bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of and Longitudinal Changes in Insulin Sensitivity and Secretion Preceding Onset of Type 2 Diabetes
Authors: Lyssenko Valeriya , Almgren Peter , Anevski Dragi , Perfekt Roland , Lahti Kaj , Nissén Michael , Isomaa Bo , Forsen Björn , Homström Nils , Saloranta Carola , Taskinen Marja-Riitta , Groop Leif , Tuomi Tiinamaija ,   for the Botnia Study Group
Published: March 2007

Identification of individuals at high risk of developing type 2 diabetes is a prerequisite for prevention of the disease. We therefore studied risk factors predicting type 2 diabetes in the Botnia Study in western Finland. A total of 2,115 nondiabetic individuals were prospectively followed with repeated oral glucose tolerance tests. After a median follow-up of 6 years, 127 (6%) subjects developed diabetes. A family history of diabetes (hazard ratio [HR] 2.2, P = 0.008), BMI (HR for comparison of values below or above the median 2.1, P < 0.001), waist-to-height index (2.3, P < 0.001), insulin resistance (2.1, P = 0.0004), and β-cell function adjusted for insulin resistance (2.7, P < 0.0001) predicted diabetes. Marked deterioration in β-cell function with modest changes in insulin sensitivity was observed during the transition to diabetes. The combination of FPG ≥5.6 mmol/l, BMI ≥30 kg/m2, and family history of diabetes was a strong predictor of diabetes (3.7, P < 0.0001). Of note, using FPG ≥6.1 mmol/l or 2-h glucose ≥7.8 mmol/l did not significantly improve prediction of type 2 diabetes. In conclusion, a marked deterioration in β-cell function precedes the onset of type 2 diabetes. These individuals can be identified early by knowledge of FPG, BMI, and family history of diabetes.
Evidence for Accelerated Rates of Glutathione Utilization and Glutathione Depletion in Adolescents With Poorly Controlled Type 1 Diabetes
Authors: Darmaun Dominique , Smith Shiela D. , Sweeten Shawn , Sager Brenda K. , Welch Susan , Mauras Nelly
Published: March 2007

Depletion of glutathione, an important antioxidant present in red cells, has been reported in type 1 diabetes, but the mechanism of this depletion has not been fully characterized. Glutathione depletion can occur through decreased synthesis, increased utilization, or a combination of both. To address this issue, 5-h infusions of l-[3,3-2H2]cysteine were performed in 16 diabetic adolescents divided into a well-controlled and a poorly controlled group and in eight healthy nondiabetic teenagers as control subjects (HbA1c 6.3 ± 0.2, 10.5 ± 0.6, and 4.8 ± 0.1%, respectively). Glutathione fractional synthesis rate was determined from 2H2-cysteine incorporation into blood glutathione. We observed that 1) erythrocyte cysteine concentration was 41% lower in poorly controlled patients compared with well-controlled patients (P = 0.009); 2) erythrocyte glutathione concentration was ∼29% and ∼36% lower in well-controlled and poorly controlled patients compared with healthy volunteers; and 3) the fractional synthesis rate of glutathione, although similar in well-controlled and healthy subjects (83 ± 14 vs. 82 ± 11% per day), was substantially higher in the poorly controlled group (141 ± 23% per day, P = 0.038). These findings suggest that in diabetic adolescents, poor control is associated with a significant depletion of blood glutathione and cysteine, due to increased rates of glutathione utilization. This weakened antioxidant defense may play a role in the pathogenesis of diabetes complications.
a-Series Gangliosides Mediate the Effects of Advanced Glycation End Products on Pericyte and Mesangial Cell Proliferation
Authors: Masson Elodie , Troncy Lysiane , Ruggiero Daniel , Wiernsperger Nicolas , Lagarde Michel , Bawab Samer El
Published: March 2007

Advanced glycation end products (AGEs) are involved in the development of microvascular complications, including alterations of retinal pericyte and renal mesangial cell growth occurring during diabetic retinopathy and diabetic nephropathy, respectively. Because gangliosides are implicated in the regulation of cell proliferation, we hypothesized that AGEs could exert cellular effects in part by modulating ganglioside levels. Results of the present study indicate that AGEs caused an inhibition of both bovine retinal pericyte (BRP) and rat renal mesangial cell (RMC) proliferation, associated with an increase of a-series gangliosides consecutive to GM3 synthase activity increase and GD3 synthase activity inhibition. Similar modifications were also found in the renal cortex of diabetic db/db mice compared with controls. Treatment of BRP and RMC with exogenous a-series gangliosides decreased proliferation and blockade of a-series gangliosides with specific antibodies partially protecting the two cell types from the AGE-induced proliferation decrease. Further, inhibition of GM3 synthase using specific SiRNA partially reversed the AGE effects on mesangial cell proliferation. These results suggest that a-series gangliosides are mediators of the adverse AGE effects on BRP and RMC proliferation. They also raise the hypothesis of common mechanisms involved in the development of diabetic retinopathy and diabetic nephropathy.
HIV-1 Accessory Protein Vpr Inhibits the Effect of Insulin on the Foxo Subfamily of Forkhead Transcription Factors by Interfering With Their Binding to 14-3-3 Proteins
Authors: Kino Tomoshige , De Martino Massimo U. , Charmandari Evangelia , Ichijo Takamasa , Outas Taoufik , Chrousos George P.
Published: March 2007

