Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. Frequently, the chemotactic activity of cytokines depends on a modified N-terminus of the polypeptide. Among those, the N-terminus of monocyte chemoattractant protein 1 (CCL2 and MCP-1) is modified to a pyroglutamate (pE-) residue protecting against degradation in vivo. Here, we show that the N-terminal pE-formation depends on glutaminyl cyclase activity. The pE-residue increases stability against N-terminal degradation by aminopeptidases and improves receptor activation and signal transduction in vitro. Genetic ablation of the glutaminyl cyclase iso-enzymes QC (QPCT) or isoQC (QPCTL) revealed a major role of isoQC for pE1-CCL2 formation and monocyte infiltration. Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration. The pharmacologic efficacy of QC/isoQC-inhibition was assessed in accelerated atherosclerosis in ApoE3*Leiden mice, showing attenuated atherosclerotic pathology following chronic oral treatment. Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers. The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

OBJECTIVEGlucose fluctuations trigger activation of oxidative stress, a main mechanism leading to secondary diabetes complications. We evaluated the relationship between glycemic variability and β-cell dysfunction.RESEARCH DESIGN AND METHODSWe conducted a cross-sectional study in 59 patients with type 2 diabetes (aged 64.2 ± 8.6 years, A1C 6.5 ± 1.0%, and BMI 29.8 ± 3.8 kg/m2[mean ± SD]) using either oral hypoglycemic agents (OHAs) (n = 34) or diet alone (nonusers). As a measure of glycemic variability, the mean amplitude of glycemic excursions (MAGE) was computed from continuous glucose monitoring data recorded over 3 consecutive days. The relationships between MAGE, β-cell function, and clinical parameters were assessed by including postprandial β-cell function (PBCF) and basal β-cell function (BBCF) obtained by a model-based method from plasma C-peptide and plasma glucose during a mixed-meal test as well as homeostasis model assessment of insulin sensitivity, clinical factors, carbohydrate intake, and type of OHA.RESULTSMAGE was nonlinearly correlated with PBCF (r = 0.54, P < 0.001) and with BBCF (r = 0.31, P = 0.025) in OHA users but failed to correlate with these parameters in nonusers (PBCF P = 0.21 and BBCF P = 0.07). The stepwise multiple regression analysis demonstrated that PBCF and OHA combination treatment were independent contributors to MAGE (R2 = 0.50, P < 0.010), whereas insulin sensitivity, carbohydrate intake, and nonglycemic parameters failed to contribute.CONCLUSIONSPBCF appears to be an important target to reduce glucose fluctuations in OHA-treated type 2 diabetes.

Employing saline-impregnated cotton threads, an implanted-wick technique was adopted in dogs to obtain specimen from the subcutaneous interstitial compartment in order to estimate its glucose concentration. By measuring the protein, potassium and haemoglobin contents, the centrifuged wick fluid was shown to contain the interstitial concentration of solutes after an equilibration time of approximately 15 min. In normal and in diabetic animals the steady state subcutaneous glucose concentration was almost identical to the circulating glucose level when ranged between 2 and 25 mmol/l. Slow alterations in the circulating glucose profile such as those which appear during an oral glucose tolerance test are closely mirrored by the respective levels in the wick fluid. Fast alterations, however, show deviations. The wick-based glucose levels are well paralleled by the current of Clark type glucose oxidase sensors implanted at the same site. Since, on the basis of in vitro calibrations the sensor outputs have only indicated apparent tissue glucose concentrations of between 70 and 90% of glycaemia, another reference is needed for calibration. Under steady state conditions, the wick method, and on this basis in routine measurements the blood glucose concentration, may be recommended as a reference of implanted sensors which can otherwise not be calibrated in situ.

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The importance of glycaemic variability (GV) as a factor in the pathophysiology of cellular dysfunction and late diabetes complications is currently a matter of debate. However, there is mounting evidence from in vivo and in vitro studies that GV has adverse effects on the cascade of physiological processes that result in chronic β-cell dysfunctions. Glucose fluctuations more than sustained chronic hyperglycaemia can induce excessive formation of reactive oxygen (ROS) and reactive nitrogen species (RNS), ultimately leading to apoptosis related to oxidative stress. The insulin-secreting β-cells are particularly susceptible to damage imposed by oxidative stress. Evidence from experiments, using isolated pancreatic islets or β-cell lines, has linked intermittent high glucose, which mimicks GV under diabetic conditions, to significant impairment of β-cell function. Several clinical studies reported a close association between GV and β-cell dysfunction, although the deleterious effects are difficult to demonstrate. Notwithstanding, early therapeutic interventions in patients with type 1 as well as type 2 diabetes, using different strategies of optimising glycaemic control, have shown that favourable outcomes on recovery and maintenance of β-cell function correlated with reduction of GV. The purpose of the present review is to discuss the detrimental effects of GV and associations with β-cell function as well as upcoming therapeutic strategies directed towards minimising glucose excursions, improving β-cell recovery and preventing progressive β-cell loss. Measuring GV has importance for management of diabetes, because it is the only one component of the dysglycaemia that reflects the degree of dysregulation of glucose homeostasis.