Factors responsible for age-related elevation in fasting plasma glucose: a cross-sectional study in Japanese men.

To evaluate the factors associated with age-related increase in fasting plasma glucose (FPG) in Japanese men with normal fasting glucose, we measured FPG, fasting immunoreactive insulin, glycated hemoglobin, total cholesterol, triglyceride, and high-density lipoprotein cholesterol levels in health check examinees. Subjects with FPG less than 6.1 mmol/L together with glycated hemoglobin less than 5.6% were enrolled in the study. The homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA-beta were used as the indices of insulin sensitivity and insulin secretion, respectively. Fasting plasma glucose increased significantly with age (r = 0.30, P < .0001), and HOMA-beta decreased significantly with age (r = 0.24, P < .0001). The HOMA-IR had no significant relation with age (r = 0.06, not significant), whereas body mass index and serum triglyceride were associated with HOMA-IR (r = 0.49, P < .0001 and r = 0.33, P < .0001, respectively). Thus, in Japanese male subjects with normal fasting glucose, it is suggested that the FPG increment with age is associated with decreased beta-cell function rather than with insulin resistance. Further analyses were performed by comparing 3 groups: low FPG (FPG <5.0 mmol/L), high FPG (5.0 < or = FPG < 5.6 mmol/L), and mild impairment of fasting glycemia (mild IFG) (5.6 < or = FPG < 6.1 mmol/L). The insulin levels in mild IFG and high FPG were significantly higher than in low FPG (P < .001), but those in mild IFG were similar to those in high FPG. Analysis of the 3 subgroups revealed that, whereas insulin sensitivity was impaired more in high FPG, there was little compensatory increase in insulin in mild IFG, suggesting that beta-cell function is already deteriorated when the FPG level is greater than 5.6 mmol/L.

Disruption of a gene encoding C4-dicarboxylate transporter-like protein increases ozone sensitivity through deregulation of the stomatal response in Arabidopsis thaliana.

To understand better the plant response to ozone, we isolated and characterized an ozone-sensitive (ozs1) mutant strain from a set of T-DNA-tagged Arabidopsis thaliana ecotype Columbia. The mutant plants show enhanced sensitivity to ozone, desiccation and sulfur dioxide, but have normal sensitivity to hydrogen peroxide, low temperature and high light levels. The T-DNA was inserted at a single locus which is linked to ozone sensitivity. Identification of the genomic sequences flanking the T-DNA insertion revealed disruption of a gene encoding a transporter-like protein of the tellurite resistance/C(4)-dicarboxylate transporter family. Plants with either of two different T-DNA insertions in this gene were also sensitive to ozone, and these plants failed to complement ozs1. Transpiration levels, stomatal conductance levels and the size of stomatal apertures were greater in ozs1 mutant plants than in the wild type. The stomatal apertures of ozs1 mutant plants responded to light fluctuations but were always larger than those of the wild-type plants under the same conditions. The stomata of the mutant and wild-type plants responded similarly to stimuli such as light, abscisic acid, high concentrations of carbon dioxide and ozone. These results suggest that OZS1 helps to close stomata, being not involved in the responses to these signals.

Impaired metabolism-secretion coupling in pancreatic beta-cells: role of determinants of mitochondrial ATP production.

Glucose-induced insulin secretion from beta-cells is often impaired in diabetic condition and by exposure to diabetogenic pharmacological agents. In pancreatic beta-cells, intracellular glucose metabolism regulates exocytosis of insulin granules, according to metabolism-secretion coupling in which glucose-induced mitochondrial ATP production plays an essential role. Impaired glucose-induced insulin secretion often results from impaired glucose-induced ATP elevation in beta-cells. Mitochondrial ATP production is driven by the proton-motive force including mitochondrial membrane potential (DeltaPsi(m)) generated by the electron transport chain. These electrons are derived from reducing equivalents, generated in the Krebs cycle and transferred from cytosol by the shuttles. Here, roles of the determinants of mitochondrial ATP production in impaired glucose-induced insulin secretion are discussed. Cytosolic alkalization, H(+) leak in the inner membrane by uncoupler (e.g. free fatty acid exposure), decrease in the supply of electron donors including NADH and FADH(2) to the respiratory chain, and endogenous mitochondrial ROS (e.g. Na(+)/K(+)-ATPase inhibition) all reduce hyperpolarlization of DeltaPsi(m) and ATP production, causing decresed glucose-induced insulin release. The decrease in the supply of NADH and FADH(2) to the respiratory chain derives from impairments in glucose metabolism including glycolysis (e.g. MODY2 and exposure to NO) and the shuttles (e.g. diabetic state and exposure to ketone body).

