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Cite This: Chem. Res. Toxicol. 2019, 32, 1351−1356
Obesity-Dependent Accumulation of Titanium in the Pancreas of Type 2 Diabetic Donors Adam Heller,*,† Sheryl S. Coffman, and Keith A. Friedman John J. McKetta Department of Chemical Engineering, University of Texas, Austin, Texas 78712, United States
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S Supporting Information *
ABSTRACT: The most widely used white pigment of foods and medications is crystalline, anatase-phase TiO2 of 110 ± 70 nm particle diameter. Recent studies by other investigators have shown that depending on its ingested pigment amount the concentration of titanium in human blood ranges between 2 and 48 ppb and that Ti accumulates in the spleen and in the liver. Here we report titanium concentrations in the pancreas head of 30 human donors, measured by inductively coupled plasma quadrupole mass spectroscopy. Of the donors, 7 were free of pancreatic disease, 4 had pancreatitis, 10 had type 2 diabetes and 9 had type 2 diabetes with pancreatitis; 3 were underweight, 6 were normal weight, 5 were overweight, and 16 were obese. Ti accumulated in the pancreas, its accumulation increasing with obesity. The pancreatic Ti concentrations ranged from 0.75 to 3.78 ppm, averaging 1.8 ppm, much higher than the reported 40−100 ppb concentration in the spleen or the 30−100 ppb concentration reported in the liver. The corresponding number density of 110 nm diameter TiO2 particles averaged 3.6 × 109 per gram of wet tissue; their potentially biological macromolecule adsorbing surface area is ∼1 cm2 per gram wet tissue.
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promote Alzheimer’s β-amyloid fibrillation19 and Parkinson’s disease α-synuclein aggregation.20 Peretz et al.18 reported that TiO2 nanoparticles accelerate hIAPP fibril assembly in DMPC:DMPG vesicle solutions compared to the peptide alone. TEM images, complementing their ThT analysis, show the effects of TiO2 upon hIAPP fibril morphology, revealing an abundance of hIAPP fibrils in the vesicle solutions after preincubation with TiO2. The 110 nm average diameter anatase-phase food-grade crystalline particles21−23 are smaller than the 300 nm average diameter rutile-phase TiO2 particles of paint.24 Their toxicology has been extensively studied both in animals and in humans.21,22,25−27 The ingested TiO2 particles enter the bloodstream, resulting in 2−48 ppb titanium concentrations.26,28 They accumulate in the spleen to 40−100 ppb and in the liver to 30−100 ppb.23 Our earlier qualitative transmission electron microscopic study of three pancreatic specimens from nondiabetic donors and eight specimens from donors suffering of T2D, some with pancreatitis (P), showed that TiO2 crystals of 110 ± 70 nm average diameter abound in the pancreas of T2D and T2D-P donors.29 Here we quantify the pancreatic Ti, showing that its accumulation in the pancreas greatly exceeds that in the liver or the spleen.23 Figures 1 and 2 are unpublished images of exemplary pancreatic TiO2 crystals that were found in in our earlier qualitative transmission electron microscopic (TEM) study.29
INTRODUCTION Insulin promotes the uptake of glucose by the cells of the body. In type 2 diabetes, T2D, impaired cellular response to insulin results in peripheral insulin-resistance.1 Insulin-resistance is obesity-associated.2−4 To maintain a normal extracellular glucose concentration, the pancreas produces more insulin; upon hypersecretion of insulin,3 hyperinsulinemia results.5 As long as healthy insulin producing pancreatic β-cells of Langerhans islets abound, they can meet the massive insulin demand. If, however, β-cells die, the increased insulin demand is no longer met and hyperglycemia, the hallmark symptom of T2D, results. Components of the immune system are altered in obesity and T2D; they are changed in the adipose tissue, the liver, the pancreatic islets, and the circulating leukocytes. The changes include fibrosis, altered levels of specific cytokines and chemokines, the number of leukocytes, and their activation. The changes in the pancreas lead to pyroptosis, meaning the inflammatory death, of β-cells.6 A specific cause of their death is activation of the NLRP3 inflammasome, also known as the NALP3 inflammasome, a multiprotein aggregate of tissueinfiltrating macrophages and of other innate phagocytes. Activation of the inflammasome induces death of proximal cells through maturation and secretion of inflammatory cytokines IL-1β and IL-18 and caspase-1.7,8 The inflammasome is activated by phagocytized fibrils of misaggregated pancreatic islet amyloid precursor peptide, hIAPP, also known as amylin. hIAPP is cosecreted with insulin by glucose-stimulated β-cells.9−17 TiO2 particles promote membrane-induced fibrillation of hIAPP,18 just as they © 2019 American Chemical Society
Received: October 15, 2018 Published: June 7, 2019 1351
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Figure 1. TEM image of a pancreatic carbon-containing TiO2 particle cluster and its electron diffraction pattern.
