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1.  Effects of zinc supplementation and zinc chelation on in vitro β-cell function in INS-1E cells 
BMC Research Notes  2014;7:84.
Background
Zinc is essential for the activities of pancreatic β-cells, especially insulin storage and secretion. Insulin secretion leads to co-release of zinc which contributes to the paracrine communication in the pancreatic islets. Zinc-transporting proteins (zinc-regulated transporter, iron-regulated transporter-like proteins [ZIPs] and zinc transporters [ZnTs]) and metal-buffering proteins (metallothioneins, MTs) tightly regulate intracellular zinc homeostasis. The present study investigated how modulation of cellular zinc availability affects β-cell function using INS-1E cells.
Results
Using INS-1E cells, we found that zinc supplementation and zinc chelation had significant effects on insulin content and insulin secretion. Supplemental zinc within the physiological concentration range induced insulin secretion. Insulin content was reduced by zinc chelation with N,N,N’,N-tektrakis(2-pyridylmethyl)-ethylenediamine. The changes in intracellular insulin content following exposure to various concentrations of zinc were reflected by changes in the expression patterns of MT-1A, ZnT-8, ZnT-5, and ZnT-3. Furthermore, high zinc concentrations induced cell necrosis while zinc chelation induced apoptosis. Finally, cell proliferation was sensitive to changes in zinc the concentration.
Conclusion
These results indicate that the β-cell-like function and survival of INS-1E cells are dependent on the surrounding zinc concentrations. Our results suggest that regulation of zinc homeostasis could represent a pharmacological target.
doi:10.1186/1756-0500-7-84
PMCID: PMC3923740  PMID: 24502363
Zinc; Insulin; Zinc transporter; Metallothionein; Chelation; TPEN; INS-1E cells; β –cell; Diabetes
2.  Influence of GLP-1 on Myocardial Glucose Metabolism in Healthy Men during Normo- or Hypoglycemia 
PLoS ONE  2014;9(1):e83758.
Background and Aims
Glucagon-like peptide-1 (GLP-1) may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency by increasing myocardial glucose uptake (MGU). We assessed the effects of GLP-1 on MGU in healthy subjects during normo- and hypoglycemia.
Materials and Methods
We included eighteen healthy men in two randomized, double-blinded, placebo-controlled cross-over studies. MGU was assessed with GLP-1 or saline infusion during pituitary-pancreatic normo- (plasma glucose (PG): 4.5 mM, n = 10) and hypoglycemic clamps (PG: 3.0 mM, n = 8) by positron emission tomography with 18fluoro-deoxy-glucose (18F-FDG) as tracer.
Results
In the normoglycemia study mean (± SD) age was 25±3 years, and BMI was 22.6±0.6 kg/m2 and in the hypoglycemia study the mean age was 23±2 years with a mean body mass index of 23±2 kg/m2. GLP-1 did not change MGU during normoglycemia (mean (+/− SD) 0.15+/−0.04 and 0.16+/−0.03 µmol/g/min, P = 0.46) or during hypoglycemia (0.16+/−0.03 and 0.13+/−0.04 µmol/g/min, P = 0.14). However, the effect of GLP-1 on MGU was negatively correlated to baseline MGU both during normo- and hypoglycemia, (P = 0.006, r2 = 0.64 and P = 0.018, r2 = 0.64, respectively) and changes in MGU correlated positively with the level of insulin resistance (HOMA 2IR) during hypoglycemia, P = 0.04, r2 = 0.54. GLP-1 mediated an increase in circulating glucagon levels at PG levels below 3.5 mM and increased glucose infusion rates during the hypoglycemia study. No differences in other circulating hormones or metabolites were found.
Conclusions
While GLP-1 does not affect overall MGU, GLP-1 induces changes in MGU dependent on baseline MGU such that GLP-1 increases MGU in subjects with low baseline MGU and decreases MGU in subjects with high baseline MGU. GLP-1 preserves MGU during hypoglycemia in insulin resistant subjects.