HIV-1 accessory protein Vpr arrests host cells at the G2/M phase of the cell cycle by interacting with members of the protein family 14-3-3, which regulate the activities of “partner” molecules by binding to their phosphorylated serine or threonine residues and changing their intracellular localization and/or stability. Vpr does this by facilitating the association of 14-3-3 to its partner protein Cdc25C, independent of the latter’s phosphorylation status. Here we report that the same viral protein interfered with and altered the activity of another 14-3-3 partner molecule, Foxo3a, a subtype of the forkhead transcription factors, by inhibiting its association with 14-3-3. Foxo3a’s transcriptional activity is normally suppressed by insulin-induced translocation of this protein from the nucleus into the cytoplasm. Vpr inhibited the ability of insulin or its downstream protein kinase Akt to change the intracellular localization of Foxo3a preferentially to the cytoplasm. This HIV-1 protein also interfered with insulin-induced coprecipitation of 14-3-3 and Foxo3a in vivo and antagonized the negative effect of insulin on Foxo3a-induced transactivation of a FOXO-responsive promoter. Moreover, Vpr antagonized insulin-induced suppression of the mRNA expression of the glucose 6-phosphatase, manganese superoxide dismutase, and sterol carrier protein 2 genes, which are known targets of insulin and FOXO, in HepG2 cells. These findings indicate that Vpr interferes with the suppressive effects of insulin on FOXO-mediated transcription of target genes via 14-3-3. Vpr thus may contribute to the tissue-selective insulin resistance often observed in HIV-1–infected individuals.
Development of a Long-Acting Insulin Analog Using Albumin Fusion Technology
Authors: Duttaroy Alokesh , Kanakaraj Palanisamy , Osborn Blaire L. , Schneider Helmut , Pickeral Oxana K. , Chen Cecil , Zhang Guiyi , Kaithamana Shashi , Singh Mallika , Schulingkamp Robert , Crossan Dan , Bock Jason , Kaufman Thomas E. , Reavey Peter , Carey-Barber Melisa , Krishnan Surekha R. , Garcia Andy , Murphy Kelly , Siskind Jana K. , McLean Malia A. , Cheng Susan , Ruben Steve , Birse Charles E. , Blondel Olivier
Published: March 2007

The primary therapeutic goal for the treatment of diabetes is maintenance of a long-term, near-normoglycemic condition and prevention of the onset or progression of the complications associated with the disease. Although several analogs of human insulin have been developed, the currently prescribed long-acting insulin analogs do not provide a stable basal glycemia for more than a few hours. Here, we report the development of Albulin, a long-acting insulin analog obtained by direct gene fusion of a single-chain human insulin to human serum albumin. Albulin showed an elimination t1/2 of ∼7 h in normoglycemic mice. In vitro pharmacodynamic profiles for Albulin characterized by receptor binding, inhibition of gluconeogenesis, induction of glucose uptake, and global regulation of gene expression in relevant cell types showed that Albulin produced similar activity profiles compared with that of recombinant human insulin. A single Albulin administration in vivo normalized blood glucose level in diabetic mice in a relatively peakless and sustained (24-h) fashion. A further reduction in glucose levels was achieved by administering a recombinant human insulin a few hours after Albulin injection in mice, indicating the potential for Albulin therapy in combination with available fast-acting insulin derivatives. In summary, Albulin displays characteristics of a potent long-acting insulin analog that can be evaluated for use as a novel insulin therapy for patients with insulin-dependent diabetes.
Increased Glucocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase Type 1 Expression in Hepatocytes May Contribute to the Phenotype of Type 2 Diabetes in db/db Mice
Authors: Liu Yanjun , Nakagawa Yuichi , Wang Ying , Sakurai Reiko , Tripathi Pinky V. , Lutfy Kabirullah , Friedman Theodore C.
Published: March 2007

Excess tissue glucocorticoid action may contribute to the hyperglycemia and insulin resistance associated with type 2 diabetes, but the associated mechanisms are poorly understood. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive 11-dehydrocorticosterone into active corticosterone, thus amplifying glucocorticoid receptor–mediated tissue glucocorticoid action, particularly in the liver. To examine the role of tissue glucocorticoid action in type 2 diabetes, we analyzed expression of glucocorticoid receptor and 11β-HSD1 and their regulation by endogenous hormones in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). We observed positive relations between expression of both glucocorticoid receptor and 11β-HSD1 in liver and insulin sensitivity and expression of PEPCK mRNA in db/db mice and db/+ controls. Increased expression of glucocorticoid receptor and 11β-HSD1 in the liver of db/db mice was correlated with elevated circulating levels of corticosterone, insulin, and blood glu-cose. Treatment of db/db mice with glucocorticoid antagonist RU486 reversed the increases in the expression of glucocorticoid receptor and 11β-HSD1 within the liver and attenuated the phenotype of type 2 diabetes. Addition of corticosterone to db/db mouse primary hepatocytes activated expression of glucocorticoid receptor, 11β-HSD1, and PEPCK, and these effects were abolished by RU486. Incubation of primary hepatocytes with increasing concentrations of glucose caused dose-dependent increases in glucocorticoid receptor and 11β-HSD1 expression, whereas insulin did not affect the expression of 11β-HSD1 and glucocorticoid receptor in primary hepatocytes. These findings suggest that activation of glucocorticoid receptor and 11β-HSD1 expression within the liver may contribute to the development of type 2 diabetes in db/db mice.
Growth Hormone Overexpression in the Central Nervous System Results in Hyperphagia-Induced Obesity Associated With Insulin Resistance and Dyslipidemia
Authors: Bohlooly-Y Mohammad , Olsson Bob , Bruder Carl E.G. , Lindén Daniel , Sjögren Klara , Bjursell Mikael , Egecioglu Emil , Svensson Lennart , Brodin Peter , Waterton John C. , Isaksson Olle G.P. , Sundler Frank , Ahrén Bo , Ohlsson Claes , Oscarsson Jan , Törnell Jan
Published: March 2007