Figure 2. TiO2 crystals of from T2D donor specimens. were overweight, having a BMI of 25−30 kg/m2; and 16 were obese with their BMI exceeding 30 kg/m2. Digestion. Fifty milligrams of pancreatic tissue was placed in a 5 mL Teflon beaker containing 2 mL of concentrated ultrapure HNO3 (Fisher Optima grade) and heated with stirring to about 90 °C for approximately 1 h to evaporate about half of the HNO3. The resulting clear yellow-orange solution was poured into a graduated HDPE centrifuge tube and the Teflon beaker was rinsed with ultrapure concentrated HNO3. The rinse was combined with the main solution and the volume was restored to 2 mL with the concentrated HNO3 and refrigerated until assayed. Immediately before the assay, 3 mL of ultrapure water (Barnstead Nanopure Diamond) and 6 μL of ultrapure HF (Fisher Optima grade) were added and the sample was sonicated for 10 min in an ice bath.31 The samples were run within 10 min after being sonicated.31 Detection of TiO2 in 6 M HNO3. The pancreatic 0.95−3.78 ppm Ti concentrations in Table 1 are based on 100-fold diluted pancreatic tissue digests. Sonication on ice and analysis within 10 min of sonication makes the method of Geertsen et al. applicable to the samples,31 as their Table 2 shows that TiO2 samples retain >90% of their initial ICP-OES signal when analyzed within 10 min of
Facets of the joined monocrystals forming the particle of Figure 1 show a carbon-coating attributed to an adsorbed and e-beam-decomposed biochemical.
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EXPERIMENTAL PROCEDURES
Specimens. Specimens of the pancreas’ head were harvested and stored frozen at −80 °C by the nPOD pancreatic tissue bank of the Juvenile Diabetes Research Foundation at the University of Florida in Gainesville as described.30 They were placed in high density polyethylene (HDPE) vials and shipped frozen to the University of Texas overnight, where they were stored frozen until they were processed. For traceability and to allow independent confirmation of the reported results as well as in order to provide for correlation with results of other laboratories, the first column of Table 1 identifies the specimens by their nPOD donor numbers. The 30 specimens included 7 from donors who were nondiabetic (ND) and had no pancreatitis (NP); 4 from ND donors with pancreatitis (P); 11 from T2D NP donors; and 8 from T2D-P donors. Of the donors, 3 were underweight, having a body mass index (BMI) of less than 20 kg/m2; 6 were normal weight, having a BMI of between 20 and 25 kg/m2; 5 1352
DOI: 10.1021/acs.chemrestox.8b00304 Chem. Res. Toxicol. 2019, 32, 1351−1356
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Chemical Research in Toxicology Table 1. Concentrations of Ti in Human Pancreatic Specimens nPOD donor number
BMI, kg/m2
classification
age
sex
6075 6369 6191 6368 6186 6290 6300 6194 6008 6280 6283 6255 6277 6297 6099 6295 6254 6188 6259 6060 6269 6308 6095 6189 6329 6288 6252 6304 6373/2 6275
14.9 18.8 19.9 20.7 20.9 22.5 23.5 23.7 24.2 28.1 28.1 29.4 29.5 29.5 30 30.4 30.5 30.6 32.3 32.7 33 34.1 35.5 36.1 36.4 37.7 37.8 37.9 39.1 41
underweight
16 44 63 38 68 58 67 47 50 47 56 55 48 60 14 47 38 36 57 24 71 13 40 48 49 55 20 52 45 48
