bluuebunny/crossref_metadata_2025 huggingface dataset:
High Glucose, High Insulin, and Their Combination Rapidly Induce Laminin-β1 Synthesis by Regulation of mRNA Translation in Renal Epithelial Cells
Authors: Mariappan Meenalakshmi M. , Feliers Denis , Mummidi Srinivas , Choudhury Goutam Ghosh , Kasinath Balakuntalam S.
Published: January 2007

Laminin is a glycoprotein that contributes to renal extracellular matrix expansion in diabetes. We investigated regulation of laminin-β1 synthesis in murine renal proximal tubular epithelial cells by 30 mmol/l glucose (high glucose), 1 nmol/l insulin (high insulin), and their combination (high glucose+high insulin), simulating conditions observed during progression of type 2 diabetes. Compared with 5 mmol/l glucose and no insulin (control), high glucose alone, high insulin alone, or high glucose+high insulin together increased laminin-β1 chain protein synthesis within 5 min, lasting for up to 60 min with no change in laminin-β1 mRNA levels. Cycloheximide, but not actinomycin-D, abrogated increased laminin-β1 synthesis. High glucose, high insulin, and high glucose+high insulin stimulated phosphorylation of 4E-BP1, a repressor binding protein for eukaryotic initiation factor 4E (eIF4E), that was dependent on activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin. High glucose, high insulin, and high glucose+high insulin also promoted release of eIF4E from 4E-BP1, phosphorylation of eIF4E, and increase in eIF4E association with eIF4G, critical events in the initiation phase of mRNA translation. High glucose, high insulin, and high glucose+high insulin increased Erk phosphorylation, which is an upstream regulator of eIF4E phosphorylation, and PD098059, which is a MEK inhibitor that blocks Erk activation, abolished laminin-β1 synthesis. This is the first demonstration of rapid increment in laminin-β1 synthesis by regulation of its mRNA translation by cells exposed to high glucose, high insulin, or high glucose+high insulin.
Oral Insulin-Mimetic Compounds That Act Independently of Insulin
Authors: García-Vicente Silvia , Yraola Francesc , Marti Luc , González-Muñoz Elena , García-Barrado María José , Cantó Carles , Abella Anna , Bour Sandy , Artuch Rafael , Sierra Cristina , Brandi Nuria , Carpéné Christian , Moratinos Julio , Camps Marta , Palacín Manuel , Testar Xavier , Gumà Anna , Albericio Fernando , Royo Miriam , Mian Alec , Zorzano Antonio
Published: January 2007

The hallmarks of insulin action are the stimulation and suppression of anabolic and catabolic responses, respectively. These responses are orchestrated by the insulin pathway and are initiated by the binding of insulin to the insulin receptor, which leads to activation of the receptor’s intrinsic tyrosine kinase. Severe defects in the insulin pathway, such as in types A and B and advanced type 1 and 2 diabetes lead to severe insulin resistance, resulting in a partial or complete absence of response to exogenous insulin and other known classes of antidiabetes therapies. We have characterized a novel class of arylalkylamine vanadium salts that exert potent insulin-mimetic effects downstream of the insulin receptor in adipocytes. These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. Administration of these compounds to animal models of diabetes lowered glycemia and normalized the plasma lipid profile. Arylalkylamine vanadium compounds also showed antidiabetic effects in severely diabetic rats with undetectable circulating insulin. These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. This represents a novel therapeutic approach for diabetic patients with severe insulin resistance.
Macrophage Scavenger Receptor-A–Deficient Mice Are Resistant Against Diabetic Nephropathy Through Amelioration of Microinflammation
Authors: Usui Hitomi Kataoka , Shikata Kenichi , Sasaki Motofumi , Okada Shinichi , Matsuda Mitsuhiro , Shikata Yasushi , Ogawa Daisuke , Kido Yuichi , Nagase Ryo , Yozai Kosuke , Ohga Sakiko , Tone Atsuhito , Wada Jun , Takeya Motohiro , Horiuchi Seikoh , Kodama Tatsuhiko , Makino Hirofumi
Published: January 2007

Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A–deficient (SR-A−/−) mice. Diabetes was induced in SR-A−/− and wild-type (SR-A+/+) mice by streptozotocin injection. Diabetic SR-A+/+ mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-β at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A−/− mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A−/− mice compared with diabetic SR-A+/+ mice. DNA microarray revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A+/+ mice and suppressed in diabetic SR-A−/− mice. Moreover, anti–SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications.
Glucose-Dependent Regulation of γ-Aminobutyric Acid (GABAA) Receptor Expression in Mouse Pancreatic Islet α-Cells
Authors: Bailey Sarah J. , Ravier Magalie A. , Rutter Guy A.
Published: January 2007

