bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuregulins Increase Mitochondrial Oxidative Capacity and Insulin Sensitivity in Skeletal Muscle Cells
Authors: Cantó Carles , Pich Sara , Paz José C. , Sanches Rosario , Martínez Vicente , Orpinell Meritxell , Palacín Manuel , Zorzano Antonio , Gumà Anna
Published: August 2007

OBJECTIVE—Neuregulins are growth factors that are essential for myogenesis and regulate muscle metabolism. The addition of a recombinant neuregulin-1 isoform, heregulin-β1177–244 (Hrg), containing 3 nmol/l of the bioactive epidermal growth factor–like domain, to developing L6E9 myocytes has acute and chronic effects on glucose uptake and enhances myogenesis. Here, we studied the metabolic adaptation of myocytes to chronic treatments with Hrg.

RESEARCH DESIGN AND METHODS—L6E9 and C2C12 myocytes were chronically treated with low concentrations of Hrg (3 pmol/l) that do not induce myogenesis. We analyzed the effects of Hrg on cellular oxidative metabolism and insulin sensitivity and explored the mechanisms of action.

RESULTS—Hrg increased the cell content of GLUT4 without affecting basal glucose uptake. Glucose and palmitate oxidation increased in Hrg-treated cells, whereas lactate release decreased. Hrg increased the abundance of oxidative phosphorylation (OXPHOS) subunits, enhanced mitochondrial membrane potential, and induced the expression of peroxisome proliferator–activated receptor (PPAR)γ coactivator1α and PPARδ. Furthermore, we identified PPARδ as an essential mediator of the stimulatory effects of Hrg on the expression of OXPHOS subunits. The higher oxidative capacity of L6E9 myotubes after neuregulin treatment also paralleled an increase in insulin sensitivity and insulin signaling potency.

CONCLUSIONS—These results indicate that neuregulins act as key modulators of oxidative capacity and insulin sensitivity in muscle cells.
AMP Kinase Activation Increases Glucose Uptake, Decreases Apoptosis, and Improves Pregnancy Outcome in Embryos Exposed to High IGF-I Concentrations
Authors: Eng Grace S. , Sheridan Rachael A. , Wyman Amanda , Chi Maggie M.-Y. , Bibee Kristin P. , Jungheim Emily S. , Moley Kelle H.
Published: August 2007

Women with polycystic ovarian syndrome are at increased risk of miscarriage. Although evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMP kinase (AMPK) activation with metformin directly improves insulin signaling within the blastocyst, leading to improved pregnancy outcomes. Murine embryos were exposed to 200 nmol/l IGF-I, similar to the concentrations that can occur during polycystic ovary syndrome (PCOS). Resulting blastocysts were compared with embryos cocultured with excess IGF-I plus metformin and embryos cultured in control medium for the following: AMPK phosphorylation, insulin-stimulated glucose uptake, and apoptosis. Study and control blastocysts were also transferred into control animals. On embryonic day (E) 14.5, resulting fetuses were examined for size and rates of fetal implantation and resorption. Compared with control blastocysts, blastocysts exposed to high concentrations of IGF-I showed a decrease in AMPK activation and insulin-stimulated glucose uptake and an increase in the number of apoptotic nuclei. Blastocysts cocultured in metformin and excess IGF-I performed as well as controls in all studies. 5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside, another AMPK activator, also prevented the effects of excess IGF-I on blastocysts. Implantation rates and fetal size at day 14.5 were significantly lower among IGF-I–exposed embryos transferred into control mothers compared with control embryos transferred into control mothers. Both of these parameters were reversed by co-incubation with metformin and IGF-I before transfer. Activation of embryonic AMPK may be the mechanism responsible for the improved pregnancy outcomes seen in PCOS patients taking metformin.
Alcohol Consumption and Type 2 Diabetes
Authors: Beulens Joline W.J. , Rimm Eric B. , Hendriks Henk F.J. , Hu Frank B. , Manson JoAnn E. , Hunter David J. , Mukamal Kenneth J.
Published: August 2007

OBJECTIVE— We sought to investigate whether a polymorphism in the alcohol dehydrogenase 1c (ADH1C) gene modifies the association between alcohol consumption and type 2 diabetes.

RESEARCH DESIGN AND METHODS— In nested case-control studies of 640 women with incident diabetes and 1,000 control subjects from the Nurses’ Health Study and 383 men with incident diabetes and 382 control subjects from the Health Professionals Follow-Up Study, we determined associations between the ADH1C polymorphism, alcohol consumption, and diabetes risk.

RESULTS— Moderate to heavy alcohol consumption (>5 g/day for women and >10 g/day for men) was associated with a decreased risk of diabetes among women (odds ratio [OR] 0.45 [95% CI 0.33–0.63]) but not men (1.08 [0.67–1.75]). ADH1C genotype modified the relation between alcohol consumption and diabetes for women (Pinteraction = 0.02). The number of ADH1C*2 alleles, related to a slower rate of ethanol oxidation, attenuated the lower risk of diabetes among women consuming ≥5 g alcohol/day (Ptrend = 0.002). These results were not significant among men. Results were similar in pooled analyses (Pinteraction = 0.02) with ORs for diabetes among moderate drinkers of 0.44 (95% CI 0.21–0.94) in ADH1C*1 homozygotes, 0.65 (0.39–1.06) for heterozygotes, and 0.78 (0.50–1.22) for ADH1C*2 homozygotes compared with those for ADH1C*1 homozygote abstainers (Ptrend = 0.02).