M M F M M M M M F M F M M M M F M M M M M F M F F M M F F M
normal
overweight
obese
sonication and their Table 3 shows applicability of ICP-MS to Ti assay in samples containing TiO2. Measurements. The 47Ti isotope was assayed with an Agilent 7500CE inductively coupled plasma mass spectrometer with a polyatomic interference-eliminating octopole reaction system (ICPQMS). In order to confirm that the measurements provided Ti concentrations, not levels of polyatomic interferants, they were examined for the consistency of the 47Ti results with 48Ti results, the 48 Ti measured with He and without gas in the reaction-collision cell. Consistency of no-gas and He-mode measured 48Ti concentrations and the 47Ti results made it unlikely that polyatomic interferences biased the results. Table 1 reports the results for the 47Ti isotope. Calibration. After the 100× digestive dilution of the 50 mg of wet pancreatic tissue to the 5 mL of injected solution volume, the ICPQMS-measured concentrations ranged from ∼1 ppb to ∼40 ppb. Correspondingly, the spectrometer was calibrated with 0, 0.1, 1, 10, 100, and 200 ppb Ti in 2% (0.3 M) HNO3, prepared from NISTtraceable standards. The blank standard had no measurable Ti, the measured concentrations being of 0.00 ± 0.02 ppb Ti. The calibration had a linear response over the full range (r2 > 0.999), and 10 ppb spiking of the blank provided recoveries between 90% and 100%. Although the samples were in 6 M HNO3, a higher HNO3 concentration than of the standards, the higher HNO3 did not change the outcome of the assays as was evident from the 6 M HNO3 also showing, in the absence of Ti spiking, only 1 ppb Ti, and from the 50 ppb spikes having recoveries between 90% to 110%. The blanks of the digests showed between 2 and 3 ppb Ti, and the recoveries of their 50 and 100 ppb spikes were 150% and 110% respectively, averaging 130%. To correct for the 2−3 ppb blank readings, 3 ppb Ti was subtracted from the ICP-QMS-measured concentrations, then the result was divided by 1.3 to adjust for the 130% recovery. The corrected concentrations were then multiplied by
pancreatic disease
Ti, ppm
ND, NP ND, NP T2D ND, NP T2D-P P T2D T2D ND, NP T2D T2D-P T2D T2D-P T2D ND, NP ND, NP P T2D T2D-P P T2D-P T2D ND, NP T2D-P T2D-P P T2D-P T2D T2D T2D-P
2.02 1.95 1.07 3.18 1.63 3.46 1.02 1.73 1.26 1.34 0.95 1.23 1.50 3.78 1.96 2.15 1.27 1.52 1.70 1.28 1.24 1.93 0.75 1.30 2.22 1.19 2.27 2.34 2.02 3.31
100× in order to account for the dilution of 50 mg of wet specimen to 5 mL of the ICP-QMS injected solution to yield the actual pancreatic tissue concentrations of Table 1. Biological Baseline. In addition to the reagent blank, a biological blank of olive oil was run. The ICP-QMS-measured Ti concentration was 0.9 ppb after the 100× dilution for the IPS-QMS assay, meaning 90 ppb Ti in the olive oil, slightly below that in the sample matrix blank. The Supporting Information also provides details of a less than successful attempt to obtain a biological baseline from six laboratoryraised same-litter rat pancreatic specimens. Of these, only three had low Ti-concentrations, because the cages of the rats were enriched with shredded-paper and with a PVC tubing on which the rats chewed. Both paper and PVC are made with 4−10 weight % TiO2.