The mechanism(s) by which glucose regulates glucagon secretion both acutely and in the longer term remain unclear. Added to isolated mouse islets in the presence of 0.5 mmol/l glucose, γ-aminobutyric acid (GABA) inhibited glucagon release to a similar extent (46%) as 10 mmol/l glucose (55%), and the selective GABAA receptor (GABAAR) antagonist SR95531 substantially reversed the inhibition of glucagon release by high glucose. GABAAR α4, β3, and γ2 subunit mRNAs were detected in mouse islets and clonal αTC1-9 cells, and immunocytochemistry confirmed the presence of GABAARs at the plasma membrane of primary α-cells. Glucose dose-dependently increased GABAAR expression in both islets and αTC1-9 cells such that mRNA levels at 16 mmol/l glucose were ∼3.0-fold (α4), 2.0-fold (β3), or 1.5-fold (γ2) higher than at basal glucose concentrations (2.5 or 1.0 mmol/l, respectively). These effects were mimicked by depolarizing concentrations of K+ and reversed by the L-type Ca2+ channel blocker nimodipine. We conclude that 1) release of GABA from neighboring β-cells contributes substantially to the acute inhibition of glucagon secretion from mouse islets by glucose and 2) that changes in GABAAR expression, mediated by changes in intracellular free Ca2+ concentration, may modulate this response in the long term.
Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1
Authors: de Heer Jocelyn , Holst Jens J.
Published: January 2007

Glucagon-like peptide (GLP)-1 mimetics have been reported to cause hypoglycemia when combined with sulfonylureas. This study investigated the impact of tolbutamide on the glucose dependence of the GLP-1–mediated effects on insulin, glucagon, and somatostatin secretion in the in situ perfused rat pancreas. At 3 mmol/l glucose, GLP-1 alone did not augment insulin secretion, whereas tolbutamide alone caused a rapid increase in insulin secretion. However, when GLP-1 and tolbutamide were administered simultaneously, insulin secretion increased significantly to 43.7 ± 6.2 pmol/min (means ± SE), exceeding the sum of the responses to GLP-1 (2.0 ± 0.6 pmol/min; P = 0.019) and tolbutamide (11.3 ± 3.8; P = 0.005) alone by a factor of 3.3. At 11 mmol/l glucose, co-infusion of GLP-1 and tolbutamide augmented insulin secretion to 141.7 ± 10.3 vs. 115.36 ± 14.1 (GLP-1) and 42.5 ± 7.3 pmol/min (tolbutamide). Interestingly, increases in somatostatin secretion, both by glucose and GLP-1, were consistently paralleled by suppression of glucagon release. In conclusion, we demonstrate uncoupling of GLP-1 from its glucose dependence by tolbutamide. This uncoupling probably explains the tendency of GLP-1 to provoke hypoglycemia in combination with sulfonylureas. The results suggest that closure of ATP-sensitive K+ channels by glucose might be involved in the glucose dependence of GLP-1’s insulinotropic effect and that somatostatin acts as a paracrine regulator of glucagon release.
Glucotoxicity in the INS-1 Rat Insulinoma Cell Line Is Mediated by the Orphan Nuclear Receptor Small Heterodimer Partner
Authors: Park Keun-Gyu , Lee Kyeong-Min , Seo Hye-Young , Suh Ji-Ho , Kim Hye-Soon , Wang Li , Won Kyu-Chang , Lee Hyoung-Woo , Park Joong-Yeol , Lee Ki-Up , Kim Jung-Guk , Kim Bo-Wan , Choi Hueng-Sik , Lee In-Kyu
Published: January 2007

Prolonged elevations of glucose concentration have deleterious effects on β-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that inhibits nuclear receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose–induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1–and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of β-cell dysfunction induced by glucotoxicity.
Haplotypes of Transcription Factor 7–Like 2 (TCF7L2) Gene and Its Upstream Region Are Associated With Type 2 Diabetes and Age of Onset in Mexican Americans
Authors: Lehman Donna M. , Hunt Kelly J. , Leach Robin J. , Hamlington Jeanette , Arya Rector , Abboud Hanna E. , Duggirala Ravindranath , Blangero John , Göring Harald H.H. , Stern Michael P.
Published: January 2007

TCF7L2 acts as both a repressor and transactivator of genes, as directed by the Wnt signaling pathway. Recently, several highly correlated sequence variants located within a haplotype block of the TCF7L2 gene were observed to associate with type 2 diabetes in three Caucasian cohorts. We previously reported linkage of type 2 diabetes in the San Antonio Family Diabetes Study (SAFADS) cohort consisting of extended pedigrees of Mexican Americans to the region of chromosome 10q harboring TCF7L2. We therefore genotyped 11 single nucleotide polymorphisms (SNPs) from nine haplotype blocks across the gene in 545 SAFADS subjects (178 diabetic) to investigate their role in diabetes pathogenesis. We observed nominal association between four SNPs (rs10885390, rs7903146, rs12255372, and rs3814573) in three haplotype blocks and type 2 diabetes, age at diagnosis, and 2-h glucose levels (P = 0.001–0.055). Furthermore, we identified a common protective haplotype defined by these four SNPs that was significantly associated with type 2 diabetes and age at diagnosis (P = 4.2 × 10−5, relative risk [RR] 0.69; P = 6.7 × 10−6, respectively) and a haplotype that confers diabetes risk that contains the rare alleles at SNPs rs10885390 and rs12255372 (P = 0.02, RR 1.64). These data provide evidence that variation in the TCF7L2 genomic region may affect risk for type 2 diabetes in Mexican Americans, but the attributable risk may be lower than in Caucasian populations.
The Rab GTPase-Activating Protein AS160 Integrates Akt, Protein Kinase C, and AMP-Activated Protein Kinase Signals Regulating GLUT4 Traffic
Authors: Thong Farah S.L. , Bilan Philip J. , Klip Amira
Published: January 2007

