bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal Glucose Homeostasis due to Chronic Hyperresistinemia
Authors: Rangwala Shamina M. , Rich A. Sophie , Rhoades Ben , Shapiro Jennifer S. , Obici Silvana , Rossetti Luciano , Lazar Mitchell A.
Published: March 2007

Resistin is an adipocyte-secreted protein that circulates at increased levels in obesity. Acute administration of resistin impairs glucose tolerance, but the effects of chronic hyperresistinemia have not been established. Here we describe the generation and characterization of transgenic mice that have high circulating levels of resistin in the setting of normal weight. Fasted blood glucose was higher in resistin-transgenic mice than in their nontransgenic littermates, and glucose tolerance was impaired in the hyperresistinemic mice. Metabolic studies in the setting of a hyperinsulinemic-euglycemic clamp protocol revealed that chronically hyperresistinemic mice have elevated glucose production. This increase in glucose production may be partly explained by increased expression of hepatic phosphoenolpyruvate carboxykinase. Thus, chronic hyperresistinemia impairs normal glucose metabolism.
Does the Glucose-Dependent Insulin Secretion Mechanism Itself Cause Oxidative Stress in Pancreatic β-Cells?
Authors: Fridlyand Leonid E. , Philipson Louis H.
Published: March 2007

Glucose-dependent insulin secretion (GDIS), reactive oxygen species (ROS) production, and oxidative stress in pancreatic β-cells may be tightly linked processes. Here we suggest that the same pathways used in the activation of GDIS (increased glycolytic flux, ATP-to-ADP ratio, and intracellular Ca2+ concentration) can dramatically enhance ROS production and manifestations of oxidative stress and, possibly, apoptosis. The increase in ROS production and oxidative stress produced by GDIS activation itself suggests a dual role for metabolic insulin secretagogues, as an initial sharp increase in insulin secretion rate can be accompanied by progressive β-cell injury. We propose that therapeutic strategies targeting enhancement of GDIS should be carefully considered in light of possible loss of β-cell function and mass.
Effects of Different Hypocaloric Diets on Protein Secretion From Adipose Tissue of Obese Women
Authors: Arvidsson Elisabet , Viguerie Nathalie , Andersson Ingalena , Verdich Camilla , Langin Dominique , Arner Peter
Published: March 2007

Little is known about common factors (e.g., macronutrients and energy supply) regulating the protein secretory function of adipose tissue. We therefore compared the effects of randomly assigned 10-week hypoenergetic (−600 kcal/day) diets with moderate-fat/moderate-carbohydrate or low-fat/high-carbohydrate content on circulating levels and production of proteins (using radioimmunoassays and enzyme-linked immunosorbent assays) from subcutaneous adipose tissue in 40 obese but otherwise healthy women. Similar results were obtained by the two diets. Body weight decreased by ∼7.5%. The secretion rate of leptin decreased by ∼40%, as did that of tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 and -8 decreased by 25–30%, whereas the secretion of plasminogen activator inhibitor 1 (PAI-1) and adiponectin did not show any changes. Regarding mRNA expression (by real-time PCR), only that of leptin and IL-6 decreased significantly. Circulating levels of leptin and PAI-1 decreased by 30 and 40%, respectively, but there were only minor changes in circulating TNF-α, IL-6, or adiponectin. In conclusion, moderate caloric restriction but not macronutrient composition influences the production and secretion of adipose tissue–derived proteins during weight reduction, leptin being the most sensitive and adiponectin and PAI-1 the least sensitive.
Flt3-Ligand Treatment Prevents Diabetes in NOD Mice
Authors: Chilton Paula M. , Rezzoug Francine , Fugier-Vivier Isabelle , Weeter Leslie A. , Xu Hong , Huang Yiming , Ray Mukunda B. , Ildstad Suzanne T.
Published: March 2007

The mechanism by which mixed chimerism reverses autoimmunity in type 1 diabetes has not been defined. NOD mice have a well-characterized defect in the production of myeloid progenitors that is believed to contribute significantly to the autoimmune process. We therefore investigated whether chimerism induces a correction of this defect. Mixed chimerism restored production of myeloid progenitors in NOD mice to normal levels. Notably, NOD bone marrow cells as well as donor bone marrow cells produced the mature myeloid progeny, and the level of donor chimerism was not correlated with the degree of restoration of the defect. Moreover, NOD bone marrow cells cultured with Flt3-ligand developed a heat-stable antigen-positive/Ly6C+ population comprised primarily of mature myeloid dendritic cells, suggesting that the underlying abnormality is not cell intrinsic but rather due to a block in development of mature myeloid progeny, including myeloid dendritic cells. Strikingly, treatment of NOD mice with Flt3-ligand significantly decreased insulitis and progression to diabetes and was associated with a significant increase in myeloid dendritic cells and in vivo induction of CD4+/CD25+ cells in the pancreatic lymph node. Therefore, Flt3-ligand treatment and/or the establishment of mixed chimerism in prediabetic candidates may provide a benign and novel approach to treat diabetes.
Interactions Between Endothelin and Nitric Oxide in the Regulation of Vascular Tone in Obesity and Diabetes
Authors: Mather Kieren J. , Lteif Amale , Steinberg Helmut O. , Baron Alain D.
Published: March 2007