It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
Bone Formation Is Impaired in a Model of Type 1 Diabetes
Authors: Thrailkill Kathryn M. , Liu Lichu , Wahl Elizabeth C. , Bunn Robert C. , Perrien Daniel S. , Cockrell Gael E. , Skinner Robert A. , Hogue William R. , Carver Adam A. , Fowlkes John L. , Aronson James , Lumpkin Charles K.
Published: March 2007

The effects of type 1 diabetes on de novo bone formation during tibial distraction osteogenesis (DO) and on intact trabecular and cortical bone were studied using nonobese diabetic (NOD) mice and comparably aged nondiabetic NOD mice. Diabetic mice received treatment with insulin, vehicle, or no treatment during a 14-day DO procedure. Distracted tibiae were analyzed radiographically, histologically, and by microcomputed tomography (μCT). Contralateral tibiae were analyzed using μCT. Serum levels of insulin, osteocalcin, and cross-linked C-telopeptide of type I collagen were measured. Total new bone in the DO gap was reduced histologically (P ≤ 0.001) and radiographically (P ≤ 0.05) in diabetic mice compared with nondiabetic mice but preserved by insulin treatment. Serum osteocalcin concentrations were also reduced in diabetic mice (P ≤ 0.001) and normalized with insulin treatment. Evaluation of the contralateral tibiae by μCT and mechanical testing demonstrated reductions in trabecular bone volume and thickness, cortical thickness, cortical strength, and an increase in endosteal perimeter in diabetic animals, which were prevented by insulin treatment. These studies demonstrate that bone formation during DO is impaired in a model of type 1 diabetes and preserved by systemic insulin administration.
Increased Fatty Acid Desaturation and Enhanced Expression of Stearoyl Coenzyme A Desaturase Protects Pancreatic β-Cells from Lipoapoptosis
Authors: Busch Anna K. , Gurisik Ebru , Cordery Damien V. , Sudlow Michelle , Denyer Gareth S. , Laybutt D. Ross , Hughes William E. , Biden Trevor J.
Published: March 2007

Increased availability of fatty acids causes cell death and dysfunction in β-cell lines, isolated islets, and animal models of diabetes. From the MIN6 β-cell line, we selected two subpools that are resistant to palmitate-induced apoptosis. Protection was not universal because palmitate-resistant cells remained sensitive to cytokine- and streptozotocin-induced apoptosis. Palmitate oxidation and incorporation into cholesterol ester (but not triglycerides) were significantly higher in palmitate-resistant cells than in control cells. Consistent with these findings, transcript profiling revealed increased expression in palmitate-resistant cells of several β-oxidation genes as well as a 2.8-fold upregulation of stearoyl-CoA desaturase 1 (SCD1). Correspondingly, the oleate-to-palmitate ratio of palmitate-resistant cells was double that of palmitate-pretreated control cells. At least some of this additional oleate in palmitate-resistant cells was incorporated into cholesterol ester stored in the form of large cytosolic lipid bodies. However, blocking cholesterol ester formation did not render palmitate-resistant cells sensitive to palmitate-induced apoptosis. On the other hand, an inhibitor of SCD1, 10,12-conjugated linoleic acid, dose dependently overcame the resistance of palmitate-resistant cells to lipoapoptosis. Our results suggest that desaturation per se is more important in protecting β-cells from the cytotoxic effects of palmitate than is the nature of neutral lipid storage pool thus generated.
Elevated Levels of Interleukin-18 Predict the Development of Type 2 Diabetes
Authors: Thorand Barbara , Kolb Hubert , Baumert Jens , Koenig Wolfgang , Chambless Lloyd , Meisinger Christa , Illig Thomas , Martin Stephan , Herder Christian
Published: March 2007