CONCLUSIONS— ADH1C genotype modifies the association between alcohol consumption and diabetes. The ADH1C*2 allele, related to a slower oxidation rate, attenuates the lower diabetes risk among moderate to heavy drinkers. This suggests that the association between alcohol consumption and diabetes may be causal but mediated by downstream metabolites such as acetate rather than ethanol itself.
Adipocyte-Derived Serum Amyloid A3 and Hyaluronan Play a Role in Monocyte Recruitment and Adhesion
Authors: Han Chang Yeop , Subramanian Savitha , Chan Christina K. , Omer Mohamed , Chiba Tsuyoshi , Wight Thomas N. , Chait Alan
Published: August 2007

Obesity is characterized by adipocyte hypertrophy and macrophage accumulation in adipose tissue. Monocyte chemoattractant protein-1 (MCP-1) plays a role in macrophage recruitment into adipose tissue. However, other adipocyte-derived factors, e.g., hyaluronan and serum amyloid A (SAA), can facilitate monocyte adhesion and chemotaxis, respectively. The objective was to test the potential involvement of these factors in macrophage recruitment. Differentiated 3T3-L1 adipocytes made hypertrophic by growth in high glucose conditions were used to study SAA and hyaluronan regulation in vitro. Two mouse models of obesity were used to study their expression in vivo. Nuclear factor-κB was upregulated and peroxisome proliferator–activated receptor (PPAR)γ was downregulated in hypertrophic 3T3-L1 cells, with increased expression of SAA3 and increased hyaluronan production. Rosiglitazone, a PPARγ agonist, reversed these changes. Hypertrophic adipocytes demonstrated overexpression of SAA3 and hyaluronan synthase 2 in vitro and in vivo in diet-induced and genetic obesity. SAA and hyaluronan existed as part of a complex matrix that increased the adhesion and retention of monocytes. This complex, purified by binding to a biotinylated hyaluronan binding protein affinity column, also showed monocyte chemotactic activity, which was dependent on the presence of SAA3 and hyaluronan but independent of MCP-1. We hypothesize that adipocyte hypertrophy leads to increased production of SAA and hyaluronan, which act in concert to recruit and retain monocytes, thereby leading to local inflammation in adipose tissue.
Physiological Hyperinsulinemia Has No Detectable Effect on Access of Macromolecules to Insulin-Sensitive Tissues in Healthy Humans
Authors: Weinhandl Heinz , Pachler Christoph , Mader Julia K. , Ikeoka Dimas , Mautner Agnes , Falk Andreas , Suppan Maria , Pieber Thomas R. , Ellmerer Martin
Published: August 2007

OBJECTIVE—Physiologically elevated insulin concentrations promote access of macromolecules to skeletal muscle in dogs. We investigated whether insulin has a stimulating effect on the access of macromolecules to insulin-sensitive tissues in humans as well.

RESEARCH DESIGN AND METHODS—In a randomized, controlled trial, euglycemic-hyperinsulinemic clamp (1.2 mU · kg−1 · min−1 insulin) and saline control experiments were performed in 10 healthy volunteers (aged 27.5 ± 4 years, BMI 22.6 ± 1.6 kg/m2). Distribution and clearance parameters of inulin were determined in a whole-body approach, combining primed intravenous infusion of inulin with compartment modeling. Inulin kinetics were measured in serum using open-flow microperfusion in interstitial fluid of femoral skeletal muscle and subcutaneous adipose tissue.

RESULTS—Inulin kinetics in serum were best described using a three-compartment model incorporating a serum and a fast and a slow equilibrating compartment. Inulin kinetics in interstitial fluid of peripheral insulin-sensitive tissues were best represented by the slow equilibrating compartment. Serum and interstitial fluid inulin kinetics were comparable between the insulin and saline groups. Qualitative analysis of inulin kinetics was confirmed by model-derived distribution and clearance parameters of inulin. Physiological hyperinsulinemia (473 ± 6 vs. 18 ± 2 pmol/l for the insulin and saline group, respectively; P < 0.001) indicated no effect on distribution volume (98.2 ± 6.2 vs. 102.5 ± 5.7 ml/kg; NS) or exchange parameter (217.6 ± 34.2 vs. 243.1 ± 28.6 ml/min; NS) of inulin to peripheral insulin-sensitive tissues. All other parameters identified by the model were also comparable between the groups.

CONCLUSIONS—Our data suggest that in contrast to studies performed in dogs, insulin at physiological concentrations does not augment recruitment of insulin-sensitive tissues in healthy humans.
Characterization of a Protein Kinase B Inhibitor In Vitro and in Insulin-Treated Liver Cells
Authors: Logie Lisa , Ruiz-Alcaraz Antonio J. , Keane Michael , Woods Yvonne L. , Bain Jennifer , Marquez Rudolfo , Alessi Dario R. , Sutherland Calum
Published: August 2007

OBJECTIVE—Abnormal expression of the hepatic gluconeogenic genes (glucose-6-phosphatase [G6Pase] and PEPCK) contributes to hyperglycemia. These genes are repressed by insulin, but this process is defective in diabetic subjects. Protein kinase B (PKB) is implicated in this action of insulin. An inhibitor of PKB, Akt inhibitor (Akti)-1/2, was recently reported; however, the specificity and efficacy against insulin-induced PKB was not reported. Our aim was to characterize the specificity and efficacy of Akti-1/2 in cells exposed to insulin and then establish whether inhibition of PKB is sufficient to prevent regulation of hepatic gene expression by insulin.

RESEARCH DESIGN AND METHODS—Akti-1/2 was assayed against 70 kinases in vitro and its ability to block PKB activation in cells exposed to insulin fully characterized.