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RESULTS AND DISCUSSION The body mass index (BMI), age, and gender of the donors, their disease(s), and the Ti-concentrations of their pancreas in ppm are ordered in Table 1 by the BMI. The Ti concentrations are in ppm, meaning in units of 10−6 g Ti per g of wet tissue. The codes are ND, no diabetes; NP, no pancreatitis; P, pancreatitis; T2D, type 2 diabetes; T2D-P type 2 diabetes with pancreatitis. Figure 3a shows that in the 15-member cohort, comprising the ND donors of any BMI as well as the underweight and normal weight T2D and T2D-P donors, the pancreatic Ti concentration does not increase with the BMI. In contrast, in the 14-member cohort comprising the overweight and obese T2D and T2D-P donors (Figure 3b), as well as in the 8member cohort comprising only the T2D-P donors (Figure 3c), the pancreatic Ti concentration increases with the BMI. 1353
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increases by 0.12 ppm per kg m−2, excluding the 3.78 ppm outlier at 29.5 kg m−2. The linear correlation coefficient of the Ti concentration with the BMI in the T2D-P overweight and obese cohort (Figure 3c) is 0.84 (r2 = 0.70) and the Ti concentration increases by 0.15 ppm per kg m−2 BMI, implying that the T2D plus T2D-P and the T2D-P only populations are similar and distinct from the population comprising all ND donors and the underweight and normal weight T2D and T2D-P donors (Figure 3a). The correlation of the pancreatic Ti concentration with the BMI was statistically significant with a p-value of 0.0002 for the 14-member overweight or obese T2D or T2D-P cohort and a p-value of 0.01 for the 8-member overweight or obese T2D-P cohort. The observed difference between the cohorts is consistent with the exclusive increase in the prevalence of T2D in the in overweight and obese U.S. adults from 5.08% in 1976−1980 to 8.83% in 1999−2004. The percentage contributions to the increase were −8% (decrease) in the 30 kg/m2 obese cohort.32 Hyperglycemia results when part of the insulin-producing βcells die because of the accumulation of mis-templated hIAPP fibrils.6,11,16 As seen in Figure 3b,c, the Ti-concentration increases with the BMI, only in the overweight and the obese T2D donors. If the TiO2 crystal surfaces, their potentially hIAPP adsorbing area scaling with the BMI mistemplate and fibrillate hIAPP,18 then the obese T2D patients become increasingly prone to hyperglycemia when TiO2 accumulates in their pancreas. In contrast with the statistically significant increase in the pancreatic Ti-concentration with the BMI in the overweight and the obese T2D and T2D-P cohort, the Ti-concentration does not vary in a statistically significant manner with age in any cohort. For the full 29-donor cohort (excluding the 3.87 ppm age 60 outlier), r2 is 0.04 and p = 0.31; for the 20-donor overweight and obese cohort, it is 0.03 and p = 0.42; and for the 14-donor overweight and obese T2D and T2D-P cohort, it is 0.1 and p = 0.28. The density of the 110 nm diameter particles is 4.23 g cm−3 and their Ti weight fraction is 0.59, meaning that at 1 ppm of Ti there are 2 × 109 TiO2 particles per gram of pancreas. At the lowest 0.95 ppm and the highest 3.78 ppm Ti concentrations (Table 1), the respective number density of the TiO2 particles is 1 × 109 and 7.5 × 109 per gram. At the average Ti concentration of 1.8 ppm, the number density is 3.6 × 109 per gram and the area is 1 cm2 per gram, sufficient to adsorb and to mistemplate the folding at steady state of about ∼1013 hIAPP molecules of ∼10−13 cm2 footprint. For the 3900 Da hIAPP molar mass, the mistemplated weight at steady state can reach 7 ng per gram of pancreatic tissue.
