Because of a huge amount of Zn 2 + in secretory granules of pancreatic islet -cells, Zn 2 + released in certain conditions might affect the function or survival of islet cells. We studied potential paracrine effects of endogenous Zn 2 + on -cell death. Zn 2 + induced insulinoma/islet cell death in a dose-dependent manner. Chelation of released endogenous Zn 2 + by CaEDTA significantly decreased streptozotocin (STZ)-induced islet cell death in an in vitro culture system simulating in vivo circumstances but not in the conventional culture system. Z n 2 + chelation in vivo by continuous CaEDTA infusion significantly decreased the incidence of diabetes after STZ administration. N-( 6 -m e t h o x y -q u i n o l y l ) -p a r a -t o l u e n esulfonamide staining revealed that Zn 2 + was densely deposited in degenerating islet cells 24 h after STZ treatment, which was decreased by CaEDTA infusion. We show here that Zn 2 + is not a passive element for insulin storage but an active participant in islet cell death in certain conditions, which in time might contribute to the development of diabetes in aged people. D i a b e t e s 4 9 :3 6 7-372, 2000 C ertain central neurons and pancreatic islet -c e l l s contain a substantial amount of chelable zinc ion ( Z n 2 + ) (1,2). Neuronal Zn 2 + is co-secreted with neurotransmitters after excitation and might be involved in the modulation of ion channel activity (3,4). R e c e n t l y, reports indicating a role of endogenous Zn 2 + in neuronal death were published. First, in vitro treatment with Z n 2 + induced neuronal cell death (5,6). Second, Zn 2 + , highly concentrated in synaptic vesicles of neurons (7), was shown to be translocated to degenerating postsynaptic neurons after cerebral ischemia or prolonged seizure (8,9). Finally, administration of a Zn 2 + chelator abrogated ischemic neuronal injury (10). These findings suggest that Zn 2 + in synaptic vesicles may be causally related to neuronal death. Similar phenomena may occur in pancreatic -cells. Islet -cells contain even more Zn 2 + than do neurons. Zn 2 + in -cells, involved in the formation of insoluble insulin hexamer in secretory granules (11,12), is also co-secreted with insulin after stimulation with secretagogues (13). Zn 2 + released in certain conditions may have an impact on pancreatic -cells if significant local concentration is achieved. The current work was carried out to explore this possibility, focusing on the role of Zn 2 + in islet cell death. RESEARCH DESIGN AND METHODSCell culture. MIN6N8 cells, SV40-transformed insulinoma cells (14) (kindly provided by Prof. Miyazaki, Osaka University, Osaka, Japan), were cultured in Dulb e c c o 's modified Eagle's medium (DMEM) (GibcoBRL, Rockville, MD)-15% fetal calf serum (FCS). The effect of Zn 2 + was examined by culturing cells in the presence of ZnSO 4 . The presence of ZnSO 4 up to 1 mmol/l did not significantly affect pH of the culture medium. In experiments studying the effect of Zn 2 + without binding to proteins or amino acids, control salt solution (...