Insulin-dependent phosphorylation of Akt target AS160 is required for GLUT4 translocation. Insulin and platelet-derived growth factor (PDGF) (Akt activators) or activation of conventional/novel (c/n) protein kinase C (PKC) and 5′ AMP-activated protein kinase (AMPK) all promote a rise in membrane GLUT4 in skeletal muscle and cultured cells. However, the downstream effectors linking these pathways to GLUT4 traffic are unknown. Here we explore the hypothesis that AS160 is a molecular link among diverse signaling cascades converging on GLUT4 translocation. PDGF and insulin increased AS160 phosphorylation in CHO-IR cells. Stimuli that activate c/n PKC or AMPK also elevated AS160 phosphorylation. We therefore examined if these signaling pathways engage AS160 to regulate GLUT4 traffic in muscle cells. Nonphosphorylatable AS160 (4P-AS160) virtually abolished the net surface GLUT4myc gains elicited by insulin, PDGF, K+ depolarization, or 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside but partly, yet significantly, inhibited the effects of 4-phorbol-12-myristate-13-acetate. However, the hypertonicity or 2,4-dinitrophenol–dependent gains in surface GLUT4myc were unaffected by 4P-AS160. RK-AS160 (GTPase-activating protein [GAP] inactive) or 4PRK-AS160 (GAP inactive, nonphosphorylatable) had no effect on surface GLUT4myc elicited by all stimuli. Collectively, these results indicate that activation of Akt, c/n PKC, or α2-AMPK intersect at AS160 to regulate GLUT4 traffic, as well as highlight the potential of AS160 as a therapy target to increase muscle glucose uptake.
Type 2 Diabetes–Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program
Authors: Florez Jose C. , Jablonski Kathleen A. , Kahn Steven E. , Franks Paul W. , Dabelea Dana , Hamman Richard F. , Knowler William C. , Nathan David M. , Altshuler David ,   for the Diabetes Prevention Program Research Groupy
Published: January 2007

The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over ∼3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-to-diabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation.
Cellular Expression Requirements for Inhibition of Type 1 Diabetes by a Dominantly Protective Major Histocompatibility Complex Haplotype
Authors: Chen Yi-Guang , Silveira Pablo A. , Osborne Melissa A. , Chapman Harold D. , Serreze David V.
Published: January 2007

The H2g7 (Kd, Ag7, Enull, and Db) major histocompatibility complex (MHC) is the primary genetic contributor to type 1 diabetes in NOD mice. NOD stocks congenically expressing other MHC haplotypes such as H2nb1 (Kb, Anb1, Ek, and Db) in a heterozygous state are type 1 diabetes resistant. Hematopoietically derived antigen-presenting cells (APCs) expressing H2nb1 MHC molecules delete or inactivate autoreactive diabetogenic T-cells. Thus, provided a relatively benign preconditioning protocol is ultimately developed, hematopoietic chimerization by APCs expressing dominantly protective MHC molecules could conceivably provide a means for type 1 diabetes prevention in humans. Before hematopoietic chimerization can be considered for type 1 diabetes prevention, it must be determined what subtype(s) of APCs (B-cells, macrophages, and/or dendritic cells) expressing protective MHC molecules most efficiently inhibit disease, as well as the engraftment level they must achieve to accomplish this. These issues were addressed through analyses of NOD background bone marrow chimeras in which H2nb1 molecules were selectively expressed on variable proportions of different APC subtypes. While a modest B-cell effect was observed, the strongest type 1 diabetes protection resulted from at least 50% of dendritic cells and macrophages expressing H2nb1 molecules. At this engraftment level, H2nb1-expressing dendritic cells and macrophages mediated virtually complete deletion of a highly pathogenic CD8 T-cell population.
Impact of Self-Reported Patient Characteristics Upon Assessment of Glycemic Control in the Veterans Health Administration
Authors: Maney Miriam , Tseng Chin-Lin , Safford Monika M. , Miller Donald R. , Pogach Leonard M.
Published: January 2007

OBJECTIVE— The purpose of this article was to evaluate the impact of self-reported patient factors on quality assessment of Veterans Health Administration medical centers in achieving glycemic control.

RESEARCH DESIGN AND METHODS— We linked survey data and administrative records for veterans who self-reported diabetes on a 1999 national weighted survey. Linear regression models were used to adjust A1C levels in fiscal year 2000 for socioeconomic status (education level, employment, and concerns of having enough food), social support (marital status and living alone), health behaviors (smoking, alcohol use, and exercise level), physical and mental health status, BMI, and diabetes duration. Medical centers were ranked by deciles, with and without adjustment for patient characteristics, on proportions of patients achieving A1C <7 or <8%.

RESULTS— There was substantial medical center level variation in patient characteristics of the 56,740 individuals from 105 centers, e.g., grade school education (mean 15.3% [range 2.3–32.7%]), being retired (38.3% [19.9−59.7%]) or married (65.2% [43.7–77.8%]), food insufficiency (13.9% [7.2–24.6%]), and no reported exercise (43.2% [31.1–53.6%]). The final model had an R2 of 7.8%. The Spearman rank coefficient comparing the thresholds adjusted only for age and sex to the full model was 0.71 for <7% and 0.64 for <8% (P < 0.0001). After risk adjustment, 4 of the 11 best-performing centers changed at least two deciles for the <7% threshold, and 2 of 11 changed two deciles for the <8% threshold.