RESULTS—Akti-1/2 exhibits high selectivity toward PKBα and PKBβ. Complete inhibition of PKB activity is achieved in liver cells incubated with 1–10 μmol/l Akti-1/2, and this blocks insulin regulation of PEPCK and G6Pase expression. Our data demonstrate that only 5–10% of maximal insulin-induced PKB is required to fully repress PEPCK and G6Pase expression. Finally, we demonstrate reduced insulin sensitivity of these gene promoters in cells exposed to submaximal concentrations of Akti-1/2; however, full repression of the genes can still be achieved by high concentrations of insulin.

CONCLUSIONS—This work establishes the requirement for PKB activity in the insulin regulation of PEPCK, G6Pase, and a third insulin-regulated gene, IGF-binding protein-1 (IGFBP1); suggests a high degree of functional reserve; and identifies Akti-1/2 as a useful tool to delineate PKB function in the liver.
Ghrelin Uses Gαi2 and Activates Voltage-Dependent K+ Channels to Attenuate Glucose-Induced Ca2+ Signaling and Insulin Release in Islet β-Cells
Authors: Dezaki Katsuya , Kakei Masafumi , Yada Toshihiko
Published: August 2007

Ghrelin reportedly serves as a physiological regulator of insulin release. This study aimed to explore signaling mechanisms for insulinostatic ghrelin action in islet β-cells, with special attention to heterotrimeric GTP-binding proteins and K+ channels. Plasma insulin and growth hormone (GH) concentrations in rats were measured by enzyme-linked immunosorbent assay (ELISA). Islets were isolated from rats, ghrelin-knockout (Ghr-KO) mice, and wild-type mice by collagenase digestion, and insulin release was determined by ELISA. In rat single β-cells, cytosolic Ca2+ concentration ([Ca2+]i) was measured by fura-2 microfluorometry, and membrane potentials and whole cell currents by patch-clamp technique. In rats, systemic ghrelin administration decreased plasma insulin concentrations, and this effect was blocked by treatment with pertussis toxin (PTX), whereas stimulation of GH release remained unaffected. In rat islets, ghrelin receptor antagonist increased and exogenous ghrelin suppressed glucose-induced insulin release in a PTX-sensitive manner. Glucose-induced insulin release from islets was greater in Ghr-KO than wild-type mice, and this enhanced secretion was blunted with PTX. Ghrelin PTX sensitively increased voltage-dependent K+ (Kv) currents without affecting ATP-sensitive K+ channels in rat β-cells. In the presence of Kv channel blockers, ghrelin failed to suppress insulin release. Ghrelin attenuated glucose-induced action potentials and [Ca2+]i increases in β-cells. Suppressions of [Ca2+]i increase and insulin release by ghrelin were blunted in β-cells treated with PTX and with antisense oligonucleotide specific for G-protein Gαi2-subunit. Ghrelin attenuates glucose-induced insulin release via PTX-sensitive Gαi2-mediated activation of Kv channels and suppression of [Ca2+]i in β-cells, representing the unique signaling of ghrelin distinct from that for GH release.
Angiopoietin-1 Production in Islets Improves Islet Engraftment and Protects Islets From Cytokine-Induced Apoptosis
Authors: Su Dongming , Zhang Nan , He Jing , Qu Shen , Slusher Sandra , Bottino Rita , Bertera Suzanne , Bromberg Jonathan , Dong H. Henry
Published: August 2007

Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a small fraction of implanted islets become engrafted. The underlying mechanisms remain elusive. To probe the mechanism of islet revascularization, we determined the effect of angiopoietin-1 (Ang-1), a proangiogenic and antiapoptotic factor, on the survival, function, and revascularization of transplanted islets using a syngeneic model. Islets were transduced with adenoviruses expressing Ang-1 or control LacZ, followed by transplantation under the renal capsule. Diabetic mice receiving a marginal mass of 150 islets pretransduced with Ang-1 vector exhibited near normoglycemia posttransplantation. In contrast, diabetic mice receiving an equivalent islet mass pretransduced with control vector remained hyperglycemic. At 30 days posttransplantation, mice were killed and islet grafts retrieved for immunohistochemistry. Islet grafts with elevated Ang-1 production retained significantly increased microvascular density, improved glucose profiles, and increased glucose-stimulated insulin release. Cultured islets expressing Ang-1 displayed improved viability and enhanced glucose-stimulated insulin secretion in the presence of cytokines. In contrast, control islets exhibited increased apoptosis and diminished glucose-stimulated insulin release in response to cytokine treatment. These results indicate that Ang-1 confers a cytoprotective effect on islets, enhancing islet engraftment and preserving functional islet mass in transplants.
Hepatic Lipin 1β Expression Is Diminished in Insulin-Resistant Obese Subjects and Is Reactivated by Marked Weight Loss
Authors: Croce Michelle A. , Eagon J. Christopher , LaRiviere Lori L. , Korenblat Kevin M. , Klein Samuel , Finck Brian N.
Published: August 2007

OBJECTIVE— Lipin 1 plays critical roles in controlling energy metabolism. We sought to determine the expression of lipin 1 isoforms (lipin 1α and -β) in liver and adipose tissue of obese subjects and to evaluate cellular mechanisms involved in the regulation of lipin 1 expression by physiologic stimuli.

RESEARCH DESIGN AND METHODS— The expression of lipin 1α and -β was quantified in liver and adipose tissue of extremely obese (average BMI 60.8 kg/m2) human subjects undergoing gastric bypass surgery (GBS). Second, the expression of lipin 1 was evaluated in HepG2 cells in response to overexpression of peroxisome proliferator–activated receptor-γ coactivator (PGC)-1α under normal or hyperinsulinemic conditions.

