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Cite This: Chem. Res. Toxicol. 2018, 31, 506−509
Association of Type 2 Diabetes with Submicron Titanium Dioxide Crystals in the Pancreas Adam Heller,*,† Karalee Jarvis,‡ and Sheryl S. Coffman† †
John J. McKetta Department of Chemical Engineering and ‡Texas Materials Institute, Cockrell School of Engineering, University of Texas, Austin, Texas 78712, United States
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S Supporting Information *
ABSTRACT: Pigment-grade titanium dioxide (TiO2) of 200−300 nm particle diameter is the most widely used submicron-sized particle material. Inhaled and ingested TiO2 particles enter the bloodstream, are phagocytized by macrophages and neutrophils, are inflammatory, and activate the NLRP3 inflammasome. In this pilot study of 11 pancreatic specimens, 8 of the type 2 diabetic pancreas and 3 of the nondiabetic pancreas, we show that particles comprising 110 ± 70 nm average diameter TiO2 monocrystals abound in the type 2 diabetic pancreas, but not in the nondiabetic pancreas. In the type 2 diabetic pancreas, the count of the crystals is as high as 108−109 per gram.
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INTRODUCTION Inhaled and ingested submicron and micron-sized crystals and crystal aggregates are associated with chronic inflammatory degenerative diseases. Diseases of the lung, exemplified by silicosis and asbestosis, result of inhalation of crystalline silica and asbestos. Crystals of sodium urate, cystine, calcium oxalate dihydrate and calcium pyrophosphate dihydrate are associated with chronic inflammatory degenerative diseases of the joints, kidneys, and urinary tract. Pigment-grade TiO2, typically of rutile phase and of 200−300 nm particle diameter, about half the wavelength of visible light, is widely used. Because of its 2.6 index of refraction, it constitutes the dominant light-scattering, that is, “white” component of indoor wall paints, drinks, foods, toothpastes, medications, cosmetics, paper, and plastics. The annual production of pigment-grade TiO2 has increased in the past 50 years from 2 × 106 tons to 6 × 106 tons, as TiO2 replaced the earlier used, more toxic, lead carbonate white pigment. Consumers and patients are routinely exposed to TiO2 crystals, inhaling and ingesting these. Earlier studies have established the uptake and pathologies associated with TiO2 nanocrystals1−9 and of the larger pigmentgrade TiO2 particles.10−21 Animal studies,22 and a study of factory workers,23 have shown that inhaled pigment-grade TiO2 crystals enter the bloodstream.23 Animal studies,22 and a study of human volunteers,24 show that also ingested TiO2 crystals enter the bloodstream. The crystals are phagocytized and are inflammatory.25−30 By binding to and activating the NLRP3(NALP3) inflammasome,12,31−33 a macromolecular complex found in macrophages, neutrophils, platelets, and microglia, the TiO2 crystals cause inflammatory cascades leading to death of proximal cells. © 2018 American Chemical Society
EXPERIMENTAL PROCEDURES
Specimens. Pancreatic specimens, from the pancreas head, were received from Juvenile Diabetes Research Foundation nPOD at the University of Florida at Gainesville. Three were nondiabetic, 4 were type 2 diabetic (T2D), and 4 were T2D with pancreatitis (T2Dp). Their pathology reports are provided in Table S1 of the Supporting Information. Transmission Electron Microscopy (TEM). A JEOL 2010F transmission electron microscope (TEM) was used for imaging the crystals. The crystals were about evenly distributed across the used 314-square, 3 mm diameter, 200 mesh copper grids with type-B carbon supports (Ted Pella Redding CA, catalog number 1810). Typically, crystals of 3 squares were TEM imaged, that is, 1% of the applied crystals were counted and examined. Crystallinity was confirmed by the crystals’ electron diffraction, and then elemental compositions were determined by energy-dispersive X-ray spectroscopy. In the elemental analyses the peaks of all elements excepting carbon were integrated. The reported values are percentages of the integrals. Processing of the Pancreatic Specimens for TEM. The pancreatic samples were processed in plastic-ware as follows: 25 mg of tissue was minced and digested overnight at ambient temperature with 1 mL of an aqueous solution containing 25 mg of trypsin (from bovine pancreas, Sigma catalog number 1426) and 25 mg of proteinase K (from Tritirachium album, Sigma catalog number P2308). The proteolytic enzyme-treated suspensions were degreased with hexane. First the suspensions were centrifuged at 12,000g for 1 h to separate an oily top layer from the aqueous phase. The oily layer solidified upon chilling to 0 °C, allowing removal of most of the oil by skimming with a 2 mm wooden applicator. Because part of the aqueous suspension was emulsified in the skimmed oil and it could have contained crystals, the oil was dissolved in 1 mL of hexane and centrifuged for 1 h at Received: February 19, 2018 Published: May 24, 2018 506
DOI: 10.1021/acs.chemrestox.8b00047 Chem. Res. Toxicol. 2018, 31, 506−509
Article
Chemical Research in Toxicology 12,000g. The top hexane layer was pipetted off, and the bottom aqueous layer was re-extracted with 0.5 mL hexane and centrifuged for 20 min at 12,000g. After the hexane was pipetted off, the aqueous centrifugate was combined with the main aqueous suspension. The combined hexane phases were re-extracted with 0.5 mL of water and centrifuged for 20 min at 12,000g, and the aqueous centrifugate was again combined with the main aqueous suspension. The aqueous suspension was recentrifuged at 12,000g for 10 min to separate residual hexane. About 1 mL of the now degreased aqueous suspension was obtained. After shaking to homogenize, 5 μL of the aqueous suspension was water diluted 200-fold to 1 mL. Although the diluted aqueous solution appeared to be clear and homogeneous, it was shaken to homogenize, then 5 μL of the solution was pipetted onto the 3 mm diameter TEM grid. The liquid on the grid was evenly distributed, and the examined squares were selected from both centers and peripheries of the grids.
