patient had suffered from coronary artery disease, abdominal aortic aneurysm, and stenoses of the bilateral renal arteries and superficial femoral arteries. Sequencing of the genomic DNA revealed that the patient was a homozygote for the mutation, a G to C transition at nucleotide position 1069 in the exon 6, resulting in an amino acid substitution of Phe for Leu303 (L303F). Approximately 6% and approximately 40% of normal LPL activity and LPL mass, respectively, were detected in the patient's postheparin plasma. An in vitro expression study demonstrated that COS7 cells transfected with L303F mutant cDNA produced a 40% amount of LPL protein in cell lysates compared with normal cDNA, but no protein was detected in the media. Lipoprotein lipase activity was completely absent in both lysates and media of the cells transfected with the mutant cDNA, suggesting that this mutation in the LPL gene results in the production of a functionally inactive protein. CONCLUSION: This case suggests that the LPL missense mutation (L303F), which impairs lipolysis but preserves the LPL mass, is proatherogenic.