bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid–Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin
Authors: Li Xiao-Nan , Song Jun , Zhang Lin , LeMaire Scott A. , Hou Xiaoyang , Zhang Cheng , Coselli Joseph S. , Chen Li , Wang Xing Li , Zhang Yun , Shen Ying H. 
Published: July 2009

OBJECTIVE
Oxidative stress induced by free fatty acids contributes to the development of cardiovascular diseases in patients with metabolic syndrome. Reducing oxidative stress may attenuate these pathogenic processes. Activation of AMP-activated protein kinase (AMPK) has been reported to reduce intracellular reactive oxygen species (ROS) levels. The thioredoxin (Trx) system is a major antioxidant system. In this study, we investigated the mechanisms involved in the AMPK-mediated regulation of Trx expression and the reduction of intracellular ROS levels.

RESEARCH DESIGN AND METHODS
We observed that activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) significantly reduced ROS levels induced by palmitic acid in human aortic endothelial cells. Activation of AMPK increased expression of the antioxidant Trx, which mediated the ROS reduction. RT-PCR showed that AMPK regulated Trx at the transcriptional level.

RESULTS
Forkhead transcription factor 3 (FOXO3) was identified as the target transcription factor involved in the upregulation of Trx expression. FOXO3 bound to the Trx promoter, recruited the histone acetylase p300 to the Trx promoter, and formed a transcription activator complex, which was enhanced by AICAR treatment. AMPK activated FOXO3 by promoting its nuclear translocation. We further showed that AICAR injection increased the expression of Trx and decreased ROS production in the aortic wall of ApoE−/− mice fed a high-fat diet.

CONCLUSIONS
These results suggest that activation of the AMPK-FOXO3 pathway reduces ROS levels by inducing Trx expression. Thus, the AMPK-FOXO3-Trx axis may be an important defense mechanism against excessive ROS production induced by metabolic stress and could be a therapeutic target in treating cardiovascular diseases in metabolic syndrome.
Dyslipidemia-Induced Neuropathy in Mice
Authors: Vincent Andrea M. , Hayes John M. , McLean Lisa L. , Vivekanandan-Giri Anuradha , Pennathur Subramaniam , Feldman Eva L. 
Published: July 2009

OBJECTIVE
Neuropathy is a frequent and severe complication of diabetes. Multiple metabolic defects in type 2 diabetic patients result in oxidative injury of dorsal root ganglia (DRG) neurons. Our previous work focused on hyperglycemia clearly demonstrates induction of mitochondrial oxidative stress and acute injury in DRG neurons; however, this mechanism is not the only factor that produces neuropathy in vivo. Dyslipidemia also correlates with the development of neuropathy, even in pre-diabetic patients. This study was designed to explore the contribution of dyslipidemia in neuropathy.

RESEARCH DESIGN AND METHODS
Mice (n = 10) were fed a control (10% kcal %fat) or high-fat (45% kcal %fat) diet to explore the impact of plasma lipids on the development of neuropathy. We also examined oxidized lipid–mediated injury in cultured DRG neurons from adult rat using oxidized LDLs (oxLDLs).

RESULTS
Mice on a high-fat diet have increased oxLDLs and systemic and nerve oxidative stress. They develop nerve conduction velocity (NCV) and sensory deficits prior to impaired glucose tolerance. In vitro, oxLDLs lead to severe DRG neuron oxidative stress via interaction with the receptor lectin-like oxLDL receptor (LOX)-1 and subsequent NAD(P)H oxidase activity. Oxidative stress resulting from oxLDLs and high glucose is additive.

CONCLUSIONS
Multiple metabolic defects in type 2 diabetes directly injure DRG neurons through different mechanisms that all result in oxidative stress. Dyslipidemia leads to high levels of oxLDLs that may injure DRG neurons via LOX-1 and contribute to the development of diabetic neuropathy.
A Major Role for Perifornical Orexin Neurons in the Control of Glucose Metabolism in Rats
Authors: Yi Chun-Xia , Serlie Mireille J. , Ackermans Mariette T. , Foppen Ewout , Buijs Ruud M. , Sauerwein Hans P. , Fliers Eric , Kalsbeek Andries 
Published: July 2009

OBJECTIVE
The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats.

