Diabetologia 3, 249-265 (1967)

Spontaneous Diabetes in Dogs and Cats* A Pathological Study

W. GEPTS and D. TOUSSAINT

Department of Pathology and Department of Ophtalmology, Brugmann University Hospital and Fondation M6dieale l~eine Elisabeth, Brussels -- Belgium

Summary. A histological study of 30 spontaneously phocytaire tr@s dense duns un riot. -- Ni chez les chiens, ni diabetic dogs and 5 spontaneously diabetic cats is chez les chats, il n'a 6t@ vu de l@sions glom@rulaires iden- presented. -- The islets of Langerhans and the B cells tiques k celles de glom6ruloscl~rose diab~tique humaine. were strongly reduced in number in a large majority of Les l@sions les plus fr@quentes consistaient en un 6pais- the diabetic dogs. The B cells were often degranulated sissement des axes membraneux des touffes glom@rulaires and hydropic. In cases of longer duration, the islets were et une hypertrophic de la paroi des arterioles aff@rcntes. -- scarce and B cells could no longer be found. -- In contrast Duns les r@tines des chiens diab@tiques il existait une to the findings in diabetic dogs, all five cats showed acellularit@ locale ou g6n6ralis@e de la paroi des capillaires. numerous islets and B cells. However in 4 cats, the B cells Un petit hombre de microan@vrysmes ont 6t6 trouv6s showed complete degranulation and hydropic changes, as chez 3 chiens diab@tiques. L'incidence plus faible des in the dogs. In one cat, the B cells had a normal appearance. 16sions de r@tinopathie vasculaire, comparativement aux Extensive hyalin deposits were found in the stroma of the diab~tiques humains, s'explique probablement par la dur6e islets in 2 cats. In one cat, an islet showed a dense de vie plus courte du chien'et du chat. I1 est possible aussi lymphocytic infiltration. -- No lesions identical to human que les capillaires r@tiniens de ces animaux soient moins diabetic glomerulosclerosis were found in any of the dogs susceptibles de d~velopper des l@sions d6g6n6ratives. -- or cats. The changes most frequently observed were a Un degr6 marqu@ de st6atose h6patique a 6t6 observ6 chez variable degree of thickening of the mesangial stalk of the beaucoup de chiens ct de chats. Les surr6nales 6talent glomerular capillaries, and an hypertrophy of the wall of souvent hypertrophi~es et contenaient des ad6nomes, the afferent arteriole. Scars resulting from chronic mais ces 16sions ne paraissent pus diff@rentes de celles que pyelonephritis, were found in a few dogs and cats. -- l'on peut trouver chez des chiens et des chats non dia- Accllular, non-functionM capillaries, with degeneration of bgtiques de m~me age. L'hypophyse a ~t~ pr@Icv@e chez 7 pericytes ("ghost-cells")were found in larger numbers in chiens. Duns 2 cas, elle contenait un ad6nome. Une @rude the retinas of the diabetic dogs than in non-diabetic cytologique plus compl@te des hypophyses sera publi~e control dogs. A very few rnicroancurysms could be found ult~rieurement. in 3 dogs. The lower incidence of the most typical lesions of diabetic retinopathy in dogs, as compared with the Spontandiabetea bei Hunden und Katzen. Eine patho- human diabetic, is probably related to the shorter logisch-anatomiache Unterauchung. duration of the disease in these animals. However, a lower susceptibility of the retina of dogs and cats to Zuaammenfassung. Die Autoren berichten fiber die develop degenerative changes cannot be excluded. -- Ergebnisse yon Untersuchungen an 30 spontan-diabeti- A severe steatosis was observed in the liver of many dogs schen Hunden und 5 spontan-diabetischen Katzen. Bei and cats. In 4 dogs, the liver showed early cirrhosis. In der grol~en Mehrzahl der diabetischen Hunde war die diabetic dogs and cats, the adrenal cortex often showed Zahl der Langerhansschen