We investigated prospectively the association between serum levels of interleukin (IL)-18 and the risk of type 2 diabetes in a case-cohort study conducted in middle-aged men and women who represented 7,936 participants of the three MONItoring of trends and determinants in CArdiovascular disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) surveys. Levels of IL-18 were measured in stored samples of 527 case subjects with incident type 2 diabetes and 1,698 noncase subjects. Elevated levels of IL-18 were associated with a significantly increased risk of type 2 diabetes after adjustment for age, sex, survey, BMI, systolic blood pressure, ratio of total cholesterol to HDL cholesterol, physical activity, alcohol intake, smoking status, and parental history of diabetes. Hazard ratios and 95% confidence intervals comparing quartile extremes were 1.73 (1.25–2.40). Further adjustment for C-reactive protein and IL-6 had no impact on the observed associations. However, the risk of developing type 2 diabetes was highest among subjects with elevated levels of both IL-18 and CRP or IL-18 and IL-6, respectively. In conclusion, elevated levels of IL-18 are associated with a considerably increased risk of type 2 diabetes. This association is independent of a generalized proinflammatory state, but subjects with elevated levels of several inflammatory markers seem to be particularly prone to develop type 2 diabetes.
Mechanism of Perturbation of Integrin-Mediated Cell-Matrix Interactions by Reactive Carbonyl Compounds and Its Implication for Pathogenesis of Diabetic Nephropathy
Authors: Pedchenko Vadim K. , Chetyrkin Sergei V. , Chuang Peale , Ham Amy-Joan L. , Saleem Moin A. , Mathieson Peter W. , Hudson Billy G. , Voziyan Paul A.
Published: March 2007

Perturbation of interactions between cells and the extracellular matrix (ECM) of renal glomeruli may contribute to characteristic histopathological lesions found in the kidneys of patients with diabetic nephropathy. However, the mechanism by which the diabetic conditions may affect cell-ECM interactions is unknown. Existing hypotheses suggest a role of glucose in direct modification of ECM. Here, we have demonstrated that carbonyl compound methylglyoxal (MGO) completely inhibited endothelial cell adhesion to recombinant α3 noncollagenous 1 domain of type IV collagen mediated via a short collagenous region containing RGD (Arg-Gly-Asp) sequence as well as binding of purified αvβ3 integrin to this protein. Specific MGO adducts of the arginine residue were detected within RGD sequence using mass spectrometry. Modification by carbonyl compounds glyoxal or glycolaldehyde had similar but smaller effects. MGO strongly inhibited adhesion of renal glomerular cells, podocytes, and mesangial cells to native collagen IV and laminin-1 as well as binding of collagen IV to its major receptor in glomerular cells, α1β1 integrin. In contrast, modification of these proteins by glucose had no effect on cell adhesion. Pyridoxamine, a promising drug for treatment of diabetic nephropathy, protected cell adhesion and integrin binding from inhibition by MGO. We suggest that in diabetes, perturbation of integrin-mediated cell-matrix interactions occurs via the modification of critical arginine residues in renal ECM by reactive carbonyl compounds. This mechanism may contribute to the development of diabetic nephropathy.
Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes
Authors: Lankas George R. , Leiting Barbara , Roy Ranabir Sinha , Eiermann George J. , Beconi Maria G. , Biftu Tesfaye , Chan Chi-Chung , Edmondson Scott , Feeney William P. , He Huaibing , Ippolito Dawn E. , Kim Dooseop , Lyons Kathryn A. , Ok Hyun O. , Patel Reshma A. , Petrov Aleksandr N. , Pryor Kelly Ann , Qian Xiaoxia , Reigle Leah , Woods Andrea , Wu Joseph K. , Zaller Dennis , Zhang Xiaoping , Zhu Lan , Weber Ann E. , Thornberry Nancy A.
Published: March 2007

Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents.
Type 1 Diabetes
Authors: Concannon Patrick , Erlich Henry A. , Julier Cecile , Morahan Grant , Nerup Jørn , Pociot Flemming , Todd John A. , Rich Stephen S. ,   the Type 1 Diabetes Genetics Consortium
Published: March 2007

Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [λS] ∼ 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific λS ∼ 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] ∼ 1.9), CTLA4 (chromosome 2q33, allelic OR ∼ 1.2), and PTPN22 (chromosome 1p13, allelic OR ∼ 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P = 2.0 × 10−52), nine non–HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10−4). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect (λS ≥ 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations.
Association Between Peroxisome Proliferator–Activated Receptor γ Haplotypes and the Metabolic Syndrome in French Men and Women
Authors: Meirhaeghe Aline , Cottel Dominique , Amouyel Philippe , Dallongeville Jean
Published: March 2007

We assessed the association of four polymorphisms (promoter P3 −681C>G, P2 −689C>T, Pro12Ala, and 1431C>T) in peroxisome proliferator–activated receptor γ (PPARγ) with the metabolic syndrome risk in a large, French population study (n = 1,155). In this sample, 279 men and women presented with metabolic syndrome according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria. When taken individually, none of the polymorphisms was significantly associated with the metabolic syndrome. Haplotype analyses, in contrast, revealed a significant enrichment of the GTGC haplotype frequency (corresponding to the P3 −681C>G, P2 −689C>T, Pro12Ala (C/G), and 1431C>T polymorphisms in this order) among those with metabolic syndrome compared with control subjects. Compared with the most common CCCC haplotype, the adjusted odds ratio (OR) (95% CI) of the metabolic syndrome for bearers of the GTGC haplotype was 2.37 (1.42–3.95; P = 0.002), 1.92 (1.00–3.72; P = 0.05), and 2.47 (1.09–5.62; P = 0.045) in the whole sample of men and women, respectively. Similar results were obtained when using another haplotype (GCCC, GTGT, CCCT, or GCCT) as a reference. Furthermore, when the GTGC haplotype frequency was tested alone (i.e., versus the frequency of the five other haplotypes together), the OR (95% CI) of the metabolic syndrome was 2.30 (1.05–5.00; P = 0.022). These data show that only the frequency of the GTGC haplotype was different between subjects with and without metabolic syndrome. Further analyses stratified on the 1431C>T single nucleotide polymorphism (SNP) indicated that the rare alleles of the P2 −689C>T and Pro12Ala SNPs were associated with an increased risk of the metabolic syndrome when combined to the 1431CC genotype. In conclusion, a specific haplotype of PPARγ polymorphisms is associated with an increased risk of the metabolic syndrome in a French general population.
Apical GLUT2
Authors: Kellett George L. , Brot-Laroche Edith
Published: March 2007