CONCLUSIONS— Adjustment for patient self-reported socioeconomic status and health impacts medical center rankings for glycemic control, suggesting the need for risk adjustment to assure valid inferences about quality.
Physical Activity in U.S. Adults With Diabetes and At Risk for Developing Diabetes, 2003
Authors: Morrato Elaine H. , Hill James O. , Wyatt Holly R. , Ghushchyan Vahram , Sullivan Patrick W.
Published: January 2007

OBJECTIVE—Given the risk of obesity and diabetes in the U.S., and clear benefit of exercise in disease prevention and management, this study aimed to determine the prevalence of physical activity among adults with and at risk for diabetes.

RESEARCH DESIGN AND METHODS—The Medical Expenditure Panel Survey is a nationally representative survey of the U.S. population. In the 2003 survey, 23,283 adults responded when asked about whether they were physically active (moderate or vigorous activity, ≥30 min, three times per week). Information on sociodemographic characteristics and health conditions were self-reported. Additional type 2 diabetes risk factors examined were age ≥45 years, non-Caucasian ethnicity, BMI ≥25 kg/m2, hypertension, and cardiovascular disease.

RESULTS—A total of 39% of adults with diabetes were physically active versus 58% of adults without diabetes. The proportion of active adults without diabetes declined as the number of risk factors increased until dropping to similar rates as people with diabetes. After adjustment for sociodemographic and clinical factors, the strongest correlates of being physically active were income level, limitations in physical function, depression, and severe obesity (BMI ≥40 kg/m2). Several traditional predictors of activity (sex, education level, and having received past advice from a health professional to exercise more) were not evident among respondents with diabetes.

CONCLUSIONS—The majority of patients with diabetes or at highest risk for developing type 2 diabetes do not engage in regular physical activity, with a rate significantly below national norms. There is a great need for efforts to target interventions to increase physical activity in these individuals.
Effect of Periodontitis on Overt Nephropathy and End-Stage Renal Disease in Type 2 Diabetes
Authors: Shultis Wendy A. , Weil E. Jennifer , Looker Helen C. , Curtis Jeffrey M. , Shlossman Marc , Genco Robert J. , Knowler William C. , Nelson Robert G.
Published: January 2007

OBJECTIVE—The purpose of this study was to investigate the effect of periodontitis on development of overt nephropathy, defined as macroalbuminuria, and end-stage renal disease (ESRD) in type 2 diabetes.

RESEARCH DESIGN AND METHODS—Individuals residing in the Gila River Indian Community aged ≥25 years with type 2 diabetes, one or more periodontal examination, estimated glomerular filtration rate ≥60 ml/min per 1.73 m2, and no macroalbuminuria (urinary albumin-to-creatinine ratio ≥300 mg/g) were identified. Periodontitis was classified as none/mild, moderate, severe, or edentulous using number of teeth and alveolar bone score. Subjects were followed to development of macroalbuminuria or ESRD, defined as onset of renal replacement therapy or death attributed to diabetic nephropathy.

RESULTS—Of the 529 individuals, 107 (20%) had none/mild periodontitis, 200 (38%) had moderate periodontitis, 117 (22%) had severe periodontitis, and 105 (20%) were edentulous at baseline. During follow-up of up to 22 years, 193 individuals developed macroalbuminuria and 68 developed ESRD. Age- and sex-adjusted incidence of macroalbuminuria and ESRD increased with severity of periodontitis. After adjustment for age, sex, diabetes duration, BMI, and smoking in a proportional hazards model, the incidences of macroalbuminuria were 2.0, 2.1, and 2.6 times as high in individuals with moderate or severe periodontitis or those who were edentulous, respectively, compared with those with none/mild periodontitis (P = 0.01). Incidences of ESRD in individuals with moderate or severe periodontitis or in those who were edentulous were 2.3, 3.5, and 4.9 times as high, respectively, compared with those with none/mild periodontitis (P = 0.02).

CONCLUSIONS—Periodontitis predicts development of overt nephropathy and ESRD in individuals with type 2 diabetes. Whether treatment of periodontitis will reduce the risk of diabetic kidney disease remains to be determined.
Serum Adiponectin and Renal Dysfunction in Men With Type 2 Diabetes
Authors: Lin Julie , Hu Frank B. , Curhan Gary
Published: January 2007

OBJECTIVE—Inflammation is associated with both chronic kidney dysfunction and type 2 diabetes. Adiponectin, a novel circulating anti-inflammatory protein made by adipocytes, has been reported to be lower in diabetic than nondiabetic subjects. In contrast, serum levels of adiponectin are elevated in end-stage renal disease. We sought to investigate the relation between adiponectin and mild to moderate renal dysfunction in men with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Multivariate logistic regression was used to evaluate the relation between serum adiponectin concentrations and the presence of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m2 by the four-variable Modification of Diet in Renal Disease equation) in participants with type 2 diabetes in the Health Professionals’ Follow-Up Study. A total of 733 men were included in this cross-sectional analysis.