RESEARCH DESIGN AND METHODS
We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies.

RESULTS
Hypothalamic disinhibition of neuronal activity by the γ-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone–containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes.

CONCLUSIONS
Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.
Examination of Type 2 Diabetes Loci Implicates CDKAL1 as a Birth Weight Gene
Authors: Zhao Jianhua , Li Mingyao , Bradfield Jonathan P. , Wang Kai , Zhang Haitao , Sleiman Patrick , Kim Cecilia E. , Annaiah Kiran , Glaberson Wendy , Glessner Joseph T. , Otieno F. George , Thomas Kelly A. , Garris Maria , Hou Cuiping , Frackelton Edward C. , Chiavacci Rosetta M. , Berkowitz Robert I. , Hakonarson Hakon , Grant Struan F.A. 
Published: July 2009

OBJECTIVE
A number of studies have found that reduced birth weight is associated with type 2 diabetes later in life; however, the underlying mechanism for this correlation remains unresolved. Recently, association has been demonstrated between low birth weight and single nucleotide polymorphisms (SNPs) at the CDKAL1 and HHEX-IDE loci, regions that were previously implicated in the pathogenesis of type 2 diabetes. In order to investigate whether type 2 diabetes risk–conferring alleles associate with low birth weight in our Caucasian childhood cohort, we examined the effects of 20 such loci on this trait.

RESEARCH DESIGN AND METHODS
Using data from an ongoing genome-wide association study in our cohort of 5,465 Caucasian children with recorded birth weights, we investigated the association of the previously reported type 2 diabetes–associated variation at 20 loci including TCF7L2, HHEX-IDE, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B, and JAZF1 with birth weight.

RESULTS
Our data show that the minor allele of rs7756992 (P = 8 × 10−5) at the CDKAL1 locus is strongly associated with lower birth weight, whereas a perfect surrogate for variation previously implicated for the trait at the same locus only yielded nominally significant association (P = 0.01; r2 rs7756992 = 0.677). However, association was not detected with any of the other type 2 diabetes loci studied.

CONCLUSIONS
We observe association between lower birth weight and type 2 diabetes risk–conferring alleles at the CDKAL1 locus. Our data show that the same genetic locus that has been identified as a marker for type 2 diabetes in previous studies also influences birth weight.
Naringenin Prevents Dyslipidemia, Apolipoprotein B Overproduction, and Hyperinsulinemia in LDL Receptor–Null Mice With Diet-Induced Insulin Resistance
Authors: Mulvihill Erin E. , Allister Emma M. , Sutherland Brian G. , Telford Dawn E. , Sawyez Cynthia G. , Edwards Jane Y. , Markle Janet M. , Hegele Robert A. , Huff Murray W. 
Published: July 2009

OBJECTIVE
The global epidemic of metabolic syndrome and its complications demands rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin, has lipid-lowering properties and inhibits VLDL secretion from cultured hepatocytes in a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production and insulin sensitivity in the context of insulin resistance in vivo.

RESEARCH DESIGN AND METHODS
LDL receptor–null (Ldlr−/−) mice fed a high-fat (Western) diet (42% calories from fat and 0.05% cholesterol) become dyslipidemic, insulin and glucose intolerant, and obese. Four groups of mice (standard diet, Western, and Western plus 1% or 3% wt/wt naringenin) were fed ad libitum for 4 weeks. VLDL production and parameters of insulin and glucose tolerance were determined.

RESULTS
We report that naringenin treatment of Ldlr−/− mice fed a Western diet corrected VLDL overproduction, ameliorated hepatic steatosis, and attenuated dyslipidemia without affecting caloric intake or fat absorption. Naringenin 1) increased hepatic fatty acid oxidation through a peroxisome proliferator–activated receptor (PPAR) γ coactivator 1α/PPARα-mediated transcription program; 2) prevented sterol regulatory element–binding protein 1c–mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic cholesterol and cholesterol ester synthesis; 4) reduced both VLDL-derived and endogenously synthesized fatty acids, preventing muscle triglyceride accumulation; and 5) improved overall insulin sensitivity and glucose tolerance.