Figure 3. (a) In the cohort comprising the nondiabetic and the underweight and normal-weight T2D donors, the pancreatic Ti concentration is approximately invariant or decreases with the BMI; the square of the linear correlation coefficient r2 is 0.08; the slope is −0.04 ppm Ti per kg/m2 and for linear correlation the p-value is 0.13, consistent with absence of a statistically significant correlation between the body mass index and the pancreatic Ti-concentration. (b) In the cohort comprising the overweight and obese T2D donors, the pancreatic Ti concentration increases with the body mass index. r2 is 0.69 and the slope is +0.12 ppm per kg/m2; the p-value is 0.0002 which is consistent with a statistically significant correlation between the body mass index and the pancreatic Ti-concentration. (c) In the cohort comprising the overweight and obese T2D-P donors, the pancreatic Ti concentration also increases with the body mass index. r2 is 0.70 and the slope is +0.15 ppm per kg/m2; the p-value is 0.01 which is consistent with a statistically significant correlation between the body mass index and the pancreatic Ti-concentration.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrestox.8b00304. Details of the validation of the ICP-QMS method of assaying Ti; concentrations of Ti in the pancreas of six rats of the same litter that were caged in Ti-containing paper and plastic enriched cages (PDF)
The linear correlation coefficient of the Ti concentration with the BMI in the T2D and T2D-P overweight and obese cohort (Figure 3b) is 0.83 (r2 = 0.69) and the Ti concentration 1354
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(5) Prager, R., Wallace, P., and Olefsky, J. M. (1987) Hyperinsulinemia does not compensate for peripheral insulin resistance in obesity. Diabetes 36 (3), 327−334. (6) Donath, M. Y., and Shoelson, S. E. (2011) Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11 (2), 98−107. (7) Martinon, F., Burns, K., and Tschopp, J. (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10 (2), 417−26. (8) Hoque, R., and Mehal, W. Z. (2015) Inflammasomes in pancreatic physiology and disease. Am. J. Physiol Gastrointest Liver Physiol 308 (8), G643−51. (9) Jaikaran, E. T., Clark, A., Mukherjee, A., Morales-Scheihing, D., Butler, P. C., and Soto, C. (2001) Islet amyloid and type 2 diabetes: from molecular misfolding to islet pathophysiology. Type 2 diabetes as a protein misfolding disease. Biochim. Biophys. Acta, Mol. Basis Dis. 1537 (3), 179−203. (10) Hull, R. L., Westermark, G. T., Westermark, P., and Kahn, S. E. (2004) Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J. Clin. Endocrinol. Metab. 89 (8), 3629−43. (11) Masters, S. L., Dunne, A., Subramanian, S. L., Hull, R. L., Tannahill, G. M., Sharp, F. A., Becker, C., Franchi, L., Yoshihara, E., Chen, Z., Mullooly, N., Mielke, L. A., Harris, J., Coll, R. C., Mills, K. H., Mok, K. H., Newsholme, P., Nunez, G., Yodoi, J., Kahn, S. E., Lavelle, E. C., and O’Neill, L. A. (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat. Immunol. 