RESULTS— The expression of lipin 1β in liver and adipose tissue was inversely related to BMI, fasting plasma insulin concentration, and the homeostasis model assessment of insulin resistance but was significantly increased by marked weight loss and insulin sensitization following GBS. Hepatic lipin 1β mRNA levels were strongly correlated with the expression of PGC-1α, and overexpression of PGC-1α in HepG2 cells increased lipin 1 expression. Conversely, hyperinsulinemic culture conditions downregulated the expression of lipin 1β, PGC-1α, and their known target genes involved in mitochondrial metabolism in HepG2 cells. Finally, overexpression of lipin 1β or PGC-1α reversed the effect of hyperinsulinemia on the expression of their target genes.

CONCLUSIONS— These studies suggest that hepatic lipin 1β and PGC-1α expression are downregulated by obesity and obesity-related metabolic perturbations in human subjects, likely due to alterations in insulin concentration or sensitivity.
Development and Validation of a New Measure to Evaluate Psychological Resistance to Insulin Treatment
Authors: Petrak Frank , Stridde Elmar , Leverkus Friedhelm , Crispin Alexander A. , Forst Thomas , Pfützner Andreas
Published: August 2007

OBJECTIVE—To develop a psychometric questionnaire to measure psychological barriers to insulin treatment in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Scale development was based on principal component analyses in two cross-sectional studies of insulin-naïve patients with type 2 diabetes. The structure of the questionnaire was developed in the first sample of 448 patients and subsequently cross-validated in an independent sample of 449 patients.

RESULTS—Analyses in the first sample yielded five components that accounted for 74.5% of the variance based on 14 items and led to the following subscales: fear of injection and self-testing, expectations regarding positive insulin-related outcomes, expected hardship from insulin treatment, stigmatization by insulin injections, and fear of hypoglycemia. In addition, an overall sum score of all values was calculated. The structure of the questionnaire was cross-validated in the second sample, with almost identical component loadings and an explained variance of 69.4%. An additional confirmatory factor analysis also indicated an acceptable to good model fit with root mean square error of approximation equal to 0.04 and comparative fit index equal to 0.97. Coefficients of reliability (Cronbach's α 0.62–0.85 and 0.78 for overall sum score) were acceptable, considering the very small number of items for each scale.

CONCLUSIONS—The Barriers to Insulin Treatment Questionnaire appears to be a reliable and valid measure of psychological insulin resistance in patients with type 2 diabetes. This short instrument is easy to administer and may be used by both clinicians and researchers to assess the psychological barriers to insulin treatment.
Childhood Obesity and Metabolic Imprinting
Authors: Hillier Teresa A. , Pedula Kathryn L. , Schmidt Mark M. , Mullen Judith A. , Charles Marie-Aline , Pettitt David J.
Published: August 2007

OBJECTIVE—The purpose of this study was to determine how the range of measured maternal glycemia in pregnancy relates to risk of obesity in childhood.

RESEARCH DESIGN AND METHODS—Universal gestational diabetes mellitus (GDM) screening (a 50-g glucose challenge test [GCT]) was performed in two regions (Northwest and Hawaii) of a large diverse HMO during 1995–2000, and GDM was diagnosed/treated using a 3-h 100-g oral glucose tolerance test (OGTT) and National Diabetes Data Group (NDDG) criteria. Measured weight in offspring (n = 9,439) was ascertained 5–7 years later to calculate sex-specific weight-for-age percentiles using U.S. norms (1963–1994 standard) and then classified by maternal positive GCT (1 h ≥ 7.8 mmol/l) and OGTT results (1 or ≥2 of the 4 time points abnormal: fasting, 1 h, 2 h, or 3 h by Carpenter and Coustan and NDDG criteria).

RESULTS—There was a positive trend for increasing childhood obesity at age 5–7 years (P < 0.0001; 85th and 95th percentiles) across the range of increasing maternal glucose screen values, which remained after adjustment for potential confounders including maternal weight gain, maternal age, parity, ethnicity, and birth weight. The risk of childhood obesity in offspring of mothers with GDM by NDDG criteria (treated) was attenuated compared with the risks for the groups with lesser degrees of hyperglycemia (untreated). The relationships were similar among Caucasians and non-Caucasians. Stratification by birth weight also revealed these effects in children of normal birth weight (≤4,000 g).

CONCLUSIONS—Our results in a multiethnic U.S. population suggest that increasing hyperglycemia in pregnancy is associated with an increased risk of childhood obesity. More research is needed to determine whether treatment of GDM may be a modifiable risk factor for childhood obesity.
Role of Insulin Resistance in Predicting Progression to Type 1 Diabetes
Authors: Xu Ping , Cuthbertson David , Greenbaum Carla , Palmer Jerry P. , Krischer Jeffrey P. ,   for the Diabetes Prevention Trial–Type 1 Study Group
Published: August 2007

OBJECTIVE—The purpose of this study was to determine whether insulin resistance is a risk factor for the development of type 1 diabetes in autoantibody-positive first-degree relatives of diabetic family members.

RESEARCH DESIGN AND METHODS—Subjects (n = 186) who had a projected 25–50% risk for diabetes and subjects (n = 170) who had a projected >50% risk for type 1 diabetes in 5 years were followed until clinical diabetes onset or the end of the study as part of the Diabetes Prevention Trial–Type 1. We assessed insulin secretion with the first-phase insulin response (FPIR) and insulin resistance with homeostasis model assessment of insulin resistance (HOMA-IR) from an intravenous glucose tolerance test. The median follow-up was 4.3 years for moderate-risk subjects and 3.7 years for high-risk subjects.