Inseln und der B-Zellen stark hypertrophy and contained adenomas; however, these herabgesctzt. Die B-Zellen waren oft degranuliert und changes have also been reported in non-diabetic aging hydropisch. Bei Hunden mit schon lung anhMtender dogs. An adcnoma was found in 2 of the 7 pituitaries Kranl~eit waren die Inseln nur noch vereinzelt und obtained from diabetic dogs; the cytological aspect of B-Zellen fiberhaupt nicht mehr nachweisbar. -- Im these adenomas and of the pituitaries will be reported in Gegensatz zu diesen Ergebnissen fanden sich bei Mien 5 a later publication. Katzen zahlreiche Inseln und B-Zellen. Bei 4 dieser Katzen jedoch waren die B-Zellen, wie bei den I.iunden, degranuliert und hydropisch entartet. Bei einer Katze Diab~te spontand chez lea chiena et lea chats. Etude hia- war das Aussehen der B-Zellen normal. Im Stroma der topathologi~ue. Inseln von 2 Katzen konnten starke Hyalinablagerungen Rdsumd. Les auteurs pr@sentent une 6rude histo- nachgewiesen werden. In einem Falle zeigten die Inseln pathologique de 30 chiens et de 5 chats spontandment eine starke lymphocyt~re Infiltration. -- Weder bei den diabdtiques. -- Los riots de Langerhans et les eellules Hunden noch bei den Katzen waren typische L~sionen B 6talent fortement diminu@s en hombre ehez la grande der Glomeruli, wie sic bei der Glomerulosklerose des majorit6 des ehiens. Los eellules B 6taient souvent menschlichen Diabetes auftreten, nachweisbar. Die h~u- d6granul6es et hydropiques. Chez les ehiens dent le figsten Ver/inderungen bestanden aus einer mehr oder diabgte avait 6volud pendant longtemps, los riots 6taient weniger ausgepr~gten Vcrdickung des mesangiMen Tefls tr@s rares et les eellules B absentes. -- Chez les 5 chats der Kapillaren der Glomeruli und aus einer HIypertrophie spontan6ment diab6tiques par centre, ]es riots et les der Wand der zuffihrenden Arterio]en. Bei einigen Hun- cellules B 6taient nombreuscs. Les eellules B 6taient den und Katzen bestanden auf chronische Pyelonephritis dggranul6es et hydropiques chez 4 chats. Chez 1 des zurfickffihrende Narben. -- In der l~etina der diabeti- chats, les eellules B paraissaient normales. De nombreux schen Hunde waren zellenlose und funktionslose Kapil- riots pr6sentaient des d@6ts de substance hyaline duns le larch vorhanden, und degenerierte Pericyten ("ghost- stroma. Chcz un chat, il cxistait une infiltration lyre- cells") waren h~ufiger Ms bei normMen I-Iunden. In drei I.iunden wurden einige ]V[ikroaneurismen beobachtet. Dal3 * Supported by the Belgian Fends de la Recherche diese ffir die ]~etinopathie des Diabetes typischen L~si- S eientifique M6dicale (Grant n ~ 711) and U.S. National onen beim Hund verh~ltnism~13ig selten auftreten kSnnte Institute of Metabolic and Arthritic Diseases (N.I.H. mit der kfirzeren Lebensdauer der Krankheit bei diesen Research grant AM-06490-03 PTI-IA). Tieren zusammenh~ngen. Es ist j edoch nicht ausgesehlos- 250 W. GENTS and D. TOVSSAI~: Spontaneous Diabetes in Dogs and Cats Diabetologia sen, dab die Retina yon Hunden und Katzen weniger zu tiseher I{nnde fanden sich Adenome, fiber deren cytolo- degenerativen Vergnderungen neigt. -- In der Leber gische Untersuchung in einer spgteren Ver6ffentlichung vieler ttunde und Katzen wurde eine schwere Steatose berichtet wird. beobachtet. In vier Hunden zeigte sich beginnende Leber- cirrhose. In diabetischen Hunden und Katzen waren die Key-words: Spontaneous Diabetes, Dog, Cat, Diabetes Nebennieren oft hypertrophisch und enthielten Adenome, in dogs and cats, Pancreas, Islets of Langerhans, B cells, die allerdings auch bei nichtdiabetischen alternden Htm- Insulitis, Hyalin, Capillaries, Kidney, Retina, Micro- den beobachtet wurden. In 2 yon 7 Hypophysen diabe- aneurysms, Pituitary.