11 (10), 897− 904. (12) Wali, J. A., Masters, S. L., and Thomas, H. E. (2013) Linking metabolic abnormalities to apoptotic pathways in Beta cells in type 2 diabetes. Cells 2 (2), 266−83. (13) Westwell-Roper, C., Dunne, A., Kim, M. L., Verchere, C. B., Masters, S. L., Kulak, K., Westermark, G. T., Papac-Milicevic, N., Renstrom, E., Blom, A. M., and King, B. C. (2013) Activating the NLRP3 inflammasome using the amyloidogenic peptide IAPP. The human serum protein C4b-binding protein inhibits pancreatic IAPPinduced inflammasome activation. Methods Mol. Biol. 1040 (8), 9−18. (14) Lee, H. M., Kim, J. J., Kim, H. J., Shong, M., Ku, B. J., and Jo, E. K. (2013) Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62 (1), 194−204. (15) Akter, R., Cao, P., Noor, H., Ridgway, Z., Tu, L. H., Wang, H., Wong, A. G., Zhang, X., Abedini, A., Schmidt, A. M., and Raleigh, D. P. (2016) Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology. J. Diabetes Res. 2016, 2798269. (16) Kulak, K., Westermark, G. T., Papac-Milicevic, N., Renstrom, E., Blom, A. M., and King, B. C. (2017) The human serum protein C4b-binding protein inhibits pancreatic IAPP-induced inflammasome activation. Diabetologia 60 (8), 1522−1533. (17) Morikawa, S., Kaneko, N., Okumura, C., Taguchi, H., Kurata, M., Yamamoto, T., Osawa, H., Nakanishi, A., Zako, T., and Masumoto, J. (2018) IAPP/amylin deposition, which is correlated with expressions of ASC and IL-1beta in beta-cells of Langerhans’ islets, directly initiates NLRP3 inflammasome activation. Int. J. Immunopathol Pharmacol. 32, 205873841878874. (18) Peretz, Y., Malishev, R., Kolusheva, S., and Jelinek, R. (2018) Nanoparticles modulate membrane interactions of human Islet amyloid polypeptide (hIAPP). Biochim. Biophys. Acta, Biomembr. 1860 (9), 1810−1817. (19) Wu, W. H., Sun, X., Yu, Y. P., Hu, J., Zhao, L., Liu, Q., Zhao, Y. F., and Li, Y. M. (2008) TiO2 nanoparticles promote beta-amyloid fibrillation in vitro. Biochem. Biophys. Res. Commun. 373 (2), 315−8. (20) Wu, J., and Xie, H. (2016) Effects of titanium dioxide nanoparticles on α-synuclein aggregation and the ubiquitinproteasome system in dopaminergic neurons. Artif. Cells, Nanomed., Biotechnol. 44 (2), 690−694. (21) Weir, A., Westerhoff, P., Fabricius, L., Hristovski, K., and von Goetz, N. (2012) Titanium dioxide nanoparticles in food and personal care products. Environ. Sci. Technol. 46 (4), 2242−50.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel: 1-512-471-9260. Fax: 1512-471-7060. ORCID
Adam Heller: 0000-0003-0181-1246 Present Address †
A.H.: McKetta Department of Chemical Engineering, University of Texas, Austin, TX 78712, U.S.A.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding
Support of the Welch Foundation through Grant F1131 is gratefully acknowledged. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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ABBREVIATIONS
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REFERENCES
The pancreatic specimens enabling this study were provided by the Juvenile Diabetes Research Foundation nPOD at the University of Florida at Gainesville. The enabling ICP-QMS assays were performed by Dr. Nathaniel R. Miller, Jackson School of Geosciences, The University of Texas at Austin. Dr. Paul Gains of Inorganic Ventures (Christiansburg, Virginia) advised on stabilizing titanium-containing samples. Dr. Karalee Jarvis of the Texas Materials Institute supervised and assisted with the TEM and diffraction imaging. An anonymous reviewer suggested the rodent pancreas blanks. These, as well as technical assistance, were provided by the Animal Resources Center of The University of Texas at Austin.