Endothelial dysfunction reflects an imbalance of vasodilators and vasoconstrictors. Endogenous endothelin activity seems to be increased in human obesity and type 2 diabetes, and cellular studies suggest that this factor may itself reduce bioavailable nitric oxide (NO). We studied 20 lean, 20 obese, and 14 type 2 diabetic individuals under three protocols, measuring leg vascular responses to intra-arterial infusions of NG-monomethyl-l-arginine (l-NMMA; an inhibitor of NO synthase) alone or in combination with BQ123 (an antagonist of type A endothelin receptors) or phentolamine (used as a control vasodilator). NO synthase inhibition alone (study 1) produced an ∼40% increase in leg vascular resistance (LVR) in all three participant groups, which was not statistically different across groups (increase in LVR: lean, 135 ± 28; obese, 140 ± 32; type 2 diabetic, 184 ± 51 units; NS). By design, BQ123 at the infused rate of 3 μmol/min produced equivalent ∼35% reductions in LVR across groups. The subsequent addition of l-NMMA produced a greater increase in LVR among obese participants than lean or type 2 diabetic participants (study 2: lean, 182 ± 48; obese, 311 ± 66; type 2 diabetic, 186 ± 40; P = 0.07). Compared with study 1, the effect of l-NMMA was magnified by BQ123 in obese participants but not in lean or type 2 diabetic participants (P = 0.005, study 1 vs. 2; P = 0.03 for group effect). Phentolamine (75 mg/min) produced vasodilation in obese participants comparable to that seen with BQ123 but failed to augment the l-NMMA response. Endothelin antagonism unmasks or augments NO synthesis capacity in obese but not type 2 diabetic participants. This suggests that impaired NO bioavailability as a result of endogenous endothelin may contribute to endothelial dysfunction in obesity, in addition to direct vasoconstrictor effects of endothelin. In contrast, endothelin antagonism alone is insufficient to restore impaired NO bioavailability in diabetes.
Prospective Isolation of Multipotent Pancreatic Progenitors Using Flow-Cytometric Cell Sorting
Authors: Suzuki Atsushi , Nakauchi Hiromitsu , Taniguchi Hideki
Published: March 2007

During pancreatic development, neogenesis, and regeneration, stem cells might act as a central player to generate endocrine, acinar, and duct cells. Although these cells are well known as pancreatic stem cells (PSCs), indisputable proof of their existence has not been reported. Identification of phenotypic markers for PSCs leads to their prospective isolation and precise characterization to clear whether stem cells exist in the pancreas. By combining flow cytometry and clonal analysis, we show here that a possible pancreatic stem or progenitor cell candidate that resides in the developing and adult mouse pancreas expresses the receptor for the hepatocyte growth factor (HGF) c-Met, but does not express hematopoietic and vascular endothelial antigens such as CD45, TER119, c-Kit, and Flk-1. These cells formed clonal colonies in vitro and differentiated into multiple pancreatic lineage cells from single cells. Some of them could largely expand with self-renewing cell divisions in culture, and, following cell transplantation, they differentiated into pancreatic endocrine and acinar cells in vivo. Furthermore, they produced cells expressing multiple markers of nonpancreatic organs including liver, stomach, and intestine in vitro. Our data strongly suggest that c-Met/HGF signaling plays an important role in stem/progenitor cell function in both developing and adult pancreas. By using this antigen, PSCs could be isolated prospectively, enabling a detailed investigation of stem cell markers and application toward regenerative therapies for diabetes.
Effects of Rosiglitazone and Metformin on Liver Fat Content, Hepatic Insulin Resistance, Insulin Clearance, and Gene Expression in Adipose Tissue in Patients With Type 2 Diabetes
Authors: Tiikkainen Mirja , Häkkinen Anna-Maija , Korsheninnikova Elena , Nyman Tuulikki , Mäkimattila Sari , Yki-Järvinen Hannele
Published: March 2007

Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 ± 3 years, fasting plasma glucose 152 ± 9 mg/dl, BMI 30.6 ± 0.8 kg/m2) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA1c, insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 ± 4 vs. 82 ± 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 ± 3 vs. 7 ± 1%, 0 vs. 16 weeks, P = 0.003) but not by metformin (13 ± 3 to 14 ± 3%, NS). Rosiglitazone (16 ± 2 vs. 20 ± 1 ml · kg−1 · min−1, P = 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r = −0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator–activated receptor-γ, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.
Expression of Adiponectin Receptor mRNA in Human Skeletal Muscle Cells Is Related to In Vivo Parameters of Glucose and Lipid Metabolism
Authors: Staiger Harald , Kaltenbach Simone , Staiger Katrin , Stefan Norbert , Fritsche Andreas , Guirguis Alke , Péterfi Claudia , Weisser Melanie , Machicao Fausto , Stumvoll Michael , Häring Hans-Ulrich
Published: March 2007