RESULTS—During the follow-up period, 53 subjects in the moderate-risk group and 70 subjects in the high-risk group developed type 1 diabetes. After adjustments for confounders using multivariate analysis, HOMA-IR and the FPIR–to–HOMA-IR ratio were significantly associated with type 1 diabetes in both risk groups. In the moderate-risk population, the hazard ratio (HR) of HOMA-IR was 2.70 (95% CI 1.45–5.06) and the HR of FPIR-to-HOMA-IR was 0.32 (95% CI 0.18–0.57). In the high-risk population, the HR of HOMA-IR was 1.83 (95% CI 1.19–2.82) and the HR of FPIR–to–HOMA-IR was 0.56 (95% CI 0.40–0.78).

CONCLUSIONS—There is clear evidence of the association between insulin resistance and progression to type 1 diabetes. The combination of FPIR and HOMA-IR could be used as a better metabolic indicator for type 1 diabetes risk for prediction and suggests possible intervention strategies for diabetes prevention.
Type 2 Diabetes and Pneumonia Outcomes
Authors: Kornum Jette B. , Thomsen Reimar W. , Riis Anders , Lervang Hans-Henrik , Schønheyder Henrik C. , Sørensen Henrik T.
Published: August 2007

OBJECTIVE—We sought to examine whether type 2 diabetes increases risk of death and complications following pneumonia and to assess the prognostic value of admission hyperglycemia.

RESEARCH DESIGN AND METHODS—This was a population-based cohort study of adults with a first-time hospitalization for pneumonia between 1997 and 2004 (n = 29,900) in northern Denmark. Information on diabetes, comorbidity, laboratory findings, pulmonary complications, and bacteremia was obtained from medical databases. We used regression to compute adjusted relative risks of pulmonary complications, bacteremia, and mortality rate ratios (MRRs) within 90 days following hospitalization among patients with and without type 2 diabetes. The prognostic impact of admission hyperglycemia was studied in a subcohort (n = 13,574).

RESULTS— In total, 2,931 (9.8%) pneumonia patients had type 2 diabetes. Mortality among diabetic patients was greater than that among other patients: 19.9 vs. 15.1% after 30 days and 27.0 vs. 21.6% after 90 days, respectively, corresponding to adjusted 30- and 90-day MRRs of 1.16 (95% CI 1.07–1.27) and 1.10 (1.02–1.18). Presence of type 2 diabetes did not predict pulmonary complications or bacteremia. Adjustment for hyperglycemia attenuated the association between type 2 diabetes and mortality. High glucose level on admission was a predictor of death among patients with diabetes and more so among those without diagnosed diabetes: adjusted 30-day MRRs for glucose level ≥14 mmol/l were 1.46 (1.01–2.12) and 1.91 (1.40–2.61), respectively.

CONCLUSIONS—Type 2 diabetes and admission hyperglycemia predict increased pneumonia-related mortality.
Participant and Parent Experiences in the Parenteral Insulin Arm of the Diabetes Prevention Trial for Type 1 Diabetes
Authors: Johnson Suzanne Bennett , Baughcum Amy E. , Hood Korey , Rafkin-Mervis Lisa E. , Schatz Desmond A. ,   for the DPT-1 Study Group
Published: August 2007

OBJECTIVE—To assess participant and parent experiences in the parenteral insulin arm of the Diabetes Prevention Trial for Type 1 Diabetes (DPT-1).

RESEARCH DESIGN AND METHODS—Before trial results were publicized, surveys were completed by 82 intervention participants (the intervention group) (who received annual 4-day insulin infusions and daily insulin injections), 81 closely monitored control subjects (the closely monitored group), and 135 parents of children in the trial.

RESULTS—Survey results suggest that participant perspective (adult, child, parent, and sex), study procedures, and group assignment have important implications when planning clinical trials. Parents rated the trial more favorably but worried about hypoglycemia and diabetes onset. Children had the least favorable reaction to the study. Parents preferred assignment to the intervention group; child/adult participants preferred assignment to the closely monitored group. The intervention group rated the annual 4-day insulin infusions more negatively than all other study procedures. Intervention group participants/parents reported poorer insulin injection adherence over the course of the study. Intervention group participants, parents, and female subjects expressed an interest in additional psychosocial support during the trial. Random assignment was viewed negatively by both study groups. Close observation for diabetes onset was viewed as the most favorable aspect of the study. Behaviors outside of the study protocol to prevent or delay diabetes onset were common and should be monitored in future prevention studies.

CONCLUSIONS—Overall, most participants were positive about the trial, and many expressed optimism about the intervention's potential for success. These results have implications for study design, recruitment, and retention procedures in future prevention trials.
Population-Based Incidence of Type 2 Diabetes in Northern Spain
Authors: Valdés Sergio , Botas Patricia , Delgado Elias , Álvarez Francisco , Cadórniga Francisco Diaz
Published: August 2007

OBJECTIVE—The aim of this study was to define the incidence of type 2 diabetes in a low-risk Caucasian population in northern Spain and its association with various risk factors.

RESEARCH DESIGN AND METHODS—The Asturias Study is a prospective, population-based survey of diabetes and cardiovascular risk factors. The baseline examination was carried out during 1998–1999 when 1,034 individuals, aged 30–75 years, were randomly selected to determine the prevalence of type 2 diabetes and pre-diabetes in the Principality of Asturias (northern Spain). In 2004–2005, these same subjects were invited for a follow-up examination; 700 participated. This study includes only those individuals who did not have diabetes at baseline. We used the World Health Organization 1999 criteria to classify glucose metabolism at both baseline and follow-up.