CONCLUSIONS
Thus, naringenin, through its correction of many of the metabolic disturbances linked to insulin resistance, represents a promising therapeutic approach for metabolic syndrome.
Generation of Novel Single-Chain Antibodies by Phage-Display Technology to Direct Imaging Agents Highly Selective to Pancreatic β- or α-Cells In Vivo
Authors: Ueberberg Sandra , Meier Juris J. , Waengler Carmen , Schechinger Wolfgang , Dietrich Johannes W. , Tannapfel Andrea , Schmitz Inge , Schirrmacher Ralf , Köller Manfred , Klein Harald H. , Schneider Stephan 
Published: July 2009

OBJECTIVE
Noninvasive determination of pancreatic β-cell mass in vivo has been hampered by the lack of suitable β-cell–specific imaging agents. This report outlines an approach for the development of novel ligands homing selectively to islet cells in vivo.

RESEARCH DESIGN AND METHODS
To generate agents specifically binding to pancreatic islets, a phage library was screened for single-chain antibodies (SCAs) on rat islets using two different approaches. 1) The library was injected into rats in vivo, and islets were isolated after a circulation time of 5 min. 2) Pancreatic islets were directly isolated, and the library was panned in the islets in vitro. Subsequently, the identified SCAs were extensively characterized in vitro and in vivo.

RESULTS
We report the generation of SCAs that bind highly selective to either β- or α-cells. These SCAs are internalized by target cells, disappear rapidly from the vasculature, and exert no toxicity in vivo. Specific binding to β- or α-cells was detected in cell lines in vitro, in rats in vivo, and in human tissue in situ. Electron microscopy demonstrated binding of SCAs to the endoplasmatic reticulum and the secretory granules. Finally, in a biodistribution study the labeling intensity derived from [125I]-labeled SCAs after intravenous administration in rats strongly predicted the β-cell mass and was inversely related to the glucose excursions during an intraperitoneal glucose tolerance test.

CONCLUSIONS
Our data provide strong evidence that the presented SCAs are highly specific for pancreatic β-cells and enable imaging and quantification in vivo.
Change in the Distribution of Albuminuria According to Estimated Glomerular Filtration Rate in Pima Indians With Type 2 Diabetes
Authors: Pavkov Meda E. , Mason Clinton C. , Bennett Peter H. , Curtis Jeffrey M. , Knowler William C. , Nelson Robert G. 
Published: July 2009

OBJECTIVE
We examined secular trends in the frequency distribution of albuminuria and estimated glomerular filtration rate (eGFR) in subjects with type 2 diabetes in 1982–1988 and 2001–2006, two periods associated with major changes in the management of diabetes.

RESEARCH DESIGN AND METHODS
The cross-sectional study included Pima Indians ≥15 years old with type 2 diabetes and measures of serum creatinine and urinary albumin-to-creatinine ratios (ACR). The continuous probability density distributions of ACR and eGFR were compared for the two time periods. eGFR was calculated using the Modification of Diet in Renal Disease Study equation.

RESULTS
The overall standardized distribution of ACR shifted toward lower values between time periods (P = 0.001), whereas the standardized distribution of eGFR did not (P = 0.45). In the first period, eGFR was &lt;60 ml/min per 1.73 m2 in 6.5% of the 837 subjects. Of these, 9.3% had normal ACR, 7.4% had microalbuminuria, and 83.3% had macroalbuminuria. In the second period, the prevalence of low eGFR was similar (6.6% of the 1,310 subjects). Among those with low eGFR, normal ACR prevalence doubled to 17.2%, microalbuminuria prevalence nearly tripled to 19.5%, and macroalbuminuria prevalence declined to 63.2%. Twice as many subjects in the second period received antihypertensive medicines and 30% more received hypoglycemic medicines than in the first period.