The adiponectin receptors, AdipoR1 and AdipoR2, are thought to transmit the insulin-sensitizing, anti-inflammatory, and atheroprotective effects of adiponectin. In this study, we examined whether AdipoR mRNA expression in human myotubes correlates with in vivo measures of insulin sensitivity. Myotubes from 40 metabolically characterized donors expressed 1.8-fold more AdipoR1 than AdipoR2 mRNA (588 ± 35 vs. 321 ± 39 fg/μg total RNA). Moreover, the expression levels of both receptors correlated with each other (r = 0.45, P < 0.01). AdipoR1 mRNA expression was positively correlated with in vivo insulin and C-peptide concentrations, first-phase insulin secretion, and plasma triglyceride and cholesterol concentrations before and after adjustment for sex, age, waist-to-hip ratio, and body fat. Expression of AdipoR2 mRNA clearly associated only with plasma triglyceride concentrations. In multivariate linear regression models, mRNA expression of AdipoR1, but not AdipoR2, was a determinant of first-phase insulin secretion independent of insulin sensitivity and body fat. Finally, insulin did not directly modify myotube AdipoR1 mRNA expression in vitro. In conclusion, we provide evidence that myotube mRNA levels of both receptors are associated with distinct metabolic functions but not with insulin sensitivity. AdipoR1, but not AdipoR2, expression correlated with insulin secretion. The molecular nature of this link between muscle and β-cells needs to be further clarified.
Identification and Cloning of a β-Cell–Specific Zinc Transporter, ZnT-8, Localized Into Insulin Secretory Granules
Authors: Chimienti Fabrice , Devergnas Séverine , Favier Alain , Seve Michel
Published: March 2007

SLC30A8, a novel member of the zinc transporter (ZnT) family, was identified by searching the human genomic and expressed sequence tag (EST) databases with the amino acid sequence of all known human ZnT. The protein (369 amino acids) predicted from this gene, ZnT-8, contains six transmembrane domains and a histidine-rich loop between transmembrane domains IV and V, like the other ZnT proteins. We demonstrated by RT-PCR on cDNA libraries and human tissue extracts that the ZnT-8 gene is solely transcribed in the pancreas, mainly in the islets of Langerhans. The gene, named SLC30A8, was cloned and sequenced. Confocal immunofluorescence analysis revealed that a ZnT-8-EGFP (enhanced green fluorescent protein) fusion product colocalized with insulin in the secretory pathway granules of the insulin-secreting INS-1 cells. Exposure of the ZnT-8-EGFP stably expressing HeLa cells to 75 μmol/l zinc caused an accumulation of zinc in intracellular vesicles compared with cells expressing EGFP alone. These results identified ZnT-8 as a ZnT specific to the pancreas and expressed in β-cells. Because ZnT-8 facilitates the accumulation of zinc from the cytoplasm into intracellular vesicles, ZnT-8 may be a major component for providing zinc to insulin maturation and/or storage processes in insulin-secreting pancreatic β-cells.
Reduced Hepatic Insulin Extraction in Response to Gastric Inhibitory Polypeptide Compensates for Reduced Insulin Secretion in Normal-Weight and Normal Glucose Tolerant First-Degree Relatives of Type 2 Diabetic Patients
Authors: Rudovich Natalia N. , Rochlitz Helmut J. , Pfeiffer Andreas F.H.
Published: March 2007

Our objective was to study whether young first-degree relatives of patients with type 2 diabetes (FDRs) have altered insulin secretion and insulin clearance in response to gastric inhibitory polypeptide (GIP) in combination with glucose and arginine. A hyperglycemic clamp (11.1 mmol/l for 115 min), followed by addition of GIP (2 pmol · kg−1 · min−1, 60–115 min) and an arginine bolus and infusion (10 mg · kg−1 · min−1, 90–115 min), was conducted on 14 healthy volunteers and 13 FDRs. Both groups had normal glucose tolerance. FDRs were more insulin resistant (HOMAIR) under basal conditions (P = 0.003). FDRs demonstrated significant global impairment in insulin secretion capacity, which was not specific for one of the secretagogues. Insulin clearance was significantly reduced in the group of FDRs under basal conditions and in response to GIP, but there was no general defect in insulin clearance in response to glucose and arginine. The HOMAIR correlated negatively (P < 0.01) with insulin clearance under basal conditions (r = −0.96) and under GIP infusion (r = −0.56). We propose that impairment in insulin secretion capacity and decreased insulin sensitivity is compensated for several mechanisms, one of which includes a GIP-dependent reduction of the insulin clearance that will increase peripheral insulin levels to maintain normoglycemia.
Impaired Cardiac Efficiency and Increased Fatty Acid Oxidation in Insulin-Resistant ob/ob Mouse Hearts
Authors: Mazumder Pradip K. , O’Neill Brian T. , Roberts Matthew W. , Buchanan Jonathan , Yun Ui Jeong , Cooksey Robert C. , Boudina Sihem , Abel E. Dale
Published: March 2007