electron diffraction patterns are shown in Figure 1 and in Figures S1−S6 of the Supporting Information. Seventeen, or 20%, of the crystals were hydrated Fe3+ oxide crystals of 140 ± 100 nm average diameter; 6, or 7%, were calcium oxalate crystals of 130 ± 70 nm average diameter; and 6, or 7%, were graphenic carbon crystals of 0.9 ± 0.4 μm average diameter. While the carbon crystals had stacked graphenic planes, their Caxes were not developed, differing in this respect from graphite. All of the TiO2 crystals were in the T2D and T2Dp specimens, and none in the nondiabetic specimens. In contrast, hydrated Fe3+ oxide crystals were found also in nondiabetic specimens. The number of calcium oxalate and carbon crystals was too small to allow analysis for differences in their distributions. Elemental compositions of the crystals are provided in Table 2.
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RESULTS To rule out labware-, water-, and reagent-associated crystal contamination, samples without pancreatic tissue were identically processed and their 5 μL droplets were applied to TEM grids. No TiO2 or other crystals were observed. Table 1
Table 2. Elemental Compositions of the Pancreatic Crystals crystal
Table 1. Counts of Crystals in the Nondiabetic, T2D, and T2Dp Pancreas Head Specimens diagnosis/ pathology
specimen
nondiabetic 6008 nondiabetic 6095 nondiabetic 6295 total, nondiabetic T2D 6255 T2D 6191 T2D 6277 T2D 6273 T2Dp 6275 T2Dp 6272 T2Dp 6259 T2Dp 6249 total, diabetic total, all specimens
tested TEM squares 3 3 3 3 3 5 3 3 3 3 3
TiO2
hydrated Fe3+ oxide
Ca2+ oxalate
graphenic carbon
0 0 0 0 18 4 2 1 4 12 5 10 56 56
1 0 1 2 6 0 2 0 1 1 3 2 15 17
0 0 1 1 0 1 2 0 2 0 0 0 5 6
2 0 0 2 0 1 3 0 0 0 0 0 4 6
averaged sample count
calcd, atom %
TiO2
22
Ti, 33.3; O, 66.7
Fe(O)(OH)· H2O CaC2O4
11
Fe, 25.0; O,75.0 (excl. H) Ca, 20.0; O, 80.0 (excl. C) C, 100.0
C
6 5
found, average atom % Ti, 28 ± 7; O, 69 ± 7 Fe, 24 ± 4; O, 76 ± 4 Ca, 22 ± 4; O, 77 ± 4 C, 100.0
Because the prevalence of T2D increases with age and body mass index (BMI), the abundance of TiO2 crystals in the T2D specimen-derived preparations could have been age or BMI associated, rather than being T2D associated. Age or BMI association was, however, not evident, as seen in Tables 3 and 4.