CONCLUSIONS
The distribution of albuminuria changed significantly among diabetic Pima Indians over the past 20 years, as treatment with medicines to control hyperglycemia and hypertension increased. The distribution of eGFR, however, remained unchanged. Consequently, the frequency of chronic kidney disease characterized by normoalbuminuria and low eGFR doubled.
Effects of Exercise Training Intensity on Pancreatic β-Cell Function
Authors: Slentz Cris A. , Tanner Charles J. , Bateman Lori A. , Durheim Michael T. , Huffman Kim M. , Houmard Joseph A. , Kraus William E. 
Published: July 2009

OBJECTIVEInsulin resistance and β-cell dysfunction both are important contributors to the pathogenesis of type 2 diabetes. Exercise training improves insulin sensitivity, but its effects on β-cell function are less well studied.RESEARCH DESIGN AND METHODSSedentary, overweight adults were randomized to control or one of three 8-month exercise programs: 1) low amount/moderate intensity, 2) low amount/vigorous intensity, or 3) high amount/vigorous intensity. Of 387 randomized, 260 completed the study and 237 had complete data. Insulin sensitivity (Si), acute insulin response to glucose (AIRg), and the disposition index (DI = Si × AIRg) were modeled from an intravenous glucose tolerance test.RESULTSCompared with control subjects, all three training programs led to increases in DI. However, the moderate-intensity group experienced a significantly larger increase in DI than either of the vigorous-intensity groups and through a different mechanism. The high-amount/vigorous-intensity group improved Si and had a compensatory reduction in AIRg, whereas the moderate-intensity group had a similar improvement in Si but almost no reduction in AIRg. Importantly, the inactive control group experienced a significant increase in fasting glucose.CONCLUSIONSTo the extent that the DI accurately reflects β-cell function, we observed that both moderate- and vigorous-intensity exercise training improved β-cell function, albeit through distinct mechanisms. It is not clear which of these mechanisms is preferable for maintenance of metabolic health. While moderate-intensity exercise led to a larger improvement in DI, which may reflect a transition toward a more normal DI, longer-term investigations would be necessary to determine which was more effective at reducing diabetes risk.
Association Between Type of Dietary Fish and Seafood Intake and the Risk of Incident Type 2 Diabetes
Authors: Patel Pinal S. , Sharp Stephen J. , Luben Robert N. , Khaw Kay-Tee , Bingham Sheila A. , Wareham Nicholas J. , Forouhi Nita G. 
Published: July 2009

OBJECTIVE
To investigate the association between fish and seafood intake and new-onset type 2 diabetes.

RESEARCH DESIGN AND METHODS
This was a population-based prospective cohort (European Prospective Investigation of Cancer [EPIC]-Norfolk) study of men and women aged 40–79 years at baseline (1993–1997). Habitual fish and seafood intake (white fish, oily fish, fried fish, and shellfish) was assessed using a semiquantitative food frequency questionnaire and categorized as less than one or one or more portions/week. During a median (interquartile range) follow-up of 10.2 (9.1–11.2) years, there were 725 incident diabetes cases among 21,984 eligible participants.

RESULTS
Higher total fish intake (one or more versus less than one portions/week) was associated with a significantly lower risk of diabetes (odds ratio [OR] 0.75 [95% CI 0.58–0.96]), in analyses adjusted for age, sex, family history of diabetes, education, smoking, physical activity, dietary factors (total energy intake, alcohol intake, and plasma vitamin C) and obesity (BMI and waist circumference). White fish and oily fish intakes were similarly inversely associated with diabetes risk, but the associations were not significant after adjustment for dietary factors (oily fish) or obesity (white fish). Fried fish was not significantly associated with diabetes risk. Consuming one or more portions/week of shellfish was associated with an increased risk of diabetes (OR 1.36 [1.02–1.81]) in adjusted analyses.

CONCLUSIONS
Total, white, and oily fish consumption may be beneficial for reducing risk of diabetes, reinforcing the public health message to consume fish regularly. Greater shellfish intake seems to be associated with an increased risk of diabetes, warranting further investigation into cooking methods and mechanisms.
Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes
Authors: Rosenstock Julio , Reusch Jane , Bush Mark , Yang Fred , Stewart Murray ,   for the Albiglutide Study Group
Published: July 2009

OBJECTIVE
To evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy.