BMI, body mass index; DMPC, 1,2-dimyristoyl-sn-glycero-3phosphocholine; DMPG, 1,2-dimyristoyl- sn-glycero-3-[phospho-rac-(1-glycerol)]; (hIAPP, human islet amyloid polypeptide; ICP-QMS, inductively coupled plasma octopole mass spectroscopy; HDPE, high density polyethylene; ND, no diabetes; NIST, the U.S. National institute of Science and Technology; NP, no pancreatitis; P, pancreatitis; PVC, polyvinyl chloride; r2, square of the linear correlation coefficient between the Ti concentration and the BMI; TEM, transmission electron microscopy; ppm, parts per million; ThT, Thioflavin T; T2D, type 2 diabetes; T2D-P, type 2 diabetes with pancreatitis
(1) Olefsky, J. M. (1976) The insulin receptor: its role in insulin resistance of obesity and diabetes. Diabetes 25 (12), 1154−62. (2) Kohrt, W. M., Kirwan, J. P., Staten, M. A., Bourey, R. E., King, D. S., and Holloszy, J. O. (1993) Insulin resistance in aging is related to abdominal obesity. Diabetes 42 (2), 273−281. (3) Ferrannini, E., Natali, A., Bell, P., Cavallo-Perin, P., Lalic, N., and Mingrone, G. (1997) Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J. Clin. Invest. 100 (5), 1166−73. (4) Ludvik, B., Nolan, J. J., Baloga, J., Sacks, D., and Olefsky, J. (1995) Effect of obesity on insulin resistance in normal subjects and patients with NIDDM. Diabetes 44 (9), 1121−1125. 1355
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Chemical Research in Toxicology (22) Yang, Y., Doudrick, K., Bi, X., Hristovski, K., Herckes, P., Westerhoff, P., and Kaegi, R. (2014) Characterization of Food-Grade Titanium Dioxide: The Presence of Nanosized Particles. Environ. Sci. Technol. 48 (11), 6391−6400. (23) Heringa, M. B., Peters, R. J. B., Bleys, R., van der Lee, M. K., Tromp, P. C., van Kesteren, P. C. E., van Eijkeren, J. C. H., Undas, A. K., Oomen, A. G., and Bouwmeester, H. (2018) Detection of titanium particles in human liver and spleen and possible health implications. Part. Fibre Toxicol. 15 (1), 15. (24) Thiele, E. S., and French, R. H. (1998) Light-scattering properties of representative, morphological rutile titania particles studied using a finite-element method. J. Am. Ceram. Soc. 81 (3), 469−479. (25) Jovanović, B. (2015) Critical Review of Public Health Regulations of Titanium Dioxide, a Human Food Additive. Integr. Environ. Assess. Manage. 11 (1), 10−20. (26) Pele, L. C., Thoree, V., Bruggraber, S. F., Koller, D., Thompson, R. P., Lomer, M. C., and Powell, J. J. (2015) Pharmaceutical/food grade titanium dioxide particles are absorbed into the bloodstream of human volunteers. Part. Fibre Toxicol. 12, 26. (27) Winkler, H. C., Notter, T., Meyer, U., and Naegeli, H. (2018) Critical review of the safety assessment of titanium dioxide additives in food. J. Nanobiotechnol. 16 (1), 51. (28) Koller, D., Bramhall, P., Devoy, J., Goenaga-Infante, H., Harrington, C. F., Leese, E., Morton, J., Nunez, S., Rogers, J., Sampson, B., and Powell, J. J. (2018) Analysis of soluble or titanium dioxide derived titanium levels in human whole blood: consensus from an inter-laboratory comparison. Analyst 143 (22), 5520−5529. (29) Heller, A., Jarvis, K., and Coffman, S. S. (2018) Association of Type 2 Diabetes with Submicron Titanium Dioxide Crystals in the Pancreas. Chem. Res. Toxicol. 31 (6), 506−509. (30) Pugliese, A., Yang, M., Kusmarteva, I., Heiple, T., Vendrame, F., Wasserfall, C., Rowe, P., Moraski, J. M., Ball, S., Jebson, L., Schatz, D. A., Gianani, R., Burke, G. W., Nierras, C., Staeva, T., Kaddis, J. S., Campbell-Thompson, M., and Atkinson, M. A. (2014) The Juvenile Diabetes Research Foundation Network for Pancreatic Organ Donors with Diabetes (nPOD) Program: goals, operational model and emerging findings. Pediatr Diabetes. 15 (1), 1−9. (31) Geertsen, V., Tabarant, M., and Spalla, O. (2014) Behavior and Determination of Titanium Dioxide Nanoparticles in Nitric Acid and River Water by ICP Spectrometry. Anal. Chem. 86 (7), 3453−3460. (32) Gregg, E. W., Cheng, Y. J., Narayan, K. M. V., Thompson, T. J., and Williamson, D. F. (2007) The relative contributions of different levels of overweight and obesity to the increased prevalence of diabetes in the United States: 1976−2004. Prev. Med. 45 (5), 348− 352.
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