Diabetes alters cardiac substrate metabolism. The cardiac phenotype in insulin-resistant states has not been comprehensively characterized. The goal of these studies was to determine whether the hearts of leptin-deficient 8-week-old ob/ob mice were able to modulate cardiac substrate utilization in response to insulin or to changes in fatty acid delivery. Ob/ob mice were insulin resistant and glucose intolerant. Insulin signal transduction and insulin-stimulated glucose uptake were markedly impaired in ob/ob cardiomyocytes. Insulin-stimulated rates of glycolysis and glucose oxidation were 1.5- and 1.8-fold higher in wild-type hearts, respectively, versus ob/ob, and glucose metabolism in ob/ob hearts was unresponsive to insulin. Increasing concentrations of palmitate from 0.4 mmol/l (low) to 1.2 mmol/l (high) led to a decline in glucose oxidation in wild-type hearts, whereas glucose oxidation remained depressed and did not change in ob/ob mouse hearts. In contrast, fatty acid utilization in ob/ob hearts was 1.5- to 2-fold greater in the absence or presence of 1 nmol/l insulin and rose with increasing palmitate concentrations. Moreover, the ability of insulin to reduce palmitate oxidation rates was blunted in the hearts of ob/ob mice. Under low-palmitate and insulin-free conditions, cardiac performance was significantly greater in wild-type hearts. However, in the presence of high palmitate and 1 nmol/l insulin, cardiac performance in ob/ob mouse hearts was relatively preserved, whereas function in wild-type mouse hearts declined substantially. Under all perfusion conditions, myocardial oxygen consumption was higher in ob/ob hearts, ranging from 30% higher in low-palmitate conditions to greater than twofold higher under high-palmitate conditions. These data indicate that although the hearts of glucose-intolerant ob/ob mice are capable of maintaining their function under conditions of increased fatty acid supply and hyperinsulinemia, they are insulin-resistant, metabolically inefficient, and unable to modulate substrate utilization in response to changes in insulin and fatty acid supply.
Increased Expression of Gi-Coupled Muscarinic Acetylcholine Receptor and Gi in Atrium of Elderly Diabetic Subjects
Authors: Richardson Mark D. , Kilts Jason D. , Kwatra Madan M.
Published: March 2007

In an ongoing investigation of the effects of age on G protein–coupled receptor signaling in human atrial tissue, we have found that the density of atrial muscarinic acetylcholine receptor (mAChR) increases with age but reaches statistical significance only in patients with diabetes. Moreover, we find that in elderly subjects of similar ages, those with diabetes have 1.7-fold higher levels of Gαi2 and twofold higher levels of Gβ1. Diabetes does not affect other atrial G proteins, including Gαi3, Gαs, Gαo, and Gβ2. These data represent the first demonstration of an increase in a Gi-coupled receptor, Gαi2, and Gβ1, in atrium of patients with diabetes. These findings suggest a molecular explanation for the increased risk of cardiac disease in patients with diabetes, because increased signaling through Gi has been shown to lead to the development of dilated cardiomyopathy.
Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia
Authors: Degn Kristine B. , Brock Birgitte , Juhl Claus B. , Djurhuus Christian B. , Grubert Jaime , Kim Dennis , Han Jenny , Taylor Kristin , Fineman Mark , Schmitz Ole
Published: March 2007

This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol · kg−1 · min−1) or placebo during a 270-min stepwise hyperinsulinemic-hypoglycemic clamp (insulin infusion 0.8 mU · kg−1 · min−1). Plasma glucose was clamped sequentially at 5.0 (0–120 min), 4.0 (120–180 min), 3.2 (180–240 min), and 2.7 mmol/l (240–270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to ∼3.2 mmol/l. The time to achieve plasma glucose ≥4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were ∼3.5-fold higher than in the placebo arm (353 ± 29 vs. 100 ± 29 pmol/min [least-square means ± SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (≤4 mmol/l) in both groups. Glucagon was suppressed in the exenatide arm during euglycemia and higher than placebo during hypoglycemia. Plasma glucose recovery time was equivalent for both treatments. The areas under the concentration-time curve from 270 to 360 min for cortisol, epinephrine, norepinephrine, and growth hormone were similar between treatment arms. There were no differences in adverse events. In the presence of exenatide, there was a preserved, glucose-dependent insulin secretory response and counterregulatory response during hypoglycemia.
Studies of Rat and Human Retinas Predict a Role for the Polyol Pathway in Human Diabetic Retinopathy
Authors: Dagher Zeina , Park Yong Seek , Asnaghi Veronica , Hoehn Todd , Gerhardinger Chiara , Lorenzi Mara
Published: March 2007

The polyol (sorbitol) pathway of glucose metabolism is activated in many cell types when intracellular glucose concentrations are high, and it can generate cellular stress through several mechanisms. The role of the polyol pathway in the pathogenesis of diabetic retinopathy has remained uncertain, in part because it has been examined preferentially in galactose-induced retinopathy and in part because inhibition studies may not have achieved full blockade of the pathway. Having observed that the streptozotocin-induced diabetic rat accurately models many cellular processes characteristic of human diabetic retinopathy, we tested in the diabetic rat if documented inhibition of the polyol pathway prevents a sequence of retinal vascular abnormalities also present in human diabetes. An inhibitor of aldose reductase, the rate-limiting enzyme in the pathway, prevented the early activation of complement in the wall of retinal vessels and the decreased levels of complement inhibitors in diabetic rats, as well as the later apoptosis of vascular pericytes and endothelial cells and the development of acellular capillaries. Both rat and human retinal endothelial cells showed aldose reductase immunoreactivity, and human retinas exposed to high glucose in organ culture increased the production of sorbitol by a degree similar to that observed in the rat. Excess aldose reductase activity can be a mechanism for human diabetic retinopathy.
Nitration and Functional Loss of Voltage-Gated K+ Channels in Rat Coronary Microvessels Exposed to High Glucose
Authors: Li Hongwei , Gutterman David D. , Rusch Nancy J. , Bubolz Aaron , Liu Yanping
Published: March 2007