RESULTS—Adiponectin was positively correlated with age (Spearman coefficient, r = 0.19, P < 0.001) and negatively correlated with weight (Spearman coefficient, r = −0.18, P < 0.001). Those with adiponectin in the second quartile or higher (>10 μg/ml) compared with those in the first quartile had a reduced odds for renal dysfunction (multivariate odds ratio 0.48 [95% CI 0.28–0.81]). These results were unchanged when serum lipids were included in the multivariate model.

CONCLUSIONS—We conclude that a higher serum adiponectin concentration is associated with reduced odds of moderate renal dysfunction in men with type 2 diabetes.
Total and High–Molecular Weight Adiponectin in Relation to Metabolic Variables at Baseline and in Response to an Exercise Treatment Program
Authors: Blüher Matthias , Brennan Aoife M. , Kelesidis Theodoros , Kratzsch Jürgen , Fasshauer Mathias , Kralisch Susan , Williams Catherine J. , Mantzoros Christos S.
Published: January 2007

OBJECTIVE—Adiponectin, an adipocyte-secreted hormone, circulates in the serum in several multimeric forms. Compared with total adiponectin, high–molecular weight (HMW) adiponectin has been suggested to be a better predictor of metabolic parameters and insulin sensitivity in humans. Our objective was to compare total adiponectin with HMW adiponectin as predictors of metabolic variables and insulin sensitivity at both baseline and after an exercise intervention.

RESEARCH DESIGN AND METHODS—We obtained blood samples from 60 men and women with normal glucose tolerance (n = 20), impaired glucose tolerance (IGT) (n = 20), or type 2 diabetes (n = 20) at baseline and after 4 weeks of training to measure metabolic variables. Using commercially available assays, we measured plasma total adiponectin using LINCO, Mediagnost, and ALPCO assays and HMW adiponectin using an ALPCO assay.

RESULTS—HMW adiponectin and total adiponectin (ALPCO) had similar ability to predict the presence of insulin resistance. Total adiponectin, as measured by radioimmunoassay (LINCO) and enzyme-linked immunosorbent assay (ELISA) (Mediagnost), correlated most strongly with measures of insulin sensitivity (P < 0.01) and lipid profile (P < 0.01) at baseline, showed greater improvements of adiponectin levels (P < 0.001), was more closely associated with improvements of lipid measures with exercise training (P < 0.01), and more accurately predicted insulin resistance and IGT in comparison with total adiponectin or HMW measured with the ALPCO ELISA.

CONCLUSIONS—These results do not support the superiority of HMW over total adiponectin (measured using currently available assays) in assessing metabolic variables at baseline or in response to physical training. Moreover, there are significant differences in the ability of commercially available assays for total adiponectin to predict metabolic variables.
Progression From Newly Acquired Impaired Fasting Glusose to Type 2 Diabetes
Authors: Nichols Gregory A. , Hillier Teresa A. , Brown Jonathan B.
Published: January 2007

OBJECTIVE—We sought to estimate the rate of progression from newly acquired (incident) impaired fasting glucose (IFG) to diabetes under the old and new IFG criteria and to identify predictors of progression to diabetes.

RESEARCH DESIGN AND METHODS—We identified 5,452 members of an HMO with no prior history of diabetes, with at least two elevated fasting glucose tests (100–125 mg/dl) measured between 1 January 1994 and 31 December 2003, and with a normal fasting glucose test before the two elevated tests. All data were obtained from electronic records of routine clinical care. Subjects were followed until they developed diabetes, died, left the health plan, or until 31 December 2005.

RESULTS—Overall, 8.1% of subjects whose initial abnormal fasting glucose was 100–109 mg/dl (added IFG subjects) and 24.3% of subjects whose initial abnormal fasting glucose was 110–125 mg/dl (original IFG subjects) developed diabetes (P < 0.0001). Added IFG subjects who progressed to diabetes did so within a mean of 41.4 months, a rate of 1.34% per year. Original IFG subjects converted at a rate of 5.56% per year after an average of 29.0 months. A steeper rate of increasing fasting glucose; higher BMI, blood pressure, and triglycerides; and lower HDL cholesterol predicted diabetes development.

CONCLUSIONS—To our knowledge, these are the first estimates of diabetes incidence from a clinical care setting when the date of IFG onset is approximately known under the new criterion for IFG. The older criterion was more predictive of diabetes development. Many newly identified IFG patients progress to diabetes in <3 years, which is the currently recommended screening interval.
Visceral Fatness and Insulin Sensitivity in Women With a Previous History of Gestational Diabetes Mellitus
Authors: Lim Soo , Choi Sung Hee , Park Young Joo , Park Kyong Soo , Lee Hong Kyu , Jang Hak C. , Cho Nam H. , Metzger Boyd E.
Published: January 2007

OBJECTIVE—The purpose of this study was to investigate the insulin sensitivity and visceral fatness in women with previous gestational diabetes mellitus (GDM), who are prone to develop type 2 diabetes.

