bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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 &lt; 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 &gt;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 &gt;140 mg/dl.
RESULTS—The mean admission blood glucose was 229 ± 6 mg/dl and A1C 8.8 ± 2%. A blood glucose target of &lt;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 &lt; 0.01). Despite increasing insulin doses, 14% of patients treated with SSI remained with blood glucose &gt;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 &lt; 10−12) with and comparable to clamp GIRs100–120 min. In subgroup analyses, GIRs100–120 min were lower (P &lt; 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 &lt; 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 &lt; 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.