RESEARCH DESIGN AND METHODS
In this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m2, A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16.

RESULTS
Dose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (−0.87, −0.79, and −0.87%, respectively) versus placebo (−0.17%, P &lt; 0.004) and exenatide (−0.54%). Weight loss (−1.1 to −1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide.

CONCLUSIONS
Weekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.
Hypertriglyceridemic Waist Phenotype Predicts Increased Visceral Fat in Subjects With Type 2 Diabetes
Authors: Sam Susan , Haffner Steven , Davidson Michael H. , D'Agostino Ralph B. , Feinstein Steven , Kondos George , Perez Alfonso , Mazzone Theodore 
Published: July 2009

OBJECTIVE
Greater accumulation of visceral fat is strongly linked to risk of cardiovascular disease. However, elevated waist circumference by itself does not always identify individuals with increased visceral fat.

RESEARCH DESIGN AND METHODS
We examined 375 subjects with type 2 diabetes from the CHICAGO cohort for presence of hypertriglyceridemic waist phenotype (waist circumference &gt;90 cm in men or &gt;85 cm in women, in conjunction with a plasma triglyceride concentration of ≥177 mg/dl) to determine its usefulness for identifying subjects with increased amounts of visceral fat. We divided subjects into three groups: group 1 (low waist circumference and low triglycerides; waist circumference ≤90 cm in men or ≤85 cm in women and triglyceride &lt;177 mg/dl, n = 18), group 2 (high waist circumference and low triglycerides; waist circumference &gt;90 cm in men or &gt;85 cm in women and triglycerides &lt;177 mg/dl, n = 230), and group 3 (high waist circumference and high triglycerides; waist circumference &gt;90 cm in men or &gt;85 cm in women and triglycerides ≥177 mg/dl, n = 127).

RESULTS
Subjects in group 3 had significantly higher visceral fat (P &lt; 0.0001), A1C (P &lt; 0.01), and coronary artery calcium (P &lt; 0.05) compared with group 2, despite similar age, BMI, and waist circumference. The relationship of the phenotype to atherosclerosis, however, was attenuated by adjustment for HDL cholesterol, triglyceride-rich lipoprotein cholesterol, apolipoprotein B, or LDL particle number.

CONCLUSIONS
The presence of hypertriglyceridemic waist phenotype in subjects with type 2 diabetes identifies a subset with greater degree of visceral adiposity. This subset also has greater degree of subclinical atherosclerosis that may be related to the proatherogenic lipoprotein changes.
Transforming Growth Factor-β1 and Incident Type 2 Diabetes
Authors: Herder Christian , Zierer Astrid , Koenig Wolfgang , Roden Michael , Meisinger Christa , Thorand Barbara 
Published: July 2009

OBJECTIVE
Subclinical inflammation leads to insulin resistance and β-cell dysfunction. This study aimed to assess whether levels of circulating transforming growth factor-β1 (TGF-β1)—a central, mainly immunosuppressive, and anti-inflammatory cytokine—were associated with incident type 2 diabetes.

RESEARCH DESIGN AND METHODS
We measured serum levels of TGF-β1 from 460 individuals with and 1,474 individuals without incident type 2 diabetes in a prospective case-cohort study within the population-based MONICA (MONItoring of Trends and Determinants in CArdiovascular Disease)/KORA (Cooperative Health Research in the Region of Augsburg) cohort.

RESULTS
Elevated TGF-β1 concentrations were associated with higher, not lower, risk for type 2 diabetes (age-, sex-, and survey-adjusted hazard ratios [95% CI] for increasing TGF-β1 tertiles: 1.0, 1.08 [0.83–1.42], and 1.41 [1.08–1.83]; Pfor trend = 0.012). Adjustment for BMI and metabolic and lifestyle factors had virtually no impact on the effect size.

CONCLUSIONS
Elevated serum concentrations of the cytokine TGF-β1 indicate an increased risk for type 2 diabetes. TGF-β1 may be upregulated to counterbalance metabolic and immunological disturbances preceding type 2 diabetes.