BackgroundIt is presently unclear whether glycemic variability is associated with diabetic cardiovascular autonomic neuropathy (CAN). The aim of this study was to examine whether short- and/or long-term glycemic variability (GV) contribute to CAN.MethodsA total of 110 patients with type 2 diabetes who underwent three-day continuous glucose monitoring (CGM) completed five standardized autonomic neuropathy tests. Short-term GV was measured by the standard deviation (SD), coefficient of variation (CV) of glucose, and the mean amplitude of glycemic excursions (MAGE) in CGM. HbA1c variability was calculated from the intrapersonal SD, adjusted SD, and CV of serial HbA1c over 2-year period. CAN was defined as the presence of at least two abnormal parasympathetic function tests. The severity of CAN was evaluated by total scores of five autonomic function tests.ResultsIn univariate analysis, not only SD and CV in CGM but also all parameters of HbA1c variability were significantly higher in the patients with CAN (n = 47, 42.7 %) than in those without CAN. In multivariate analysis, CV (Odds ratio [OR] 1.07, 95 % confidence interval [CI] 1.01–1.13; p = 0.033), but neither SD nor MAGE in CGM, independently correlated with the presence of CAN. All parameters of HbA1c variability, such as SD of HbA1c (OR 12.10 [95 % CI 2.29–63.94], p = 0.003), adjusted SD of HbA1c (OR 17.02 [95 % CI 2.66–108.86], p = 0.003), and log CV of HbA1c (OR 24.00 [95 % CI 3.09–186.48], p = 0.002), were significantly associated with the presence of CAN. The patients with higher HbA1c variability had an increased risk of advanced CAN.ConclusionCV in CGM and all parameters of HbA1c variability were independently associated with the presence of CAN in patients with inadequately controlled type 2 diabetes requiring CGM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0233-0) contains supplementary material, which is available to authorized users.

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The alpha-glucosidase inhibitor 1-deoxynojirimycin (DNJ) is one of the simplest naturally occurring carbohydrate mimics, with promising biological activity in vivo. Although there is considerable interest in the pharmacological effects of DNJ, the antidiabetic effects of DNJ in type 2 diabetes mellitus have received little attention. In this work, DNJ was isolated from the silkworm (Bombyx mori), and its antidiabetic effects were evaluated in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes mellitus, and in control Long-Evans Tokushima Otsuka (LETO) rats. DNJ treatment showed significant antidiabetic effects in OLETF rats, with significant improvements in fasting blood glucose levels and glucose tolerance and, especially, increased insulin sensitivity. Furthermore, there was significant loss of body weight in both groups. DNJ also showed significant antihyperglycemic effects in streptozotocin- and high-fat-diet-induced hyperglycemic rats. Its efficacy and dose profiles were better than those of acarbose, a typical alpha-glucosidase inhibitor in clinical use. Furthermore, a substantial fraction of DNJ was absorbed into the bloodstream within a few minutes of oral administration. DNJ was also detected in the urine. These findings suggest that its postprandial hypoglycemic effect in the gastrointestinal tract is a possible but insufficient mechanism of action underlying the antidiabetic effects of DNJ. Its antiobesity effect and improvement of insulin sensitivity are other possible antidiabetic effects of DNJ.

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NCT01404676.

Materials and Methods Materials. Monoclonal anti-actin (mouse IgG2a isotype), anti-β-tubulin, BPA, Bouin's solution, corn oil, dimethyl sulfoxide (DMSO), hematoxylin, HEPES, medium 199, trypan blue, and Tween-20 were purchased from Sigma Chemical Co. (St. Louis, MO, USA). We purchased anti-aromatase from Acris Antibodies (San Diego, CA, USA); anticalbindin-D9k from Swant Swiss Antibodies (Bellinzona, Switzerland); antibody specific for cleaved (active form) caspase-3 antibody from Cell Signaling (Beverly, MA, USA); anti-FSH (follicle-stimulating hormone) antibody from AbD Serotec (Kidlington, UK); anti-3β-HSD, anti-CYP17A1, proliferating cell nuclear antigen (PCNA), and rabbit IgG anti bodies from Santa Cruz Biotech (Delaware, CA, USA); anti-P450scc antibody from Chemicon (Temecula, CA, USA); and anti-StAR and anti-LH (luteinizing hormone) anti bodies from Abcam (Cambridge, UK). Animals and BPA exposure. Adult female Sprague-Dawley rats [8 weeks of age, 200-250 g body weight (BW)

The independent association between standard deviation and the extent of albuminuria was lost when the measures were normalized by mean glucose level. At least in terms of relative measures of glycaemic variability, we failed to demonstrate an independent association between glycaemic variability and albuminuria extent in patients with inadequately controlled Type 2 diabetes.