ClinicalTrials.gov registration numbers: NCT00418288: (hypoglycemia) and NCT00256256: (normoglycemia).
doi:10.1371/journal.pone.0083758
PMCID: PMC3882300  PMID: 24400077
3.  Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia 
Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P=0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P=0.039) but not to the same extent in all regions (P=0.022). The unidirectional glucose transfer across the blood–brain barrier remained unchanged (P=0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P=0.013 and 0.017), leading to increased net clearance of the glucose tracer (P=0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.
doi:10.1038/jcbfm.2012.118
PMCID: PMC3519409  PMID: 22929437
blood–brain barrier; 2-deoxy-glucose; diabetes; energy metabolism; GLP-1; glucagon-like peptide-1; glucose; pharmacology
4.  Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain 
In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven healthy men in a randomized, double-blinded placebo-controlled cross-over experimental design. The acute effect of GLP-1 on glucose transfer in the brain was measured by positron emission tomography (PET) during a hypoglycemic clamp (3 mM plasma glucose) with 18F-fluoro-2-deoxy-glucose (FDG) as tracer of glucose. In addition, we jointly analyzed cerebrometabolic effects of GLP-1 from the present hypoglycemia study and our previous hyperglycemia study to estimate the Michaelis-Menten constants of glucose transport and metabolism. The GLP-1 treatment lowered the vascular volume of brain tissue. Loading data from hypo- to hyperglycemia into the Michaelis-Menten equation, we found increased maximum phosphorylation velocity (Vmax) in the gray matter regions of cerebral cortex, thalamus, and cerebellum, as well as increased blood-brain glucose transport capacity (Tmax) in gray matter, white matter, cortex, thalamus, and cerebellum. In hypoglycemia, GLP-1 had no effects on net glucose metabolism, brain glucose concentration, or blood-brain glucose transport. Neither hexokinase nor transporter affinities varied significantly with treatment in any region. We conclude that GLP-1 changes blood-brain glucose transfer and brain glucose metabolic rates in a PG concentration-dependent manner. One consequence is that hypoglycemia eliminates these effects of GLP-1 on brain glucose homeostasis.
doi:10.3389/fnene.2013.00002
PMCID: PMC3608902  PMID: 23543638
glucagon-like peptide -1; hypoglycemia; hyperglycemia; blood-brain barrier; cerebral metabolic rate for glucose; Michaelis-Menten; cerebral glucose transport
5.  The Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Project: rationale and planned nationwide studies of genetic predictors, physical exercise, and individualized pharmacological treatment 
Clinical Epidemiology  2012;4(Suppl 1):7-13.
Here we provide an overview of the rationale and methods of a series of planned population based studies within the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Project. The project aims to support and evaluate ongoing political and administrative efforts to implement nationwide guidelines for maintaining metabolic control in newly diagnosed type 2 diabetes (T2D) patients to prevent diabetic complications and improve quality of life. The DD2 is designed as a prospective cohort study (collection of epidemiological data) supplemented by randomized clinical intervention trials (on physical exercise and individualized pharmacological treatment) and the establishment of a biobank comprised of material from a large number of newly diagnosed T2D patients. Inclusion of the majority of newly diagnosed T2D patients as they are diagnosed at their general practitioner or diabetes hospital outpatient clinics and entered into the DD2 cohort will establish a nationwide database comprising a large number of future incident cases of T2D in Denmark. These cases will form the project cohort of the DD2. Within the first 6 months of diagnosis, all patients will be invited to contribute to a biobank of DNA, plasma, urine, and tissue sampling. The DNA biobank will enable future studies of the effect of pharmacological treatment and outcome in subsets of patients with specific genetic risk profiles covering disease etiology and specific drug kinetics and metabolism. We will also perform two clinical intervention trials examining: the effectiveness of physical exercise on diabetes-related outcomes and the impact of trial outcomes on individualized pharmacological treatment. Moreover, the DD2 will serve as a platform for testing and developing new antidiabetic drugs. All together, we expect this study to contribute to substantially improved diabetes care in T2D patients locally and abroad.