Understanding the mechanisms that determine postprandial fluctuations in blood glucose concentration is central for effective glycemic control in the management of diabetes. Intestinal sugar absorption is one such mechanism, and studies on its increase in experimental diabetes led us to propose a new model of sugar absorption. In the apical GLUT2 model, the glucose transported by the Na+/glucose cotransporter SGLT1 promotes insertion of GLUT2 into the apical membrane within minutes, so that the mechanism operates during assimilation of a meal containing high–glycemic index carbohydrate to provide a facilitated component of absorption up to three times greater than by SGLT1. Here we review the evidence for the apical GLUT2 model and describe how apical GLUT2 is a target for multiple short-term nutrient-sensing mechanisms by dietary sugars, local and endocrine hormones, cellular energy status, stress, and diabetes. These mechanisms suggest that apical GLUT2 is a potential therapeutic target for novel dietary or pharmacological approaches to control intestinal sugar delivery and thereby improve glycemic control.
Aldose Reductase Deficiency Prevents Diabetes-Induced Blood-Retinal Barrier Breakdown, Apoptosis, and Glial Reactivation in the Retina of db/db Mice
Authors: Cheung Alvin K.H. , Fung Maggie K.L. , Lo Amy C.Y. , Lam Terence T.L. , So Kwok Fai , Chung Stephen S.M. , Chung Sookja K.
Published: March 2007

In 15-month-old db/db mice, signs of diabetic retinopathy, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and proliferation of blood vessels, were evident. These changes in the diabetic retina were associated with increased expression of aldose reductase (AR). To further understand the role of AR in the pathogenesis of diabetic retinopathy, we generated db/db mice with an AR null mutation (AR−/− db/db). AR deficiency led to fewer retinal blood vessels with IgG leakage, suggesting that AR may contribute to blood-retinal barrier breakdown. AR deficiency also prevented diabetes-induced reduction of platelet/endothelial cell adhesion molecule-1 expression and increased expression of vascular endothelial growth factor, which may have contributed to blood-retinal barrier breakdown. In addition, long-term diabetes-induced neuro-retinal stress and apoptosis and proliferation of blood vessels were less prominent in AR−/− db/db mice. These findings indicate that AR is responsible for the early events in the pathogenesis of diabetic retinopathy, leading to a cascade of retinal lesions, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and neovascularization.
Insulin-Stimulated Glucose Uptake Does Not Require p38 Mitogen-Activated Protein Kinase in Adipose Tissue or Skeletal Muscle
Authors: Turban Sophie , Beardmore Victoria A. , Carr Julia M. , Sakamoto Kei , Hajduch Eric , Arthur J. Simon C. , Hundal Harinder S.
Published: March 2007

It has been proposed that p38 mitogen-activated protein kinase (MAPK) isoforms sensitive to the pyridinylimidazole compounds SB 203580 and SB 202190 may participate in the acute insulin-dependent activation of glucose transporters recruited to the plasma membrane of adipocytes and skeletal muscle. Here, we explore whether these kinases support the insulin stimulation of glucose uptake in these tissues by investigating the effects of a genetic loss in p38β and that of the p38 MAPK inhibitor SB 203580. Glucose uptake in adipocytes and soleus muscle was stimulated by insulin by up to fourfold irrespective of whether tissues were isolated from wild-type or p38β-null mice. Consistent with this finding, mice lacking p38β exhibited normal glucose tolerance, insulinemia, and glycemia compared with their wild-type counterparts. Insulin-stimulated glucose uptake was not inhibited by SB 203580 when adipocytes were preincubated with the drug at a cytocrit of 50%, but intriguingly, uptake was suppressed (by 35%) when the cytocrit was reduced by one-half. Despite the activation of glucose uptake at the higher cytocrit, insulin failed to induce any detectable activation of p38 MAPK, whereas p38 signaling was robustly activated by anisomycin in a SB 203580–sensitive manner. Although insulin also failed to induce any detectable activation of p38 MAPK in muscle, insulin-dependent glucose uptake was reduced by SB 203580 (∼ 44%) in muscle of both wild-type and p38β-null mice. Our results indicate that p38β is not required for insulin-stimulated glucose uptake in adipocytes or muscle. Moreover, given that insulin fails to promote any significant activation of p38 MAPK in these tissues and the finding that sensitivity of glucose uptake, but not that of the kinase, to SB 203580 can be influenced by cytocrit, we suggest that p38 signaling is unlikely to participate in any putative activation of transporters recruited to the cell surface by insulin and that SB 203580 suppresses insulin-stimulated glucose transport by a mechanism unrelated to its inhibitory effect on p38 MAPK.
Activation of ATP-Sensitive K+ Channels in the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses to Hypoglycemia in Normal and Recurrently Hypoglycemic Rats
Authors: McCrimmon Rory J. , Evans Mark L. , Fan Xiaoning , McNay Ewan C. , Chan Owen , Ding Yuyan , Zhu Wanling , Gram Dorte X. , Sherwin Robert S.
Published: March 2007