RESULTS—The incidence of diabetes adjusted for the age and sex structure of Asturias was 10.8 cases/1,000 person-years (95% CI 8.1–14.8). The incidence rates were 5 cases/1,000 person-years in individuals with normoglycemia, 21 cases/1,000 person-years in individuals with isolated impaired glucose tolerance (IGT), 34.7 cases/1,000 person-years in individuals with isolated impaired fasting glucose (IFG), and 95.2 cases/1,000 person-years in individuals with combined IFG-IGT. Stepwise multiple logistic regression analysis showed that, together with fasting plasma glucose (FPG) and 2-h plasma glucose, which were the strongest predictors of diabetes, triglycerides and BMI were also independently associated with progression to diabetes.

CONCLUSIONS—In this 6-year prospective population-based study, we found an incidence of type 2 diabetes of 10.8 cases/1,000 person-years. Both FPG and 2-h plasma glucose were strongly predictive of diabetes, and their effect was additive.
Fertility in Women With Type 1 Diabetes
Authors: Jonasson Junmei Miao , Brismar Kerstin , Sparén Pär , Lambe Mats , Nyrén Olof , Östenson Claes-Göran , Ye Weimin
Published: August 2007

OBJECTIVE—The purpose of this study was to assess fertility in women with type 1 diabetes and the risk of congenital malformations in their offspring.

RESEARCH DESIGN AND METHODS—This was a register-based cohort study in Sweden. All 5,978 women hospitalized for type 1 diabetes at age ≤16 years identified in the Swedish Inpatient Register during 1965–2004 were followed until the end of 2004 through linkage to nationwide registers. A standardized fertility ratio (SFR), the ratio of observed to expected number of live births, with 95% CIs, was used to express the relative fertility rate. The proportion of newborns with congenital malformations was compared with that of the general population.

RESULTS—We observed 4,013 live births (SFR 0.80 [95% CI 0.77–0.82]). The SFRs for those who had retinopathy, nephropathy, neuropathy, or cardiovascular complications were 0.63, 0.54, 0.50, and 0.34, respectively. Stratified analyses by year of first hospitalization showed that the reduced fertility was confined to women first hospitalized before 1985, but the presence of complications was associated with subfertility in all calendar-year strata. The proportions of newborns with congenital malformations decreased from 11.7% during 1973–1984 to 6.9% during 1995–2004 but were consistently higher than the corresponding figures for the general population.

CONCLUSIONS—Women with type 1 diabetes have reduced fertility, but it appears that normalization has occurred among women with uncomplicated disease and an onset in the past 20 years. Our results suggest that the stricter metabolic control exercised in the past 20 years may have helped prevent subfertility. However, although the risk of congenital malformations has decreased, it is still higher than that for the general population.
Matrix Metalloproteinase-2 Dysregulation in Type 1 Diabetes
Authors: Thrailkill Kathryn M. , Bunn Robert C. , Moreau Cynthia S. , Cockrell Gael E. , Simpson Pippa M. , Coleman Hannah N. , Frindik J. Paul , Kemp Stephen F. , Fowlkes John L.
Published: August 2007

OBJECTIVE—Dysregulation of matrix metalloproteinase (MMP)-2 may contribute pathologically to the development of diabetes complications, including diabetic retinopathy and coronary and peripheral arterial disease. Our objective was to explore whether systemic MMP-2 dysregulation could be demonstrated in type 1 diabetes and to determine how MMP-2 concentration relates to disease status.

RESEARCH DESIGN AND METHODS—In this cross-sectional study, MMP-2 concentrations and MMP-2 activity were measured in plasma and timed urine samples from 93 type 1 diabetic and 50 healthy control subjects, aged 14–40 years. Relationships between MMP-2 concentrations in these biological fluids and subject characteristics (sex, age, and duration of type 1 diabetes), indexes of glycemic control (A1C, fasting plasma glucose, and continuous glucose monitoring system average daily glucose), and measurements of renal function (urinary albumin excretion and glomerular filtration rate) were examined.

RESULTS—Urine and plasma MMP-2 concentrations and plasma MMP-2 activity were all significantly elevated in type 1 diabetic subjects compared with those in control subjects. Urine MMP-2 concentrations, in particular, were correlated with several clinical parameters that infer increased risk for diabetic comorbidity and specifically for diabetic nephropathy, including higher A1C, longer duration of disease, evidence of renal hyperfiltration, and the presence of microalbuminuria.

CONCLUSIONS—Urine and plasma MMP-2 concentrations are dysregulated in type 1 diabetes; urinary excretion of MMP-2, in particular, might provide a unique biomarker of diabetes-induced intrarenal pathologic processes.
Randomized Study of Basal-Bolus Insulin Therapy in the Inpatient Management of Patients With Type 2 Diabetes (RABBIT 2 Trial)
Authors: Umpierrez Guillermo E. , Smiley Dawn , Zisman Ariel , Prieto Luz M. , Palacio Andres , Ceron Miguel , Puig Alvaro , Mejia Roberto
Published: August 2007

OBJECTIVE—We sought to study the optimal management of hyperglycemia in non–intensive care unit patients with type 2 diabetes, as few studies thus far have focused on the subject.