Spontaneous Diabetes mellitus has been reported Material andMethods repeatedly in dogs and cats. Its incidence is not known Thirty dogs and five cats have been studied. The exactly, but it is estimated by M~I~R [26] at 1/200 in clinical data, when available, have been listed in dogs and l/s00 in cats. Several excellent studies and Tables 1 and 2. No special racial predisposition emer- reviews have been published on spontaneous canine ges from our material. The age of the dogs varied from diabetes [26, 14, 35, 32, 4, 42, 8, 40, 41, 5, 17, 11, 28, 2 to 13 years; in cats from 7 to 11 years. There is a

Table 1. Clinical data on spontaneously diabetic dogs

2fir. Race Age (years) Sex Weight (kg) Duration of diab. Glycemia Glucosuria g.~ g.% 0 26 Poodle ? ? 15 ? ? 10 28 Shepherd 7 9 30 ~ 60 days ? 40 29 Fox 14 9 7 210 days ? 50 35 Mongrel ? ? ? ? 4,41 50 37 Poodle 8 ~ 10 60 days ? 5 40 Poodle 9,5 9 ? 2 years ? 40 45 Mongrel 12 ~ 15 8 days 2 + 50 Loulou 6 c~ ? ? ? 2 58 Shepherd 14 9 ? ? ? + 59 Mongrel 12 9 ? ? ? + 60 Cocker 5,5 9 ? 90 days 2 20 64 Fox ? c~ ? 75 days 2 20 65 Mongrel 10 ~ ? ? 2 20 66 Shepherd lO 9 18 180 days ? + + 67 Groenendael 14 9 22 180 days 8,5 15 68 Fox 4 9 10 ? 2,30 + 72 Skipperke ? 9 10 2 years 2,40 10 73 Samoyede ? 9 12 ? ? + + 83 Skipperke 7 9 7 ? 2 + + 84 Pincher 8 c~ 7 8 days 2 10 87 Pure-bred 11 ~ ? ? ? + 88 Spaniel 9 9 15 60 days ? + + + 89 Fox 8 ~ ? ? ? + + 91 Mongrel 13 ~ 20 150 days 3,70 + 92 Doberman 2 9 3 ? 3,50 + + + 93 Mongrel 13 ~ 10 ? 2,10 + + + 94 Collie 8 ~ ? ? > 2 + + 90 Shepherd 10 9 30 120 days 4,50 + + + 95 Fox 6 c~ 7 ? 3,30 + + + 96 Shepherd 7 ~ 35 ? 3 + +

36, 9]. On spontaneously diabetic cats the information Table 2. Clinical data on spontaneously diabetic cats is scarce and mostly confined to single case reports ~r. Age Sex Duration Glycemia Glycosuria [35, 34, 33, 25, 15, 18]. of diab. g/1 g/1 For many years we have been collecting material 36 7 9 ? 2 ++ from spontaneously diabetic dogs and cats. The largest 47 11 9 1 month 2 + + part of it was obtained through private veterinarians, 5t :tO 3' ? ? ++ who had performed the autopsy after killing the ani- 62 7 9 2 months ? ++ mal at the owner's request. For this reason detailed 70 8 ~ 7months ? +++ biochemical data are not available on these cases. Our study is aimed principally at the morphological chan- slight preponderance of females in both dogs and cats. ges that have been found in the pancreas, the kidneys, We have no data on an eventual diabetic heredity the retinas and in other organs of these dogs and ca.ts. except for dog 28, on which we have been informed Vol. 3, No. 2, 1967 W. GEPTS and D. ToussAII~: Spontaneous Diabetes in Dogs and Cats 251

:Fig. 1. Diabetic Dog (No. 50). Islet of Langerhans. Swelling and hydropie change of the B cells. Hemalum-erytrosine-saffron. A:A cells -- B:B ceils. 800 x

that the mother and a female litter-mate were also the retina was dissected and incubated with a 1~/o diabetic. trypsin solution for 2 hours. The isolated retinal vas- The duration of the diabetes was estimated from culature was mounted on a glass slide and stained the symptoms related by the owners of the animals. In with PAS, toluidine blue, and the May-Grunwald dogs it ranged from a few days to 3 years, in eats from method. The retinas from 7 non-diabetic dogs and 1 to 7 months. The diagnosis of diabetes was based 4 non-diabetic cats were used as controls. on clinical symptoms (polydipsia, polyuria, weight loss), glyeosuria and/or hyperglycemia. Histologic findings Slices of pancreas, kidney, liver, the adrenals and Pancreas (Table 3) in some of the cases the pituitary were fixed in Ro- A. Dogs The chief histological findings in the islet meis' or in Bouin's fluid. Paraffin sections were stained tissue are summarized in Table 3. In 18 dogs the islets by hemalum-erythrosine-saffron, Gomori's chromium were markedly reduced in number. In 5 of these 18 hematoxylin-phloxine method, aldehyde-fuchsin trich- cases, a careful study of numerous slides failed to disco- rome [20], Ivic's Victoria Blue method [16], Manoe- ver one single islet. In the remaining 13 cases a few chio's toluidine blue reaction for metachromatic cells islets were found, most of them small in size. In 2 of [23], and Dominici's toluidine blue-erythrosine-orange these cases they contained only small cells that some- [24]. times stained with phloxin, as A cells, but often did One of the eyeballs was fixed either in Romeis' or not show any particular staining affinity. In the in Bouin's fluid. An equatorial segment comprising remaining ll cases B cells were still present; they were the optic nerve was embedded in paraffin, cut at 5 #, completely degranulated, swollen and vacuolated and stained with hematoxylin-eosin and the periodic (Fig. 1) in 8 cases; in 3 other cases, they showed de- acid Schiff reagent (PAS). The remaining part of this granulation but no hydropic change. retina was fiat mounted and embedded in paraffin, Ii/7 dogs the islets were still numerous. I-Iowever, cut at 5 # and stained with the same methods. The in 2 of them, they were small and composed of small other eyeball was fixed in 10~o formalin; after fixation undifferentiated cells. In 2 dogs with fairly numerous 252 W. GEs and D. ToussAI~T: Spontaneous Diabetes in Dogs and Cats Diabetologia