The mechanism(s) by which glucosensing neurons detect fluctuations in glucose remains largely unknown. In the pancreatic β-cell, ATP-sensitive K+ channels (KATP channels) play a key role in glucosensing by providing a link between neuronal metabolism and membrane potential. The present study was designed to determine in vivo whether the pharmacological opening of ventromedial hypothalamic KATP channels during systemic hypoglycemia would amplify hormonal counterregulatory responses in normal rats and those with defective counterregulation arising from prior recurrent hypoglycemia. Controlled hypoglycemia (∼2.8 mmol/l) was induced in vivo using a hyperinsulinemic (20 mU · kg−1 · min−1) glucose clamp technique in unrestrained, overnight-fasted, chronically catheterized Sprague-Dawley rats. Immediately before the induction of hypoglycemia, the rats received bilateral ventromedial hypothalamic microinjections of either the potassium channel openers (KCOs) diazoxide and NN414 or their respective controls. In normal rats, both KCOs amplified epinephrine and glucagon counterregulatory responses to hypoglycemia. Moreover, diazoxide also amplified the counterregulatory responses in a rat model of defective hormonal counterregulation. Taken together, our data suggest that the KATP channel plays a key role in vivo within glucosensing neurons in the ventromedial hypothalamus in the detection of incipient hypoglycemia and the initiation of protective counterregulatory responses. We also conclude that KCOs may offer a future potential therapeutic option for individuals with insulin-treated diabetes who develop defective counterregulation.
Restitution of Defective Glucose-Stimulated Insulin Secretion in Diabetic GK Rat by Acetylcholine Uncovers Paradoxical Stimulatory Effect of β-Cell Muscarinic Receptor Activation on cAMP Production
Authors: Dolz Manuel , Bailbé Danielle , Giroix Marie-Hélène , Calderari Sophie , Gangnerau Marie-Noelle , Serradas Patricia , Rickenbach Katharina , Irminger Jean-Claude , Portha Bernard
Published: March 2007

Because acetylcholine (ACh) is a recognized potentiator of glucose-stimulated insulin release in the normal β-cell, we have studied ACh’s effect on islets of the Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes. We first verified that ACh was able to restore the insulin secretory glucose competence of the GK β-cell. Then, we demonstrated that in GK islets 1) ACh elicited a first-phase insulin release at low glucose, whereas it had no effect in Wistar; 2) total phospholipase C activity, ACh-induced inositol phosphate production, and intracellular free calcium concentration ([Ca2+]i) elevation were normal; 3) ACh triggered insulin release, even in the presence of thapsigargin, which induced a reduction of the ACh-induced [Ca2+]i response (suggesting that ACh produces amplification signals that augment the efficacy of elevated [Ca2+]i on GK exocytosis); 4) inhibition of protein kinase C did not affect [Ca2+]i nor the insulin release responses to ACh; and 5) inhibition of cAMP-dependent protein kinases (PKAs), adenylyl cyclases, or cAMP generation, while not affecting the [Ca2+]i response, significantly lowered the insulinotropic response to ACh (at low and high glucose). In conclusion, ACh acts mainly through activation of the cAMP/PKA pathway to potently enhance Ca2+-stimulated insulin release in the GK β-cell and, in doing so, normalizes its defective glucose responsiveness.
Is There a Role for Locally Produced Interleukin-1 in the Deleterious Effects of High Glucose or the Type 2 Diabetes Milieu to Human Pancreatic Islets?
Authors: Welsh Nils , Cnop Miriam , Kharroubi Ilham , Bugliani Marco , Lupi Roberto , Marchetti Piero , Eizirik Décio L.
Published: March 2007

Different degrees of β-cell failure and apoptosis are present in type 1 and type 2 diabetes. It has been recently suggested that high glucose–induced β-cell apoptosis in type 2 diabetes shares a final common pathway with type 1 diabetes, involving interleukin-1β (IL-1β) production by β-cells, nuclear factor-κB (NF-κB) activation, and death via Fas-FasL. The aim of this study was to test whether human islet exposure to high glucose in vitro, or to the type 2 diabetes environment in vivo, induces IL-1β expression and consequent activation of NF-κB–dependent genes. Human islets were isolated from five normoglycemic organ donors. The islets were cultured for 48 h to 7 days at 5.6, 11, or 28 mmol/l glucose. For comparative purposes, islets were also exposed to IL-1β. Gene mRNA expression levels were assessed by real-time RT-PCR in a blinded fashion. Culture of the human islets at 11 and 28 mmol/l glucose induced a four- to fivefold increase in medium insulin as compared with 5.6 mmol/l glucose, but neither IL-1β nor IL-1 receptor antagonist (IL-1ra) expression changed. IL-1β and IL-1ra protein release to the medium was also unchanged. Stimulated human monocytes, studied in parallel, released >50-fold more IL-1β than the islets. There was also no glucose-induced islet Fas expression. Expression of the NF-κB–dependent genes IκB-α and monocyte chemoattractant protein (MCP)-1 was induced in human islets by IL-1β but not by high glucose. In a second set of experiments, human islets were isolated from seven type 2 diabetic patients and eight control subjects. The findings on mRNA levels were essentially the same as in the in vitro experiments, namely the in vivo diabetic state did not induce IL-1β, Fas, or MCP-1 expression in human islets, and also did not modify IL-1ra expression. The present findings suggest that high glucose in vitro, or the diabetic milieu in vivo, does not induce IL-1β production or NF-κB activation in human islets. This makes it unlikely that locally produced IL-1β is an important mediator of glucotoxicity to human islets and argues against the IL-1β–NF-κB–Fas pathway as a common mediator for β-cell death in type 1 and type 2 diabetes.
Susceptibility to Diabetic Nephropathy Is Related to Dicarbonyl and Oxidative Stress
Authors: Beisswenger Paul J. , Drummond Keith S. , Nelson Robert G. , Howell Scott K. , Szwergold Benjamin S. , Mauer Michael
Published: March 2007