RESEARCH DESIGN AND METHODS—We conducted a prospective, multicenter, randomized trial to compare the efficacy and safety of a basal-bolus insulin regimen with that of sliding-scale regular insulin (SSI) in patients with type 2 diabetes. A total of 130 insulin-naive patients were randomized to receive glargine and glulisine (n = 65) or a standard SSI protocol (n = 65). Glargine was given once daily and glulisine before meals at a starting dose of 0.4 units · kg−1 · day−1 for blood glucose 140–200 mg/dl or 0.5 units · kg−1 · day−1 for blood glucose 201–400 mg/dl. SSI was given four times per day for blood glucose >140 mg/dl.

RESULTS—The mean admission blood glucose was 229 ± 6 mg/dl and A1C 8.8 ± 2%. A blood glucose target of <140 mg/dl was achieved in 66% of patients in the glargine and glulisine group and in 38% of those in the SSI group. The mean daily blood glucose between groups ranged from 23 to 58 mg/dl, with an overall blood glucose difference of 27 mg/dl (P < 0.01). Despite increasing insulin doses, 14% of patients treated with SSI remained with blood glucose >240 mg/dl. There were no differences in the rate of hypoglycemia or length of hospital stay.

CONCLUSIONS—Treatment with insulin glargine and glulisine resulted in significant improvement in glycemic control compared with that achieved with the use of SSI alone. Our study indicates that a basal-bolus insulin regimen is preferred over SSI in the management of non–critically ill, hospitalized patients with type 2 diabetes.
The Clamp-Like Index
Authors: Anderwald Christian , Anderwald-Stadler Marietta , Promintzer Miriam , Prager Gerhard , Mandl Martina , Nowotny Peter , Bischof Martin G. , Wolzt Michael , Ludvik Bernhard , Kästenbauer Thomas , Pacini Giovanni , Luger Anton , Krebs Michael
Published: August 2007

OBJECTIVE—Insulin resistance, the underlying pathophysiological mechanism of the metabolic syndrome, can not only predict type 2 diabetes development but also cardiovascular disease. Thus, precise insulin resistance measurement in individuals at risk for metabolic diseases would support clinical risk stratification. However, the gold standard for measuring insulin resistance, the hyperinsulinemic clamp test, is too labor intensive to be performed in large clinical studies/settings.

RESEARCH DESIGN AND METHODS—Using plasma glucose and C-peptide concentrations from oral glucose tolerance tests (OGTTs), we developed the novel “clamp-like index” (CLIX) for insulin sensitivity calculation and compared CLIX to clamp glucose infusion rates (GIR) (100–120 min). We evaluated CLIX in 89 nondiabetic subjects (58 female and 31 male, aged 45 ± 1 years, BMI 27.5 ± 0.8 kg/m2) who underwent frequently sampled 3-h 75-g OGTTs and 2-h hyperinsulinemic-isoglycemic clamp (40 mU/min per m2) tests.

RESULTS—CLIX, calculated as serum creatinine (×0.85 if male)/(mean AUCglucose × mean AUCC-peptide) × 6,600, was highly correlated (r = 0.670, P < 10−12) with and comparable to clamp GIRs100–120 min. In subgroup analyses, GIRs100–120 min were lower (P < 0.005) in type 2 diabetic offspring (6.2 ± 0.7 mg · min−1 · kg−1) than in sex-, age-, and BMI-matched subjects without a family history of type 2 diabetes (8.6 ± 0.5 mg · min−1 · kg−1), which was also reflected by CLIX (insulin-resistant offspring 6.4 ± 0.6 vs. those without a family history of type 2 diabetes 9.0 ± 0.5; P < 0.002). When compared with normal-weight subjects (GIR 8.8 ± 0.4 mg · min−1 · kg−1; CLIX 9.0 ± 0.5), both GIRs100–120 min and CLIX of obese (5.2 ± 0.9 mg · min −1 · kg−1; 5.7 ± 0.9) and morbidly obese (2.4 ± 0.4 mg · min −1 · kg−1; 3.3 ± 0.5) humans were lower (each P < 0.02).

CONCLUSIONS—CLIX, a novel index obtained from plasma OGTT glucose and C-peptide levels and serum creatinine, without inclusion of anthropometrical measures to calculate insulin sensitivity in nondiabetic humans, highly correlates with clamp GIRs and reveals even slight insulin sensitivity alterations over a broad BMI range and is as sensitive as the hyperinsulinemic clamp test.
γ-Glutamyltransferase Activity and Development of the Metabolic Syndrome (International Diabetes Federation Definition) in Middle-Aged Men and Women
Authors: André Philippe , Balkau Beverley , Vol Sylviane , Charles Marie Aline , Eschwège Eveline ,   on behalf of the DESIR Study Group
Published: August 2007

OBJECTIVE—Among hepatic enzymes, γ-glutamyltransferase (GGT) is the main predictor of type 2 diabetes incidence, although it has not been shown that GGT predicts pre-diabetes states. Our aim was to study the association of GGT with the development of the metabolic syndrome (MetS).

RESEARCH DESIGN AND METHODS—We analyzed the 3-year data from the Data from Epidemiological Study on the Insulin Resistance Syndrome prospective cohort of 1,656 men and 1,889 women without MetS at baseline, according to the International Diabetes Federation definition.

RESULTS—Over 3 years, 309 participants developed the MetS. After adjustment for age, alcohol intake, physical activity, smoking habits, and alanine aminotransferase (ALT), the odds ratios for incident MetS increased across baseline GGT quartiles (1, 1.96, 2.25, and 3.81 in men, P < 0.03; and 1, 1.23, 1.80, and 1.58 in women, P < 0.05). After additional adjustment for insulin resistance markers (fasting insulin or homeostasis model assessment of insulin resistance index), the association was attenuated and the linear relation no longer significant in both sexes (P = 0.08, P = 0.16). However, men in the highest in comparison to the lowest quartile of GGT retained a significant risk for incident MetS. In women, there was no longer a significant risk. GGT was significantly associated with the 3-year incidence of individual components of the MetS. The incidence of the MetS also increased with ALT, but after adjustment on GGT this association remained significant only in women.