RESEARCH DESIGN AND METHODS—A 75-g oral glucose tolerance test (OGTT) performed 1 year postpartum identified 21 GAD− women with previous GDM and impaired glucose tolerance (GDM-IGT). Sixty age- and BMI-matched women with normal glucose tolerance (GDM-NGT) were selected by 1:3 matching to the GDM-IGT group. Another 18 women with normal glucose metabolism during a previous pregnancy and no family history of diabetes were recruited as the normal control group. Age and BMI matching was performed using a range of ±1.0 years and ±1.0 kg/m2, respectively. Total body fat was measured by tetrapolar bioelectrical impedance, and visceral fat was determined using a single cut of a computed tomography scan. Insulin sensitivity was determined by the minimal model technique using the frequently sampled intravenous glucose tolerance test.

RESULTS—One year postpartum, visceral fat was greater in the GDM-IGT group than in the age- and BMI-matched GDM-NGT or normal control groups. The insulin sensitivity index was lower in the GDM-IGT group than in the GDM-NGT or normal control groups. β-Cell function, as measured by the acute insulin response to glucose, was also lower in GDM-IGT.

CONCLUSIONS—High body fat content, especially visceral fat content, and a low insulin response to glucose seem to contribute simultaneously to the development of impaired glucose metabolism in Korean women with previous GDM.
Probe-to-Bone Test for Diagnosing Diabetic Foot Osteomyelitis
Authors: Lavery Lawrence A. , Armstrong David G. , Peters Edgar J.G. , Lipsky Benjamin A.
Published: January 2007

OBJECTIVE—We sought to assess the accuracy of the probe-to-bone (PTB) test in diagnosing foot osteomyelitis in a cohort of diabetic patients with bone culture proven disease.

RESEARCH DESIGN AND METHODS—In this 2-year longitudinal cohort study, we enrolled 1,666 consecutive diabetic individuals who underwent an initial standardized detailed foot assessment, followed by examinations at regular intervals. Patients were instructed to immediately come to the foot clinic if they developed a lower-extremity complication. For all patients with a lower-extremity wound, we compared the results of the PTB test with those of a culture of the affected bone. We called PTB positive if the bone or joint was palpable and defined osteomyelitis as a positive bone culture.

RESULTS—Over a mean of 27.2 months of follow-up, 247 patients developed a foot wound and 151 developed 199 foot infections. Osteomyelitis was found in 30 patients: 12% of those with a foot wound and 20% in those with a foot infection. When all wounds were considered, the PTB test was highly sensitive (0.87) and specific (0.91); the positive predictive value was only 0.57, but the negative predictive value was 0.98.

CONCLUSIONS—The PTB test, when used in a population of diabetic patients with a foot wound among whom the prevalence of osteomyelitis was 12%, had a relatively low positive predictive value, but a negative test may exclude the diagnosis.
The Loss of Postprandial Glycemic Control Precedes Stepwise Deterioration of Fasting With Worsening Diabetes
Authors: Monnier Louis , Colette Claude , Dunseath Gareth J. , Owens David R.
Published: January 2007

OBJECTIVE— The aim of the study was to determine whether the loss of fasting and postprandial glycemic control occurs in parallel or sequentially in the evolution of type 2 diabetes.

RESEARCH DESIGN AND METHODS— In 130 type 2 diabetic patients, 24-h glucose profiles were obtained using a continuous glucose monitoring system. The individuals with type 2 diabetes were divided into five groups according to A1C levels: 1 (<6.5%, n = 30), 2 (6.5–6.9%, n = 17), 3 (7–7.9%, n = 32), 4 (8–8.9%, n = 25), and 5 (≥9%, n = 26). The glucose profiles between the groups were compared. The overall glucose concentrations for the diurnal, nocturnal, and morning periods, which represent the postprandial, fasting, and the dawn phenomenon states, respectively, were also compared.

RESULTS— Glucose concentrations increased steadily from group 1 to 5 in a stepwise manner. The initial differences in mean glucose concentrations reaching statistical significance occurred 1) between groups 1 and 2 (6.4 vs. 7.7 mmol/l, P = 0.0004) for daytime postprandial periods, followed by differences; 2) between groups 2 and 3 (7.5 vs. 9.3 mmol/l, P = 0.0003) for the morning periods (dawn phenomenon); and finally 3) between groups 3 and 4 (6.3 vs. 8.4 mmol/l, P < 0.0001) for nocturnal fasting periods.

CONCLUSIONS— The deterioration of glucose homeostasis in individuals with type 2 diabetes progressed from postprandial to fasting hyperglycemia following a three-step process. The first step related to the three diurnal postmeal periods considered as a whole, the second step occurred during the morning period, and the third and final step corresponded to sustained hyperglycemia over the nocturnal fasting periods. Such a description of the key stages in the evolution of type 2 diabetes may be of interest for implementing antidiabetes treatment.
Retinopathy Predicts Cardiovascular Mortality in Type 2 Diabetic Men and Women
Authors: Juutilainen Auni , Lehto Seppo , Rönnemaa Tapani , Pyörälä Kalevi , Laakso Markku
Published: January 2007

OBJECTIVE—To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences.

RESEARCH DESIGN AND METHODS—Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality.

RESULTS—Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98–1.83), 1.30 (0.86–1.96), and 1.18 (0.74–1.89), respectively, for background retinopathy and 3.05 (1.70–5.45), 3.32 (1.61–6.78), and 2.54 (1.07–6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17–2.22), 1.71 (1.17–2.51), and 1.79 (1.13–2.85), respectively, for background retinopathy and 2.92 (1.41–6.06), 3.17 (1.38–7.30), and 4.98 (2.06–12.06), respectively, for proliferative retinopathy.