Type-1 diabetes mellitus with insufficient serum immunoreactive insulin elevation after subcutaneous NPH-insulin injection.

We report a case of Type-1 diabetes with insufficient serum immunoreactive insulin (IRI) elevation after subcutaneous NPH-insulin injection. Favorable glycemic control was achieved by a continuous subcutaneous insulin infusion (CSII) using regular insulin. A 34-year-old woman with Type-1 diabetes (height 158 cm, weight 43.4 kg) was admitted to our hospital to improve glycemic control. On admission, her glycosylated hemoglobin (HbA(1c)) level was 10.9% and her fasting plasma glucose (FPG) level was 332 mg/dl. After admission, her insulin regimen was altered from two injections a day using premixed insulin to four injections a day using regular insulin before each meal and NPH insulin at bedtime. Although the dosage of NPH insulin at bedtime was increased to 32 U/day, there was no improvement in the FPG level. The peak IRI value after NPH insulin injection was not observed but that after the regular insulin injection was observed. Therefore, her insulin administration regimen was changed to CSII, using regular insulin alone. Her fasting plasma glucose level decreased, glycosylated hemoglobin (HbA(1c)) level improved to 7.0%, her body weight increased to 46.6 kg 4 months after starting CSII.

Ouabain suppresses glucose-induced mitochondrial ATP production and insulin release by generating reactive oxygen species in pancreatic islets.

We examined the effects of reduced Na(+)/K(+)-ATPase activity on mitochondrial ATP production and insulin release from rat islets. Ouabain, an inhibitor of Na(+)/K(+)-ATPase, augmented 16.7 mmol/l glucose-induced insulin release in the early period but suppressed it after a delay of 20-30 min. Unexpectedly, the ATP content in an islet decreases in the presence of 16.7 mmol/l glucose when Na(+)/K(+)-ATPase activity is diminished by ouabain, despite the reduced consumption of ATP by the enzyme. Ouabain also suppressed the increment of ATP content produced by glucose even in Ca(2+)-depleted or Na(+)-depleted conditions. That mitochondrial membrane hyperpolarization and O(2) consumption in islets exposed to 16.7 mmol/l glucose were suppressed by ouabain indicates that the glycoside inhibits mitochondrial respiration but does not produce uncoupling. Ouabain induced mitochondrial reactive oxygen species (ROS) production that was blocked by myxothiazol, an inhibitor of site III of the mitochondrial respiratory chain. An antioxidant, alpha-tocopherol, also blocked ouabain-induced ROS production as well as the suppressive effect of ouabain on ATP production and insulin release. However, ouabain did not directly affect the mitochondrial ATP production originating from succinate and ADP. These results indicate that ouabain suppresses mitochondrial ATP production by generating ROS via transduction, independently of the intracellular cationic alternation that may account in part for the suppressive effect on insulin secretion.

Prior exposure to high glucose augments depolarization-induced insulin release by mitigating the decline of ATP level in rat islets.

A brief exposure to elevated glucose augments the insulin secretory response of islets to subsequent stimulation. The site of this priming effect of glucose in the mechanism of the regulation of insulin secretion is not completely known, however. Insulin release triggered by a depolarizing concentration of K+ in the presence of basal glucose is markedly enhanced in primed rat islets. To clarify the role of priming on Ca(2+) and ATP efficacy in the exocytotic apparatus, islets were electrically permeabilized to vary the intracellular Ca(2+) and ATP concentrations according to the extracellular medium, and insulin release was evaluated. Ca(2+) and ATP efficacy in Ca(2+)- and ATP-dependent insulin secretion was not affected by priming, and alteration of the intracellular Ca(2+) concentration after depolarization cannot account for the phenomenon. There was no difference in ATP content before depolarization between nonprimed and primed islets. Moreover, the decline in ATP level after depolarization with basal glucose was observed in both primed and nonprimed islets. However, a reduced decline in ATP level in the early phase was observed in primed islets. In addition, oligomycin, a mitochondrial metabolism inhibitor, abolished the difference in ATP level between primed and nonprimed islets, suggesting that mitochondrial ATP production may be linked to the phenomenon.