Dicarbonyl and oxidative stress may play important roles in the development of diabetes complications, and their response to hyperglycemia could determine individual susceptibility to diabetic nephropathy. This study examines the relationship of methylglyoxal, 3-deoxyglucosone (3DG), and oxidative stress levels to diabetic nephropathy risk in three populations with diabetes. All subjects in the Overt Nephropathy Progressor/Nonprogressor (ONPN) cohort (n = 14), the Natural History of Diabetic Nephropathy study (NHS) cohort (n = 110), and the Pima Indian cohort (n = 45) were evaluated for clinical nephropathy, while renal structural measures of fractional mesangial volume [Vv(Mes/glom)] and glomerular basement membrane (GBM) width were determined by electron microscopy morphometry in the NHS and Pima Indian cohorts. Methylglyoxal and 3DG levels reflected dicarbonyl stress, while reduced glutathione (GSH) and urine 8-isoprostane (8-IP) measured oxidative stress. Cross-sectional measures of methylglyoxal production by red blood cells incubated in 30 mmol/l glucose were increased in nephropathy progressors relative to nonprogressors in the ONPN (P = 0.027) and also reflected 5-year GBM thickening in the NHS cohort (P = 0.04). As nephropathy progressed in the NHS cohort, in vivo levels of methylglyoxal (P = 0.036), 3DG (P = 0.004), and oxidative stress (8-IP, P = 0.007 and GSH, P = 0.005) were seen, while increased methylglyoxal levels occurred as nephropathy progressed (P = 0.0016) in the type 2 Pima Indian cohort. Decreased glyceraldehyde-3-phosphate dehydrogenase activity also correlated with increased methylglyoxal levels (P = 0.003) in the NHS cohort. In conclusion, progression of diabetic nephropathy is significantly related to elevated dicarbonyl stress and possibly related to oxidative stress in three separate populations, suggesting that these factors play a role in determining individual susceptibility.
Sequence Variation inPPARGMay Underlie Differential Response to Troglitazone
Authors: Wolford Johanna K. , Yeatts Kimberly A. , Dhanjal Sharanjeet K. , Black Mary Helen , Xiang Anny H. , Buchanan Thomas A. , Watanabe Richard M.
Published: March 2007

Thiazolidinediones (TZDs) are peroxisome proliferator–activated receptor-γ (PPARG) agonists used to treat type 2 diabetes. TZDs can also be used to reduce rates of type 2 diabetes in at-risk individuals. However, a large fraction of TZD-treated patients (30–40%) do not respond to TZD treatment with an improvement in insulin sensitivity (Si). We hypothesized that variation within the gene encoding PPARG may underlie this differential response to TZD therapy. We screened ∼40 kb of PPARG in 93 nondiabetic Hispanic women (63 responders and 30 nonresponders) with previous gestational diabetes who had participated in the Troglitazone In the Prevention Of Diabetes study. TZD nonresponse was defined as the lower tertile in change in Si after 3 months of treatment. Baseline demographic and clinical measures were not different between responders and nonresponders. We identified and genotyped 131 variants including 126 single nucleotide polymorphisms and 5 insertion-deletion polymorphisms. Linkage disequilibrium analysis identified five haplotype blocks. Eight variants were associated with TZD response (P < 0.05). Three variants were also associated with changes in Si as a continuous variable. Our results suggest that PPARG variation may underlie response to TZD therapy in women at risk for type 2 diabetes.
The Fatty Acid–Binding Protein-2 A54T Polymorphism Is Associated With Renal Disease in Patients With Type 2 Diabetes
Authors: Canani Luis H. , Capp Clarissa , Ng Daniel P.K. , Choo Serena G.L. , Maia Ana Luiza , Nabinger Gustavo B. , Santos Kátia , Crispim Daisy , Roisemberg Israel , Krolewski Andrzej S. , Gross Jorge L.
Published: March 2007

