Association of Type 2 Diabetes with Submicron Titanium Dioxide

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Association of Type 2 Diabetes with Submicron Titanium Dioxide Crystals in the Pancreas Adam Heller, Karalee Jarvis, and Sheryl S. Coffman Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.8b00047 • Publication Date (Web): 24 May 2018 Downloaded from http://pubs.acs.org on May 27, 2018

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Chemical Research in Toxicology

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Association of Type 2 Diabetes with Submicron Titanium Dioxide Crystals in the Pancreas Adam Heller*1, Karalee Jarvis2 and Sheryl S. Coffman1 1

John J. McKetta Department of Chemical Engineering, University of Texas, Austin, Texas

78712, United States 2

Texas Materials Institute, Cockrell School of Engineering, University of Texas, Austin, Texas

78712, United States *

[email protected] Tel: 1-512-471-9260, Fax 1-512-471-7060

ACS Paragon Plus Environment

Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Transmission electron microscopic image of a cluster of TiO2 crystals of which > 108 /g were found in the type 2 diabetic pancreas


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ABSTRACT. Pigment-grade titanium dioxide (TiO2) of 200-300 nm particle diameter is one of the most widely used submicron-sized particle materials. Inhaled and ingested TiO2 particles are known to enter the bloodstream, to be phagocytized by macrophages and neutrophils, to be inflammatory, and to activate the NLRP3 inflammasome. In this pilot study of 11 pancreatic specimens, 8 of the type 2 diabetic pancreas and 3 of the non-diabetic pancreas, we show that 110±70 nm average diameter TiO2 crystals abound in the type 2 diabetic pancreas, but not in the non-diabetic pancreas. In the type 2 diabetic pancreas, their count is as high as 108 -109 per gram.

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. Other crystals, like 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 rutile phase and of 200-300 nm particle diameter--about half the wavelength of visible light---is most widely used. Because of its 2.6 index of refraction, it constitutes the dominant light-scattering i.e. “white” component of indoor wall paints, foods, toothpastes, medications, cosmetics, paper and plastics. The annual production of pigment-grade TiO2 increased in the past 50 years from 2 x 106 tons to 6 x 106 tons as TiO2 replaced the earlier used, more toxic, lead carbonate white pigment. Consumers and patients are routinely exposed to pigment-grade TiO2 crystals, inhaling and ingesting these. Earlier studies have established the uptake and pathologies associated with TiO2 nanocrystals 1-9 as well as of the larger pigment-grade 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, 31-34 a macromolecular complex found in



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macrophages, neutrophils, platelets and microglia, the TiO2 crystals cause inflammatory cascades, leading to death of proximal cells.

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 non-diabetic, 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, i.e. 1 % of the applied crystals was counted and examined. Crystallinity was confirmed by the crystals’ electron diffraction, 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 de-greased with hexane. First the suspensions were centrifuged at 12,000 G for 1 hour 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 hour at 12,000 G. The top hexane layer was pipetted off and the bottom aqueous layer was re-extracted with 0.5 mL hexane, centrifuged for 20 min at 12,000 G. After the hexane was pipetted off, the aqueous centrifugate was combined with the main aqueous suspension. The combined hexane phases were re-


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extracted with 0.5 mL of water, centrifuged for 20 min at 12,000 G, and the aqueous centrifugate was again combined with the main aqueous suspension. The aqueous suspension was recentrifuged at 12,000 G 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 solutions appeared to be clear and homogeneous, they were 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.

RESULTS To rule out lab-ware-, 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 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 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; six, or 7 %, were calcium oxalate crystals of 130 ± 70 nm average diameter; and six, or 7 %, were graphenic carbon crystals of 0.9 ± 0.4 µm average diameter. While the carbon crystals had stacked graphenic planes, their C-axes were not developed, differing in this respect from graphite. All of the TiO2 crystals were in T2D and T2Dp specimens, none in the non-diabetic specimens. In contrast, hydrated Fe3+ oxide crystals were found also in non-diabetic 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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Table 1. Counts of crystals in the non-diabetic, T2D and T2Dp pancreas head specimens Diagnosis/ Pathology Non-diabetic