doi:10.2147/CLEP.S30188
PMCID: PMC3469285  PMID: 23071406
type 2 diabetes; prognosis; intervention; physical exercise
7.  Potential role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes 
Background:
Linagliptin is an oral antihyperglycemic agent that selectively inhibits the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of DPP-4 increases the levels of the incretin hormones glucagon-like peptide and glucose-dependent insulinotropic polypeptide by preventing their degradation.
Objective:
We reviewed the role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes.
Methods:
A comprehensive literature search was performed using the term “linagliptin.” Original research articles and review articles were included in our examination.
Results:
Linagliptin has a similar mode of action as other gliptins, with comparable efficacy, safety profile, and tolerability. Differences in pharmacokinetic parameters that distinguish linagliptin from other gliptins include that linagliptin is not renally excreted and does not require dose reduction with renal impairment.
Conclusion:
Linagliptin is an oral, once-daily, antihyperglycemic agent that significantly reduces glycated hemoglobin (HbA1c) when used alone or in combination with other antidiabetic drugs in people with type 2 diabetes. Pharmacokinetics, such as the lack of renal excretion, distinguishes linagliptin from other gliptins.
doi:10.2147/DMSO.S16288
PMCID: PMC3430084  PMID: 22952411
DPP-4 inhibitors; linagliptin; type 2 diabetes
9.  Chemical Blocking of Zinc Ions in CNS Increases Neuronal Damage Following Traumatic Brain Injury (TBI) in Mice 
PLoS ONE  2010;5(4):e10131.
Background
Traumatic brain injury (TBI) is one of the leading causes of disability and death among young people. Although much is already known about secondary brain damage the full range of brain tissue responses to TBI remains to be elucidated. A population of neurons located in cerebral areas associated with higher cognitive functions harbours a vesicular zinc pool co-localized with glutamate. This zinc enriched pool of synaptic vesicles has been hypothesized to take part in the injurious signalling cascade that follows pathological conditions such as seizures, ischemia and traumatic brain injury. Pathological release of excess zinc ions from pre-synaptic vesicles has been suggested to mediate cell damage/death to postsynaptic neurons.
Methodology/Principal Findings
In order to substantiate the influence of vesicular zinc ions on TBI, we designed a study in which damage and zinc movements were analysed in several different ways. Twenty-four hours after TBI ZnT3-KO mice (mice without vesicular zinc) were compared to littermate Wild Type (WT) mice (mice with vesicular zinc) with regard to histopathology. Furthermore, in order to evaluate a possible neuro-protective dimension of chemical blocking of vesicular zinc, we treated lesioned mice with either DEDTC or selenite. Our study revealed that chemical blocking of vesicular zinc ions, either by chelation with DEDTC or accumulation in zinc-selenium nanocrystals, worsened the effects on the aftermath of TBI in the WT mice by increasing the number of necrotic and apoptotic cells within the first 24 hours after TBI, when compared to those of chemically untreated WT mice.
Conclusion/Significance
ZnT3-KO mice revealed more damage after TBI compared to WT controls. Following treatment with DEDTC or selenium an increase in the number of both dead and apoptotic cells were seen in the controls within the first 24 hours after TBI while the degree of damage in the ZnT3-KO mice remained largely unchanged. Further analyses revealed that the damage development in the two mouse strains was almost identical after either zinc chelation or zinc complexion therapy.
doi:10.1371/journal.pone.0010131
PMCID: PMC2852423  PMID: 20396380
10.  SLC30A3 Responds to Glucose- and Zinc Variations in ß-Cells and Is Critical for Insulin Production and In Vivo Glucose-Metabolism During ß-Cell Stress 
PLoS ONE  2009;4(5):e5684.