Coronary microvessels generate reactive oxygen species in response to high glucose (HG), resulting in vasodilator defects involving an impaired function of vascular K+ channels. Inhibition of voltage-gated K+ (Kv) channels by peroxynitrite (ONOO−), formed by the interaction of superoxide and nitric oxide, may contribute to impaired dilation. The present study investigated whether HG induces ONOO− formation to mediate nitration and impairment of Kv channels in rat small coronary arteries (RSCAs). Exposure to ONOO− reduced the dilator influence of Kv channels in RSCAs. Patch-clamp studies revealed that ONOO− diminished whole-cell and unitary Kv currents attributable to the Kv1 gene family in smooth muscle cells. Subsequently, immunohistochemically detected enhancement of nitrotyrosine residues in RSCAs that were cultured in HG (23 mmol/l) compared with normal glucose (5.5 mmol/l) for 24 h correlated with the nitration of Kv1.2 channel α-subunits. HG-induced nitrotyrosine formation was partially reversed by scavenging ONOO−. Finally, RSCAs that were exposed to HG for 24 h showed a loss of Kv channel dilator influence that also was partially restored by the ONOO− scavengers urate and ebselen. We conclude that ONOO− generated by HG impairs Kv channel function in coronary microvessels, possibly by nitrating tyrosine residues in the pore-forming region of the Kv channel protein.
Functional Variants in the Glutathione Peroxidase-1 (GPx-1) Gene Are Associated With Increased Intima-Media Thickness of Carotid Arteries and Risk of Macrovascular Diseases in Japanese Type 2 Diabetic Patients
Authors: Hamanishi Tohru , Furuta Hiroto , Kato Hisako , Doi Asako , Tamai Masanori , Shimomura Hiroko , Sakagashira Setsuya , Nishi Masahiro , Sasaki Hideyuki , Sanke Tokio , Nanjo Kishio
Published: March 2007

Atherosclerosis in type 2 diabetic patients has been linked to increased oxidative stress. Glutathione peroxidase-1 (GPx-1) plays an important role in the antioxidant defense of the vascular wall. To assess the association between variants in the GPx-1 gene and atherosclerosis, we screened the gene in 184 Japanese type 2 diabetic patients and identified four polymorphisms (−602A/G, +2C/T, Ala5/Ala6, and Pro198Leu). Among these polymorphisms, −602G, +2T, Ala6, and 198Leu were in strong linkage disequilibrium with each other. The patients were divided into two groups on the basis of the codon 198 polymorphism, Pro/Pro (n = 151) and Pro/Leu (n = 33), to analyze clinical characteristics. The mean intima-media thickness (IMT) of common carotid arteries (P = 0.0028) and the prevalence of cardiovascular disease (P = 0.035) and peripheral vascular disease (P = 0.027) were significantly higher in the Pro/Leu group than in the Pro/Pro group. In vitro functional analyses indicated that the combination of polymorphisms (Ala6/198Leu) of the GPx-1 gene had a 40% decrease in enzyme activity, and the combination of polymorphisms (−602G/+2T) had a 25% decrease in transcriptional activity. These results suggest that functional variants in the GPx-1 gene are associated with increased IMT of carotid arteries and risk of cardiovascular and peripheral vascular diseases in type 2 diabetic patients.
Adiponectin and the Development of Type 2 Diabetes
Authors: Duncan Bruce B. , Schmidt Maria Inês , Pankow James S. , Bang Heejung , Couper David , Ballantyne Christie M. , Hoogeveen Ron C. , Heiss Gerardo
Published: March 2007

Adipocyte-derived secretory proteins have been increasingly linked to diabetes. To investigate whether adiponectin, a major adipocyte secretory protein, predicts diabetes, we conducted a case-cohort study representing the ∼9-year experience of the 10,275 middle-aged, U.S. African-American and white participants of the Atherosclerosis Risk in Communities (ARIC) study. Adiponectin was measured on stored plasma of 581 incident diabetes case subjects and 572 noncase subjects. Overall hazard ratios (95% CIs) for developing diabetes, for those in the second, third, and fourth (versus the first) quartile of adiponectin were 0.57 (0.41–0.78), 0.39 (0.27–0.56), and 0.18 (0.11–0.27), respectively, after adjustment for age, sex, ethnicity, study center, parental history of diabetes, and hypertension and 0.72 (0.48–1.09), 0.67 (0.43–1.04), and 0.58 (0.34–0.99), respectively, after additional adjustment for BMI, waist-to-hip ratio, fasting glucose, insulin, and a score composed of six inflammation markers. The association was of similar magnitude in men and women and in whites and African Americans, but was absent in smokers and in those with a greater inflammation score (interaction P < 0.01 for each). In conclusion, in this community-based sample of U.S. adults, higher adiponectin levels were associated with a lower incidence of diabetes.
Metabolic Regulation of the Pancreatic Beta-Cell ATP-Sensitive K+ Channel
Authors: Tarasov Andrei , Dusonchet Julien , Ashcroft Frances
Published: March 2007