CONCLUSIONS—Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination.
Comparison of Vildagliptin and Rosiglitazone Monotherapy in Patients With Type 2 Diabetes
Authors: Rosenstock Julio , Baron Michelle A. , Dejager Sylvie , Mills David , Schweizer Anja
Published: January 2007

OBJECTIVE—To compare the efficacy and tolerability of vildagliptin and rosiglitazone during a 24-week treatment in drug-naïve patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—This was a double-blind, randomized, active-controlled, parallel-group, multicenter study of 24-week treatment with vildagliptin (100 mg daily, given as equally divided doses; n = 519) or rosiglitazone (8 mg daily, given as a once-daily dose; n = 267).

RESULTS—Monotherapy with vildagliptin and rosiglitazone decreased A1C (baseline = 8.7%) to a similar extent during the 24-week treatment, with most of the A1C reduction achieved by weeks 12 and 16, respectively. At end point, vildagliptin was as effective as rosiglitazone, improving A1C by −1.1 ± 0.1% (P < 0.001) and −1.3 ± 0.1% (P < 0.001), respectively, meeting the statistical criterion for noninferiority (upper-limit 95% CI for between-treatment difference ≤0.4%). Fasting plasma glucose decreased more with rosiglitazone (−2.3 mmol/l) than with vildagliptin (−1.3 mmol/l). Body weight did not change in vildagliptin-treated patients (−0.3 ± 0.2 kg) but increased in rosiglitazone-treated patients (+1.6 ± 0.3 kg, P < 0.001 vs. vildagliptin). Relative to rosiglitazone, vildagliptin significantly decreased triglycerides, total cholesterol, and LDL, non-HDL, and total-to-HDL cholesterol (−9 to −16%, all P ≤ 0.01) but produced a smaller increase in HDL cholesterol (+4 vs. +9%, P = 0.003). The proportion of patients experiencing an adverse event was 61.4 vs. 64.0% in patients receiving vildagliptin and rosiglitazone, respectively. Only one mild hypoglycemic episode was experienced by one patient in each treatment group, while the incidence of edema was greater with rosiglitazone (4.1%) than vildagliptin (2.1%).

CONCLUSIONS—Vildagliptin is an effective and well-tolerated treatment option in patients with type 2 diabetes, demonstrating similar glycemic reductions as rosiglitazone but without weight gain.
Thiazolidinediones and Risk of Repeat Target Vessel Revascularization Following Percutaneous Coronary Intervention
Authors: Riche Daniel M. , Valderrama Rodrigo , Henyan Nickole N.
Published: January 2007

OBJECTIVE—Thiazolidinediones (TZDs) (rosiglitazone and pioglitazone) are a class of antidiabetes agents that have a high affinity for peroxisome proliferator–activated receptor-γ. TZDs initiate a multitude of physiologic processes that may elicit benefits as systemic agents for the prevention of restenosis requiring revascularization following percutaneous coronary intervention (PCI). Numerous trials have evaluated the impact of TZDs on repeat target vessel revascularization (TVR) in patients following PCI; however, several limitations (small sample size, inconclusive results, and risk factor stratification) complicate definitive conclusions. A meta-analysis was performed to evaluate the impact of TZDs on repeat TVR following PCI.

RESEARCH DESIGN AND METHODS—Included trials met the following criteria: 1) prospective, randomized controlled trials evaluating available TZDs versus standards of care; 2) well-described protocol; 3) minimum of 6 months of follow-up; and 4) data provided on repeat TVR. Data are presented as relative risks (RRs) with 95% CIs.

RESULTS—Seven clinical trials (n = 608) met the inclusion criteria. Upon meta-analysis, the risk of repeat TVR was significantly reduced in patients who received TZD therapy compared with standards of care (RR 0.35 [95% CI 0.22–0.57]). In studies using rosiglitazone (0.45 [0.25–0.83]) and pioglitazone (0.24 [0.11–0.51]), risk of repeat TVR was significantly reduced. Risk of repeat TVR was also significantly reduced among patients with (0.34 [0.19–0.63]) and without (0.37 [0.18–0.77]) diabetes.

CONCLUSIONS—Results from this meta-analysis suggest that TZDs effectively reduce the risk of repeat TVR following PCI.
Should Central Obesity Be an Optional or Essential Component of the Metabolic Syndrome?
Authors: Lee Jeannette , Ma Stefan , Heng Derrick , Tan Chee-Eng , Chew Suok-Kai , Hughes Kenneth , Tai E-Shyong
Published: January 2007

OBJECTIVE—The International Diabetes Federation (IDF) proposes that central obesity is an “essential” component of the metabolic syndrome, while the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) proposes that central obesity is an “optional” component. This study examines the effect of the metabolic syndrome with and without central obesity in an Asian population with ischemic heart disease (IHD).

RESEARCH DESIGN AND METHODS—From the population-based cohort study (baseline 1992–1995), 4,334 healthy individuals were grouped by the presence or absence of the metabolic syndrome and central obesity and followed up for an average of 9.6 years by linkage with three national registries. Cox’s proportional hazards model was used to obtain adjusted hazard ratios (HRs) for risk of a first IHD event.