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DISCUSSION The number of crystals per gram of pancreas (Table 5) can be estimated through the product N × 1/W × D × A × F. N is the crystal count in 3 squares of the TEM grid. For 0.025 g tissue samples, 1/W = 1/0.025 = 40 g−1. Because 5 μL of the enzymedigested and hexane extracted preparations were diluted to 1 mL, D = 1000/5 = 200. Because 5 μL of the 1 mL diluted solution were applied to the 3 mm, 314-squares TEM grid, A = 1000/5 = 200. Becasue crystals were counted in 3 of the 314 squares of the grid, F = 314/3 = 105. The number of crystals per gram of tissue is, therefore, N × 40 × 200 × 200 × 105 = N × 1.6 × 108, that is, each detected crystal represents 0.16 billion
shows the number of crystals on TEM grids to which 5 μL preparation droplets were applied. Of the 85 observed crystals, 56, or 66%, were TiO2 crystals of 110 ± 70 nm average diameter. Exemplary TiO2 crystals and their selected area
Figure 1. TEM Image of aTiO2 crystal of a T2D pancreas and its electron diffraction pattern. The inset shows the spacings of the atoms. 507
DOI: 10.1021/acs.chemrestox.8b00047 Chem. Res. Toxicol. 2018, 31, 506−509
Chemical Research in Toxicology
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CONCLUSION This pilot study raises the possibility that T2D could be a chronic crystal-associated inflammatory disease of the pancreas, analogous to chronic crystal-caused inflammatory lung diseases like silicosis and asbestosis. The dominant T2D-ssociated pancreatic particles consist of 110 ± 70 nm average diameter TiO2 crystals, attributable to ingested white, that is, visible light scattering, pigment used in drinks, foods and medications, and/ or to inhaled indoor wall-paint pigment, transported to the pancreas in the bloodstream. The study raises the possibility that humanity’s increasing use of TiO2 pigment accounts for part of the global increase in the incidence of T2D. Being a pilot study, it requires sufficient expansion of sample sizes for statistical analysis as well as blinded studies. Should these confirm that pancreatic TiO2 pigment crystals are associated with T2D, studies mapping pathways of ingested and/or inhaled crystals to the pancreas would be warranted, as would be studies of mechanisms by which the inflammasome activating crystals reduce insulin supply by causing the death of proximal pancreatic beta-cells.
Table 3. Apparent Independence of the TiO2 Crystal Count of Age specimen
type
donor age
TiO2 crystals per 3 TEM squares
6095 6249 6273 6295 6275 6277 6008 6255 6259 6272 6191
nondiabetic T2Dp T2D nondiabetic T2Dp T2D nondiabetic T2D T2Dp T2Dp T2D
40 45 45 47 48 48 50 55 57 57 62
0 10 1 0 4 1.2 0 18 5 12 4
Table 4. Apparent Independence of the TiO2 Crystal Count of Body Mass Index specimen
type
donor BMI
TiO2 crystals per 3 TEM squares
6191 6008 6255 6277 6272 6295 6249 6259 6095 6273 6275
T2D nondiabetic T2D T2D T2Dp nondiabetic T2Dp T2Dp nondiabetic T2D T2Dp
19.9 24.2 29.4 29.5 29.6 30.4 32.3 32.3 35.5 39.1 41
4 0 18 1.2 12 0 10 5 0 1 4
Article
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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.8b00047. Pathology reports of the pancreatic specimens. TEM images and electron diffraction patterns of six pancreatic TiO2 crystals (PDF)
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Table 5. Billions of Crystals per Gram of the Nondiabetic, T2D, and T2Dp Pancreas specimen
type
TiO2
hydrated Fe(III) oxide
Ca oxalate
graphenic carbon
6008 6095 6295 6255 6191 6277 6273 6275 6272 6259 6249
nondiabetic nondiabetic nondiabetic T2D T2D T2D T2D T2Dp T2Dp T2Dp T2Dp
0.0 0.0 0.0 2.9 0.6 0.2 0.2 0.6 1.9 0.8 1.6
0.2 0.0 0.2 1.0 0.0 0.2 0.0 0.2 0.2 0.5 0.3
0.0 0.0 0.2 0.0 0.2 0.2 0.0 0.3 0.0 0.0 0.0
0.3 0.0 0.0 0.0 0.2 0.3 0.0 0.0 0.0 0.0 0.0
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel: 1-512-471-9260. Fax 1512-471-7060. ORCID
Adam Heller: 0000-0003-0181-1246 Karalee Jarvis: 0000-0002-3560-0239 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The pancreatic specimens enabling this study were provided by the Juvenile Diabetes Research Foundation nPOD at the University of Florida at Gainesville. The study was supported in part by Welch Foundation grant no. F-1131.
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ABBREVIATIONS NALP3, a protein component of the inflammasome, containing NACHT, LRR and PYD domains, encoded by the NLRP3 gene. It is expressed predominantly in macrophages and neutrophils. Inflammasome activation by crystal or pathogen motifs triggers release of inflammatory agents and leads to the death of nearby cells; TEM, transmission electron microscopy; T2D, type 2 diabetes; T2Dp, type 2 diabetes with pancreatitis; BMI, body mass index
crystals per gram of pancreas. As seen in Table 5, TiO2 crystals abound in the T2D and the T2Dp pancreas, but not in the nondiabetic pancreas. Hydrated Fe3+ oxide crystals, which are well-known residents of the brain,34 are also prevalent in the diabetic pancreas, but their count is only 1/4 of that of the TiO2 crystals, and, unlike the TiO2 crystals, they are found also in the nondiabetic pancreas. If the very high count of TiO2 crystals in specimen 6255 would be considered as an outlier, then the count of crystals could be higher in the T2Dp specimens than in the T2D specimens, that is, in T2D with pancreatitis, the count would be the highest.
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