CONCLUSIONS—GGT, a predictor of type 2 diabetes, was associated with a risk of incident MetS. This association was mainly related with insulin resistance but was independent of other confounding factors.
Continuing Stability of Center Differences in Pediatric Diabetes Care: Do Advances in Diabetes Treatment Improve Outcome?
Authors: de Beaufort Carine E. , Swift Peter G.F. , Skinner Chas T. , Aanstoot Henk J. , Åman Jan , Cameron Fergus , Martul Pedro , Chiarelli Francesco , Daneman Dennis , Danne Thomas , Dorchy Harry , Hoey Hilary , Kaprio Eero A. , Kaufman Francine , Kocova Mirjana , Mortensen Henrik B. , Njølstad Pal R. , Phillip Moshe , Robertson Kenneth J. , Schoenle Eugen J. , Urakami Tatsuhiko , Vanelli Maurizio ,   on behalf of the Hvidoere Study Group on Childhood Diabetes 2005
Published: August 2007

OBJECTIVE—To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis.

RESEARCH DESIGN AND METHODS—This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11–18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005.

RESULTS—Mean A1C was 8.2 ± 1.4%, with substantial variation between centers (mean A1C range 7.4–9.2%; P < 0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 ± 2.0% vs. 8.2 ± 1.4% for those with language difficulties vs. those without, respectively; P < 0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C.

CONCLUSIONS—Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.
Risk Perception for Diabetes Among Women With Histories of Gestational Diabetes Mellitus
Authors: Kim Catherine , McEwen Laura N. , Piette John D. , Goewey Jennifer , Ferrara Assiamira , Walker Elizabeth A.
Published: August 2007

OBJECTIVE—To examine risk perception for diabetes among women with histories of gestational diabetes mellitus (GDM).

RESEARCH DESIGN AND METHODS—We surveyed 217 women with histories of GDM who were enrolled in a managed-care plan and who did not currently have diabetes. In a cross-sectional design, we assessed the associations between risk perceptions and current lifestyle behavioral practices, plans to modify behaviors, and recent lifestyle behavior changes. Multivariable models included participant characteristics as well as potential modifiers of risk perception (knowledge of diabetes risk factors, optimistic bias, perceived personal control, and beliefs in the benefits and barriers of lifestyle modification).

RESULTS—Ninety percent of women recognized that GDM was a risk factor for future diabetes, but only 16% believed that they themselves had a high chance of developing diabetes; perceived risk increased to 39% when women were asked to estimate their risk assuming they maintained their current lifestyle. Women who consumed three or more but less than five servings a day of fruits and vegetables reported lower odds of moderate/high risk perception (adjusted odds ratio [OR] 0.39 [95% CI 0.16–0.92]) than women who consumed less than three servings a day, although this association was not significant after further adjustment for income. Women who perceived themselves to be at moderate/high risk more often planned to modify their future lifestyle behaviors (9.1 [0.16–0.92]).

CONCLUSIONS—Despite understanding the association between GDM and postpartum diabetes, women with histories of GDM usually do not perceive themselves to be at elevated risk.
Serum C3 Is a Stronger Inflammatory Marker of Insulin Resistance Than C-Reactive Protein, Leukocyte Count, and Erythrocyte Sedimentation Rate
Authors: Muscari Antonio , Antonelli Serafina , Bianchi Giampaolo , Cavrini Giulia , Dapporto Susanna , Ligabue Amedeo , Ludovico Cosimo , Magalotti Donatella , Poggiopollini Guido , Zoli Marco ,   on behalf of the Pianoro Study Group
Published: August 2007

OBJECTIVE—This study was performed to ascertain the relative relevance of some inflammatory markers in insulin resistance.

RESEARCH DESIGN AND METHODS—Four inflammatory markers (leukocyte count, erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [CRP], and C3 complement) were assessed as possible determinants of the homeostasis model assessment (HOMA) index, together with the five elements of the metabolic syndrome (National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III] definition), total cholesterol, physical activity, and four indicators of adiposity (BMI, waist circumference, percent body fat, and hepatic steatosis) in an unselected population of 990 subjects aged 65–91 years (the Pianoro Study).

RESULTS—In univariable analysis, C3, CRP, and leukocyte count, but not ESR, were significantly correlated with HOMA index. In multivariable analysis, C3 remained associated with insulin resistance with the highest partial R2 value (0.049), independently of all other covariates. The other most significant (P < 0.0001) determinants of HOMA index were total cholesterol (inverse association, R2 = 0.026), waist circumference (R2 = 0.023), triglycerides (R2 = 0.022), and hepatic steatosis (R2 = 0.021) (R2 = 0.450 for the whole model).

The adjusted relative risks of having the metabolic syndrome for the subjects with inflammatory markers in the high tertile, with respect to those with lower values, were (prevalence ratio [95% CI]): 1.77 (1.41–2.22) for C3, 1.38 (1.12–1.70) for leukocyte count, 1.17 (0.94–1.46) for CRP, and 1.13 (0.91–1.40) for ESR.

CONCLUSIONS—Of the four inflammatory markers simultaneously assessed in our elderly population, only C3 was strongly associated with insulin resistance, independently of the components of the metabolic syndrome and the main indexes of abdominal and general obesity.