RESULTS—The prevalence of metabolic syndrome was 17.7% by IDF criteria and 26.2% by AHA/NHLBI criteria using Asian waist circumference cutoff points for central obesity. Asian Indians had higher rates than Chinese and Malays. There were 135 first IHD events. Compared with individuals without metabolic syndrome, those with central obesity/metabolic syndrome and no central obesity/metabolic syndrome were at significantly increased risk of IHD, with adjusted HRs of 2.8 (95% CI 1.8–4.2) and 2.5 (1.5–4.0), respectively.

CONCLUSIONS—Having metabolic syndrome either with or without central obesity confers IHD risk. However, having central obesity as an “optional” rather than “essential” criterion identifies more individuals at risk of IHD in this Asian cohort.
Prevention of Cardiovascular Disease
Authors: Bloomgarden Zachary T.
Published: January 2007

Perspectives on the News commentaries are now part of a new, free monthly CME activity. The Mount Sinai School of Medicine, New York, New York, is designating this activity for 2.0 AMA PRA Category 1 credits. If you wish to participate, review this article and visit www.diabetes.procampus.net to complete a posttest and receive a certificate. The Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Surface analysis of the size-fractioned urban aerosols by secondary ion mass spectrometry (ToF-SIMS)
Authors: Rogowski J. , Bem H.
Published: January 2007

The secondary ion mass spectrometry method (ToF-SIMS) has been applied to the analysis of some mineral and organic species on the surface layers of airborne urban particulates. Particulate matter was collected on aluminum sheets of the 8-stage Anderson type cascade impactor from three different sampling sites in the city of Lodz, Poland, which were different in terms of aerosol source apportionment. The obtained results show that vehicle combustion products occur mainly in fine fraction with aerodynamic diameters below 1µm. The main contribution to the mineral components comes from direct and traffic related soil resuspension.
Cyclic AMP-dependent PKA phosphorylates starfish sperm proteins during acrosome reaction
Authors: Sadiqul Islam M. , Hoshi Motonori , Matsumoto Midori
Published: January 2007

The induction of acrosome reaction (AR) happens when starfish spermatozoa encounter the egg jelly (EJ). This complex process involves different signal transduction pathways, such as elevation of cAMP and the activation of protein kinase A (PKA). The specific inhibitors of PKA (H89 and KT5720) have been shown to inhibit the EJ-induced Ca2+ elevation and AR. By using a Phospho-Ser/Thr PKA substrate antibody, we have detected an increased phosphorylation of 150, 200 and 220-kDa protein bands when starfish spermatozoa treated with EJ. The specific PKA inhibitors effectively inhibit phosphorylation of these proteins, suggesting an involvement of PKA on EJ-induced AR.
Trematodes from Red Sea fishes: On the validity of Helicometra marmoratae Nagaty et Abdel-Aal, 1962 and the description of H. aegyptense sp. nov. (Opecoelidae Ozaki, 1925)
Authors: Hassanine Reda
Published: January 2007

Specimens of the fishes Siganus spinus L. (Siganidae) and Sargocentron spiniferum Forsskål (Holocentridae) were caught in the Red Sea off the coast of Sharm El-Sheikh, South Sinai, Egypt. Twenty-three (46%) and 12 (20%) of these fishes, respectively, were found to harbour intestinal trematodes. Siganus spinus was parasitized by Helicometra marmoratae Nagaty et Abdel-Aal, 1962 (Opecoelidae Ozaki, 1925) and S. spiniferum by Helicometra aegyptense sp. nov. (Opecoelidae Ozaki, 1925). Based on a large number of specimens collected from its type host and locality, H. marmoratae is broadly redescribed for the first time, and its type specimen is re-examined. The validity of this species is discussed and considered a new synonym of H. fasciata (Rudolphi, 1819) Odhner, 1902 (type species of the genus). Helicometra aegyptense sp. nov. is similar to H. equilata (Manter, 1933) Siddiqi et Cable, 1960, H. nasae Nagaty et Abdel-Aal, 1962, H. pteroisi (Gupta, 1956) Fischthal et Kuntz, 1965 and H. interrupta Hassanine, 2005 in having a short forebody and a long cirrus sac extending posterior to the ventral sucker, but differs significantly from them or unique in having a distinctly elongate pharynx, a larger sucker ratio and vitelline follicles grouped in small clusters arranged in two lateral rows on each side of the body. The valid species of Helicometra are listed in four principal groups.
Diving behavior reduces genera richness of lice (Insecta, Phthiraptera) of mammals
Authors: Felső Bernadett , Rózsa Lajos
Published: January 2007

Lice of mammals spend the entire life cycle in the host hair, thus, the microclimate found near the mammal skin is likely to influence the structure of louse communities. Here we use a comparative approach to examine the effect of mammals’ diving behavior on the taxonomic richness of their lice. We compared the mean genera richness of lice, and — as potential confounding variables — the mean species richness of host, and the mean body mass of host between diving clades and their non-diving sister clades. Louse genera richness was significantly lower in clades of aquatic mammals than on their non-diving sister clades. Host species richness was not significantly different between these clades. Body mass was significantly higher in clades of aquatic mammals, however, the direction of this difference cannot explain the difference in parasite taxonomic richness. This study suggests that mammals’ diving behavior can effectively shape their ectoparasite communities.