Closure of ATP-sensitive K+ channels (KATP channels) is a key step in glucose-stimulated insulin secretion. The precise mechanism(s) by which glucose metabolism regulates KATP channel activity, however, remains controversial. It is widely believed that the principal determinants are the intracellular concentrations of the metabolic ligands, ATP and ADP, which have opposing actions on KATP channels, with ATP closing and MgADP opening the channel. However, the sensitivity of the channel to these nucleotides in the intact cell, and their relative contribution to the regulation of channel activity, remains unclear. The precise role of phosphoinositides and long-chain acyl-CoA esters, which are capable of modulating the channel ATP sensitivity, is also uncertain. Furthermore, it is still a matter of debate whether it is changes in the concentration of ATP, of MgADP, or of other agents, which couples glucose metabolism to KATP channel activity. In this article, we review current knowledge of the metabolic regulation of the KATP channel and provide evidence that MgADP (or MgATP hydrolysis), acting at the regulatory subunit of the channel, shifts the ATP concentration-response curve into a range in which the channel pore can respond to dynamic changes in cytosolic ATP. This metabolic pas de deux orchestrates the pivotal role of ATP in metabolic regulation of the KATP channel.
Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues
Authors: Rustenbeck Ingo , Wienbergen Antje , Bleck Claudia , Jörns Anne
Published: March 2007

Prolonged stimulation of insulin secretion by depolarization and Ca2+ influx regularly leads to a reversible state of decreased secretory responsiveness to nutrient and nonnutrient stimuli. This state is termed “desensitization.” The onset of desensitization may occur within 1 h of exposure to depolarizing stimuli. Desensitization by exposure to sulfonylureas, imidazolines, or quinine produces a marked cross-desensitization against other ATP-sensitive K+ channel (KATP channel)-blocking secretagogues. However, desensitized β-cells do not necessarily show changes in KATP channel activity or Ca2+ handling. Care has to be taken to distinguish desensitization-induced changes in signaling from effects due to the persisting presence of secretagogues. The desensitization by depolarizing secretagogues is mostly accompanied by a reduced content of immunoreactive insulin and a marked reduction of secretory granules in the β-cells. In vitro recovery from a desensitization by the imidazoline efaroxan was nearly complete after 4 h. At this time point the depletion of the granule content was partially reversed. Apparently, recovery from desensitization affects the whole lifespan of a granule from biogenesis to exocytosis. There is, however, no direct relation between the β-cell granule content and the secretory responsiveness. Even though a prolonged exposure of isolated islets to depolarizing secretagogues is often associated with the occurrence of ultrastructural damage to β-cells, we could not find a cogent link between depolarization and Ca2+ influx and apoptotic or necrotic β-cell death.
The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium
Authors: Quast Ulrich , Stephan Damian , Bieger Susanne , Russ Ulrich
Published: March 2007

Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K+ channel (KATP channel) in the pancreatic β-cell membrane. KATP channels subserve important functions also in the heart. First, KATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia. Second, KATP channels in the sarcolemma of cardiomyocytes (sarcKATP channels) are required for adaptation of the heart to stress. In addition, the opening of sarcKATP channels and of KATP channels in the inner membrane of mitochondria (mitoKATP channels) plays a central role in ischemic preconditioning. Opening of sarcKATP channels also underlies the ST-segment elevation of the electrocardiogram, the primary diagnostic tool for initiation of lysis therapy in acute myocardial infarction. Therefore, inhibition of cardiovascular KATP channels by insulin secretagogues is considered to increase cardiovascular risk. Electrophysiological experiments have shown that the secretagogues differ in their selectivity for the pancreatic over the cardiovascular KATP channels, being either highly selective (∼1,000×; short sulfonylureas such as nateglinide and mitiglinide), moderately selective (10–20×; long sulfonylureas such as glibenclamide [glyburide]), or essentially nonselective (<2×; repaglinide). New binding studies presented here give broadly similar results. In clinical studies, these differences are not yet taken into account. The hypothesis that the in vitro selectivity of the insulin secretagogues is of importance for the cardiovascular outcome of diabetic patients with coronary artery disease needs to be tested.
Five Stages of Evolving Beta-Cell Dysfunction During Progression to Diabetes
Authors: Weir Gordon C. , Bonner-Weir Susan
Published: March 2007

This article proposes five stages in the progression of diabetes, each of which is characterized by different changes in β-cell mass, phenotype, and function. Stage 1 is compensation: insulin secretion increases to maintain normoglycemia in the face of insulin resistance and/or decreasing β-cell mass. This stage is characterized by maintenance of differentiated function with intact acute glucose-stimulated insulin secretion (GSIS). Stage 2 occurs when glucose levels start to rise, reaching ∼5.0–6.5 mmol/l; this is a stable state of β-cell adaptation with loss of β-cell mass and disruption of function as evidenced by diminished GSIS and β-cell dedifferentiation. Stage 3 is a transient unstable period of early decompensation in which glucose levels rise relatively rapidly to the frank diabetes of stage 4, which is characterized as stable decompensation with more severe β-cell dedifferentiation. Finally, stage 5 is characterized by severe decompensation representing a profound reduction in β-cell mass with progression to ketosis. Movement across stages 1–4 can be in either direction. For example, individuals with treated type 2 diabetes can move from stage 4 to stage 1 or stage 2. For type 1 diabetes, as remission develops, progression from stage 4 to stage 2 is typically found. Delineation of these stages provides insight into the pathophysiology of both progression and remission of diabetes.
ATP-Sensitive K+ Channel–Dependent Regulation of Glucagon Release and Electrical Activity by Glucose in Wild-Type and SUR1−/− Mouse α-Cells
Authors: Gromada Jesper , Ma Xiaosong , Høy Marianne , Bokvist Krister , Salehi Albert , Berggren Per-Olof , Rorsman Patrik
Published: March 2007