The intestinal fatty–acid binding protein-2 (FABP2) gene codes a protein responsible for the absorption of long-chain fatty acids. To test whether FABP2 is a candidate gene for renal disease in patients with type 2 diabetes, a functional A54T polymorphism was genotyped in 1,042 Brazilians with type 2 diabetes. Patients were classified as having normoalbuminuria (urinary albumin excretion [UAE] <20 μg/min; n = 529), microalbuminuria (UAE 20–199 μg/min; n = 217), or proteinuria (UAE >199 μg/min; n = 160). Patients with end-stage renal disease (ESRD) (n = 136) were also included. The prevalence of the TT genotype was higher in patients with renal involvement compared with those with normoalbuminuria (odds ratio [95% CI] 2.4 [1.1–5.4]) following adjustment for type 2 diabetes duration, BMI, hypertension, A1C, and cholesterol levels. The risk was similar considering different stages of renal involvement. In a second independent patient sample (483 type 2 diabetic Caucasians residing in Massachusetts), a significant association was also observed between the TT genotype and proteinuria or ESRD (2.7 [1.0–7.3]; P = 0.048). This study thus provides evidence that FABP2 confers susceptibility to renal disease in type 2 diabetic patients.
Risk of Diabetic Nephropathy in Type 1 Diabetes Is Associated With Functional Polymorphisms in RANTES Receptor Gene (CCR5)
Authors: Mlynarski Wojciech M. , Placha Grzegorz P. , Wolkow Pawel P. , Bochenski Jacek P. , Warram James H. , Krolewski Andrzej S.
Published: March 2007

Chemokines and their receptors have been implicated in the development of diabetic nephropathy. To determine whether the risk of diabetic nephropathy is influenced by two functional polymorphisms in the regulated upon activation normal T-cell expressed and secreted (RANTES) receptor gene (CCR5), we recruited patients with type 1 diabetes, including 496 case subjects with overt proteinuria or end-stage renal disease and 298 control subjects with normoalbuminuria. Male carriers of the 59029G allele, which is associated with diminished expression of CCR5 on the surface of immunocompetent cells, had significantly higher risk of developing diabetic nephropathy than noncarriers (OR [95% CI] 1.9 [1.2–3.0]). Similarly, male carriers of the 32-bp deletion, which causes truncation of the protein, had significantly higher risk of diabetic nephropathy than noncarriers (2.3 [1.3–4.2]). Combining both polymorphisms, three haplotypes were distinguished: one nonrisk haplotype carrying the 59029A allele and the 32-bp insertion and two risk haplotypes carrying the 59029A allele with the 32-bp deletion and carrying the 59029G allele with the 32-bp insertion. The distribution of these haplotypes differed significantly (P < 0.00001) in men with and without diabetic nephropathy but was not associated with diabetic nephropathy in women. In conclusion, two functional polymorphisms in CCR5 that decrease expression of the RANTES receptor on immunocompetent cells are associated with increased risk of diabetic nephropathy in type 1 diabetes, but only in men.
Peripheral Hyperinsulinemia Promotes Tau Phosphorylation In Vivo
Authors: Freude Susanna , Plum Leona , Schnitker Jessika , Leeser Uschi , Udelhoven Michael , Krone Wilhelm , Bruning Jens C. , Schubert Markus
Published: March 2007

Cerebral insulin receptors play an important role in regulation of energy homeostasis and development of neurodegeneration. Accordingly, type 2 diabetes characterized by insulin resistance is associated with an increased risk of developing Alzheimer’s disease. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases. Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser202 in the central nervous system. Phospho-FoxO1 and PI-3,4,5-phosphate immunostainings of brains from insulin-stimulated mice showed neuronal staining throughout the brain, not restricted to brain areas without functional blood-brain barrier. Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration.
Peroxisome Proliferator–Activated Receptor (PPAR)α Activation Increases Adiponectin Receptors and Reduces Obesity-Related Inflammation in Adipose Tissue
Authors: Tsuchida Atsushi , Yamauchi Toshimasa , Takekawa Sato , Hada Yusuke , Ito Yusuke , Maki Toshiyuki , Kadowaki Takashi
Published: March 2007

We examined the effects of activation of peroxisome proliferator–activated receptor (PPAR)α, PPARγ, and both of them in combination in obese diabetic KKAy mice and investigated the mechanisms by which they improve insulin sensitivity. PPARα activation by its agonist, Wy-14,643, as well as PPARγ activation by its agonist, rosiglitazone, markedly improved insulin sensitivity. Interestingly, dual activation of PPARα and -γ by a combination of Wy-14,643 and rosiglitazone showed increased efficacy. Adipocyte size in Wy-14,643–treated KKAy mice was much smaller than that of vehicle- or rosiglitazone-treated mice, suggesting that activation of PPARα prevents adipocyte hypertrophy. Moreover, Wy-14,643 treatment reduced inflammation and the expression of macrophage-specific genes in white adipose tissue (WAT). Importantly, Wy-14,643 treatment upregulated expression of the adiponectin receptor (AdipoR)-1 and AdipoR2 in WAT, which was decreased in WAT of KKAy mice compared with that in nondiabetic control mice. Furthermore, Wy-14,643 directly increased expression of AdipoRs and decreased monocyte chemoattractant protein-1 expression in adipocytes and macrophages. Rosiglitazone increased serum adiponectin concentrations and the ratio of high molecular weight multimers of adiponectin to total adiponectin. A combination of rosiglitazone and Wy-14,643 increased both serum adiponectin concentrations and AdipoR expression in WAT. These data suggest that PPARα activation prevents inflammation in WAT and that dual activation of PPARα and -γ enhances the action of adiponectin by increasing both adiponectin and AdipoRs, which can result in the amelioration of obesity-induced insulin resistance.