Background
Ion transporters of the Slc30A- (ZnT-) family regulate zinc fluxes into sub-cellular compartments. β-cells depend on zinc for both insulin crystallization and regulation of cell mass.
Methodology/Principal Findings
This study examined: the effect of glucose and zinc chelation on ZnT gene and protein levels and apoptosis in β-cells and pancreatic islets, the effects of ZnT-3 knock-down on insulin secretion in a β-cell line and ZnT-3 knock-out on glucose metabolism in mice during streptozotocin-induced β-cell stress. In INS-1E cells 2 mM glucose down-regulated ZnT-3 and up-regulated ZnT-5 expression relative to 5 mM. 16 mM glucose increased ZnT-3 and decreased ZnT-8 expression. Zinc chelation by DEDTC lowered INS-1E insulin content and insulin expression. Furthermore, zinc depletion increased ZnT-3- and decreased ZnT-8 gene expression whereas the amount of ZnT-3 protein in the cells was decreased. Zinc depletion and high glucose induced apoptosis and necrosis in INS-1E cells. The most responsive zinc transporter, ZnT-3, was investigated further; by immunohistochemistry and western blotting ZnT-3 was demonstrated in INS-1E cells. 44% knock-down of ZnT-3 by siRNA transfection in INS-1E cells decreased insulin expression and secretion. Streptozotocin-treated mice had higher glucose levels after ZnT-3 knock-out, particularly in overt diabetic animals.
Conclusion/Significance
Zinc transporting proteins in β-cells respond to variations in glucose and zinc levels. ZnT-3, which is pivotal in the development of cellular changes as also seen in type 2 diabetes (e.g. amyloidosis in Alzheimer's disease) but not previously described in β-cells, is present in this cell type, up-regulated by glucose in a concentration dependent manner and up-regulated by zinc depletion which by contrast decreased ZnT-3 protein levels. Knock-down of the ZnT-3 gene lowers insulin secretion in vitro and affects in vivo glucose metabolism after streptozotocin treatment.
doi:10.1371/journal.pone.0005684
PMCID: PMC2683566  PMID: 19492079
11.  Zinc transporter gene expression is regulated by pro-inflammatory cytokines: a potential role for zinc transporters in beta-cell apoptosis? 
Background
β-cells are extremely rich in zinc and zinc homeostasis is regulated by zinc transporter proteins. β-cells are sensitive to cytokines, interleukin-1β (IL-1β) has been associated with β-cell dysfunction and -death in both type 1 and type 2 diabetes. This study explores the regulation of zinc transporters following cytokine exposure.
Methods
The effects of cytokines IL-1β, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on zinc transporter gene expression were measured in INS-1-cells and rat pancreatic islets. Being the more sensitive transporter, we further explored ZnT8 (Slc30A8): the effect of ZnT8 over expression on cytokine induced apoptosis was investigated as well as expression of the insulin gene and two apoptosis associated genes, BAX and BCL2.
Results
Our results showed a dynamic response of genes responsible for β-cell zinc homeostasis to cytokines: IL-1β down regulated a number of zinc-transporters, most strikingly ZnT8 in both islets and INS-1 cells. The effect was even more pronounced when mixing the cytokines. TNF-α had little effect on zinc transporter expression. IFN-γ down regulated a number of zinc transporters. Insulin expression was down regulated by all cytokines. ZnT8 over expressing cells were more sensitive to IL-1β induced apoptosis whereas no differences were observed with IFN-γ, TNF-α, or a mixture of cytokines.
Conclusion
The zinc transporting system in β-cells is influenced by the exposure to cytokines. Particularly ZnT8, which has been associated with the development of diabetes, seems to be cytokine sensitive.
doi:10.1186/1472-6823-9-7
PMCID: PMC2651882  PMID: 19243577

Results 1-11 (11)