Patch-clamp recordings and glucagon release measurements were combined to determine the role of plasma membrane ATP-sensitive K+ channels (KATP channels) in the control of glucagon secretion from mouse pancreatic α-cells. In wild-type mouse islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC50] = 2.5 mmol/l) reduction of glucagon release. Maximum inhibition (∼50%) was attained at glucose concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 μmol/l) and glibenclamide (100 nmol/l) inhibited glucagon secretion to the same extent as a maximally inhibitory concentration of glucose. In mice lacking functional KATP channels (SUR1−/−), glucagon secretion in the absence of glucose was lower than that observed in wild-type islets and both glucose (0–20 mmol/l) and the sulfonylureas failed to inhibit glucagon secretion. Membrane potential recordings revealed that α-cells generate action potentials in the absence of glucose. Addition of glucose depolarized the α-cell by ∼7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the α-cell (∼17 mV) and reduced action potential amplitude (43%). Whereas insulin secretion increased monotonically with increasing external K+ concentrations (threshold 25 mmol/l), glucagon secretion was paradoxically suppressed at intermediate concentrations (5.6–15 mmol/l), and stimulation was first detectable at >25 mmol/l K+. In α-cells isolated from SUR1−/− mice, both tolbutamide and glucose failed to produce membrane depolarization. These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1−/− α-cells. Recordings of the free cytoplasmic Ca2+ concentration ([Ca2+]i) revealed that, whereas glucose lowered [Ca2+]i to the same extent as application of tolbutamide, the Na+ channel blocker tetrodotoxin, or the Ca2+ channel blocker Co2+ in wild-type α-cells, the sugar was far less effective on [Ca2+]i in SUR1−/− α-cells. We conclude that the KATP channel is involved in the control of glucagon secretion by regulating the membrane potential in the α-cell in a way reminiscent of that previously documented in insulin-releasing β-cells. However, because α-cells possess a different complement of voltage-gated ion channels involved in action potential generation than the β-cell, moderate membrane depolarization in α-cells is associated with reduced rather than increased electrical activity and secretion.
Gastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes
Authors: Nauck Michael A. , Baller Birgit , Meier Juris J.
Published: March 2007

The incretin effect denominates the phenomenon that oral glucose elicits a higher insulin response than does intravenous glucose. The two hormones responsible for the incretin effect, glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1), are secreted after oral glucose loads and augment insulin secretion in response to hyperglycemia. In patients with type 2 diabetes, the incretin effect is reduced, and there is a moderate degree of GLP-1 hyposecretion. However, the insulinotropic response to GLP-1 is well maintained in type 2 diabetes. GIP is secreted normally or hypersecreted in type 2 diabetes; however, the responsiveness of the endocrine pancreas to GIP is greatly reduced. In ∼50% of first-degree relatives of patients with type 2 diabetes, similarly reduced insulinotropic responses toward exogenous GIP can be observed, without significantly changed secretion of GIP or GLP-1 after oral glucose. This opens the possibility that a reduced responsiveness to GIP is an early step in the pathogenesis of type 2 diabetes. On the other hand, this provides a basis to use incretin hormones, especially GLP-1 and its derivatives, to replace a deficiency in incretin-mediated insulin secretion in the treatment of type 2 diabetes.
Amylin Agonists: A Novel Approach in the Treatment of Diabetes
Authors: Schmitz Ole , Brock Birgitte , Rungby Jorgen
Published: March 2007

Amylin is a peptide hormone that is cosecreted with insulin from the pancreatic β-cell and is thus deficient in diabetic people. It inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent. Amylin replacement could therefore possibly improve glycemic control in some people with diabetes. However, human amylin exhibits physicochemical properties predisposing the peptide hormone to aggregate and form amyloid fibers, which may play a part in β-cell destruction in type 2 diabetes. This obviously makes it unsuitable for pharmacological use. A stable analog, pramlintide, which has actions and pharmacokinetic and pharmacodynamic properties similar to the native peptide, has been developed. The efficacy and safety of pramlintide administration has been tested in a vast number of clinical trials. Aproximately 5,000 insulin-treated patients have received pramlintide and ∼250 for ≥2 years. The aims of this review are to 1) briefly describe actions of amylin as demonstrated in animal and human models and 2) primarily review results from clinical trials with the amylin analog pramlintide.
The Potential Role of SOCS-3 in the Interleukin-1β-Induced Desensitization of Insulin Signaling in Pancreatic Beta-Cells
Authors: Emanuelli Brice , Glondu Murielle , Filloux Chantal , Peraldi Pascal , Van Obberghen Emmanuel
Published: March 2007