Specimen 6008 6095 6295

Tested TEM squares 3 3 3

0 0 0

Hydrated Fe3+ oxide 1 0 1

Ca2+ oxalate 0 0 1

Graphenic carbon 2 0 0

0

2

1

2

18 4 2 1 4 12 5 10

6 0 2 0 1 1 3 2

0 1 2 0 2 0 0 0

0 1 3 0 0 0 0 0

56

15

5

4

56

17

6

6

TiO2

Count of crystals in the 3 non-diabetic specimens

6255 6191 6277 6273 6275 6272 6259 6249

T2D

T2Dp

3 3 5 3 3 3 3 3

Count of crystals in the 8 diabetic specimens Crystals, total

Table 2: Elemental Compositions of the Pancreatic Crystals Crystal TiO2

Averaged Sample Size 22

Calc., atom % Ti, 33.3; O, 66.7

Found, average atom % Ti, 28 ± 7; O, 69 ± 7

Fe(O)(OH).H2O CaC2O4

11 6

Fe, 25.0; O,75.0 (excl. H) Ca, 20.0; O, 80.0 (excl. C)

Fe, 24 ± 4; O, 76 ± 4 Ca, 22 ± 4; O, 77 ± 4

C

5

C, 100.0

C, 100.0


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Figure 1: TEM Image of aTiO2 crystal of a T2D pancreas and its electron diffraction pattern. The insert shows the spacings of the atoms. 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

Non-diabetic T2Dp T2D Non-diabetic T2Dp T2D Non-diabetic 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

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,



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rather than being T2D associated. Age or BMI association was, however, not evident, as seen in Tables 3 and 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 Non-diabetic T2D T2D T2Dp Non-diabetic T2Dp T2Dp Non-diabetic 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

DISCUSSION The number of crystals per gram of pancreas (Table 5) can be estimated through the product N x 1/W x D x A x F, where N is the crystal count in 3 squares of the TEM grid for 0.025 g tissue samples, i.e. 1/W =1/0.025=40 g-1; 5 µL of the enzyme-digested and hexane extracted preparations having been diluted to 1 mL, i.e. D= 1000/5=200; 5 µL of the 1 mL diluted solution having been applied to the 3 mm, 314 squares TEM grid, i.e. A=1000/5=200; and crystals counted in 3 of the 314 squares of the grid, i.e. F=314/3=105. For these values the number of crystals per gram of tissue is N x 40 x 200 x 200 x105 = N x 1.6 x 108, i.e. each detected crystal represents 0.16 billion crystals per gram of pancreas. As seen in Table 5 TiO2 crystals abound only in the T2D and the T2Dp pancreas, not in the non-diabetic pancreas.


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Table 5. Count of crystals in non-diabetic, T2D and T2Dp pancreas, billions per gram Specimen

TiO2

Hydrated Fe(III)oxide

Ca oxalate

Graphenic carbon

6008

Non-diabetic

0.0

0.2

0.0

0.3

6095

Non-diabetic

0.0

0.0

0.0

0.0

6295

Non-diabetic

0.0

0.2

0.2

0.0

6255

T2D

2.9

1.0

0.0

0.0

6191

T2D

0.6

0.0

0.2

0.2

6277

T2D

0.2

0.2

0.2

0.3

6273

T2D

0.2

0.0

0.0

0.0

6275

T2Dp

0.6

0.2

0.3

0.0

6272

T2Dp

1.9

0.2

0.0

0.0

6259

T2Dp

0.8

0.5

0.0

0.0

6249

T2Dp

1.6

0.3

0.0

0.0

Hydrated Fe3+ oxide crystals, which are well known residents of the brain, 35 are also prevalent in the diabetic pancreas, but their count is only ¼ of that of the TiO2 crystals and, unlike the TiO2 crystals, they are found also in the non-diabetic 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, i.e. in T2D with pancreatitis the count would be the highest. Conclusion: Our 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 crystals are 110 ± 70 m average diameter TiO2 crystals, attributable to ingested white, i.e. visible light scattering, pigment used in foods and medications and/or to inhaled indoor wall-paint pigment, either or both 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



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incidence of T2D. Being a pilot study, it requires expansion to sample sizes sufficient for statistical analysis including 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 crystals might trigger or propagate T2D.

Conflict of Interest Statement: The authors declare that they have no conflict of interest.

Supporting Information: Pathology reports of the pancreatic specimens. TEM images and electron diffraction patterns of six pancreatic TiO2 crystals. Acknowledgements. 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 # F-1131.

Abbreviations: NALP3 is 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. SI, Supporting Information. BMI, body mass index.

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Association of Type 2 Diabetes with Submicron Titanium Dioxide

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