Defects in insulin secretion, resulting from loss of function or destruction of pancreatic β-cells, trigger diabetes. Interleukin (IL)-1β is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs β-cell survival and function. Because effective insulin signaling is required for the optimal β-cell function, we assessed the effect of IL-1β on the insulin pathway in a rat pancreatic β-cell line. We show that IL-1β decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1β-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1β inhibitory effect on insulin signaling in these cells. We show that IL-1β increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1β treatment in RINm5F cells. We propose that IL-1β decreases insulin action in β-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced β-cell survival.
Autoimmune Diabetes and Resistance to Xenograft Transplantation Tolerance in NOD Mice
Authors: Gordon Ethel J. , Wicker Linda S. , Peterson Laurence B. , Serreze David V. , Markees Thomas G. , Shultz Leonard D. , Rossini Aldo A. , Greiner Dale L. , Mordes John P.
Published: March 2007

Costimulation blockade induces prolonged rat islet and skin xenograft survival in C57BL/6 mice. Nonobese diabetic (NOD) mice, which are used to model human autoimmune diabetes, are resistant to costimulation blockade-induced allograft tolerance. We tested the hypothesis that NOD mice would also be resistant to costimulation blockade-induced rat xenograft tolerance. We report that rat islet xenograft survival is short in spontaneously diabetic NOD mice treated with a tolerizing regimen of donor-specific transfusion and anti-CD154 antibody. Rat islet xenograft survival is only marginally longer in chemically diabetic NOD mice treated with costimulation blockade but is prolonged further in NOD Idd congenic mice bearing C57-derived chromosome 3 loci. Reciprocally, the presence of NOD-derived chromosome 3 loci shortens islet xenograft survival in tolerized C57BL/6 mice. Islet xenograft survival is longer in tolerized NOD.CD4a−/− and (NOD × C57BL/6)F1 mice than in NOD mice but still much shorter than in C57BL/6 mice. Skin xenograft survival in (NOD × C57BL/6)F1 mice treated with costimulation blockade is short, suggesting a strong genetic resistance to skin xenograft tolerance induction. We conclude that the resistance of NOD mice to xenograft tolerance induction involves some mechanisms that also participate in the expression of autoimmunity and other mechanisms that are distinct.
Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury
Authors: Bose Amal K. , Mocanu Mihaela M. , Carr Richard D. , Brand Christian L. , Yellon Derek M.
Published: March 2007

Glucagon-like peptide 1 (GLP-1), a gut incretin hormone that stimulates insulin secretion, also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinase in pancreatic and insulinoma cells. Since these kinases have been shown to protect against myocardial injury, we hypothesized that GLP-1 could directly protect the heart against such injury via these prosurvival signaling pathways. Both isolated perfused rat heart and whole animal models of ischemia/reperfusion were used, with infarct size measured as the end point of injury. In both studies, GLP-1 added before ischemia demonstrated a significant reduction in infarction compared with the valine pyrrolidide (an inhibitor of its breakdown) or saline groups. This protection was abolished in the in vitro hearts by the GLP-1 receptor antagonist exendin (9-39), the cAMP inhibitor Rp-cAMP, the PI3kinase inhibitor LY294002, and the p42/44 mitogen-activated protein kinase inhibitor UO126. Western blot analysis demonstrated the phosphorylation of the proapoptotic peptide BAD in the GLP-1–treated groups. We show for the first time that GLP-1 protects against myocardial infarction in the isolated and intact rat heart. This protection appears to involve activating multiple prosurvival kinases. This finding may represent a new therapeutic potential for this class of drug currently undergoing clinical trials in the treatment of type 2 diabetes.
Physical Activity in the Prevention of Type 2 Diabetes
Authors: Laaksonen David E. , Lindström Jaana , Lakka Timo A. , Eriksson Johan G. , Niskanen Leo , Wikström Katja , Aunola Sirkka , Keinänen-Kiukaanniemi Sirkka , Laakso Mauri , Valle Timo T. , Ilanne-Parikka Pirjo , Louheranta Anne , Hämäläinen Helena , Rastas Merja , Salminen Virpi , Cepaitis Zygimantas , Hakumäki Martti , Kaikkonen Hannu , Härkönen Pirjo , Sundvall Jouko , Tuomilehto Jaakko , Uusitupa Matti ,   for the Finnish Diabetes Prevention Study Group
Published: March 2007

Clinical trials have demonstrated that lifestyle changes can prevent type 2 diabetes, but the importance of leisure-time physical activity (LTPA) is still unclear. We carried out post hoc analyses on the role of LTPA in preventing type 2 diabetes in 487 men and women with impaired glucose tolerance who had completed 12-month LTPA questionnaires. The subjects were participants in the Finnish Diabetes Prevention Study, a randomized controlled trial of lifestyle changes including diet, weight loss, and LTPA. There were 107 new cases of diabetes during the 4.1-year follow-up period. Individuals who increased moderate-to-vigorous LTPA or strenuous, structured LTPA the most were 63–65% less likely to develop diabetes. Adjustment for changes in diet and body weight during the study attenuated the association somewhat (upper versus lower third: moderate-to-vigorous LTPA, relative risk 0.51, 95% CI 0.26–0.97; strenuous, structured LTPA, 0.63, 0.35–1.13). Low-intensity and lifestyle LTPA and walking also conferred benefits, consistent with the finding that the change in total LTPA (upper versus lower third: 0.34, 0.19–0.62) was the most strongly associated with incident diabetes. Thus increasing physical activity may substantially reduce the incidence of type 2 diabetes in high-risk individuals.