Fig. 2. Diabetic Dog (No. 35). Islet of Langerhans. The B cells are numerous and dcgranulated. _&:A cells --B:B cells. Chromium hematoxylin-phloxine. 400 x

Table 3. Histological changes in the islet tissue of spontaneously diabetic dogs

No islets found Strong / (5) reduction in the number \ / No B-cells found of islets \ / 9Islets scarce ( Hydropic (13) ~ /ball. deg. B-cells present/-- (8) (n) 25 CASE S NDegranul. (3) /No B-cells found Sligh% in/ (2) reduction Hydropio the number \ /ball. deg. of islets N~ / (2) B-ceNs present ~. (4) \ "Degranul. (3) islets, the B cells were completely degranulated, With the PAS method variable amounts of glyco- swollen and vacuolated. In the remaining 2 dogs of gen could be demonstrated. Many of these cells had this group, the B cells showed only a varying degree a ballooned appearance and showed nuclear pyenosis. of degranulation (Fig. 2). In other B cells, especially in those with a less extreme Vol. 3, No. 2, 1967 W. GEPTS and D. Touss~N~: Spontaneous Diabetes in Dogs and Cats 253

Fig. 3. Diabetic Dog (No. 50). Islet of Langerhans. Hydropic change of the B cells. B: B cells -- K: "KOrnehen". Toluidine ]31ue. 800 x

degree of hydropic change, the cytoplasm contained Table 4. Histological changes in the islet tissue of spon. irregular small particles (Fig. 3), which were parti- taneously diabetic cats cularly well brought out with toluidine blue. A pre- 5 cases vious incubation of the section with 0.1~o ribonu- Number of islets----Normal in all cases clease abolished this staining affinity. It appears B-cells numerous in all cases therefore, that these particles represent I~NA, present in increased amounts in the cytoplasm of these ]~ cells. Hydropie change B-cells normal The quantitative changes in the A cells, ]) cells Ballooning degener. and in the metachromatie cells roughly paralleled 4 cases 1 case those of the islets and of the B cells. In the few cases in which the B cells were" relatively numerous, typical / A cells, D cells and metachromatic cells were easy to Insulitis Hyalinosis + find; they showed no abnormality whatsoever. In the i case other cases, with few islets and few or no B cells, these Hyalinosis cells were also strongly reduced in number or could 1 case not be found at all. B. Cats (Table 4). In all 5 cats the islets were Vacuolisation of the epithelium of the inter- and numerous and often large. Quantitative measurements intralobular ducts was the most prominent change in have not been performed, but the amount of islet the exocrine part of the pancreas. Focal acute pancrea- tissue in the pancreas of our cats often suggested some titis was observed in 4 dogs and a diffuse acute pan- degree of hyperplasia. creatitis in one dog. Focal chronic pancreatitis and In 4 cats, the islets were composed mainly of pancreatic fibrosis of the perflobular type were present degranulated, swollen, and hydropie B cells (Fig. 4). in a small number of dogs. In many islet cells the vacuolisation had attained an 254 W. GnPTs and D. TOVSSAI~T: Spontaneous Diabetes in Dogs and Cats Diabctologia

]~ig. 4. Diabetic Cat (No. 47). Islet of Langcrhans. ttydropic B cells. A: A cells -- B:B cells, ttemalum-erytrosine-saffron. 400 x

Table 5. Histological changes in the kidneys of spontaneously diabetic dogs and cats

Thickening of glomer. Normal basement membr. Pyelonephritis Glycogen glomer, mesangial diffuse in tub. epith. + ++ +++ Dogs 10 9 5 2 2 2 7 23 cases Cats 5 0 0 0 0 2 3 5 cases extreme degree and was associated with nuclear cytes was discovered in one islet (Fig. 6). No other pyenosis, recalling the ballooning degeneration as example of this lesion could be found either in numer- described by LAzArus and VOLK [20]. Small amounts ous sections from the same pancreas, or in the other of glycogen could be demonstrated in these vacuolated diabetic cats. In the islet showing inflammatory in- islets cells. In the central area of the islet cells a small filtration, the B cells were hydropic. core of A cells was often present. In 1 eat, the islets were not only numerous but In 2 cats abundant deposits of a hyaline substance contained well granulated A and B ceils. As a matter were present in numerous islets (Fig. 5). This hyaline of fact no abnormality whatsoever could be demon- substance had the tinctorial characteristics of amyloid. strated in the islet tissue of this animal. In several islets it replaced almost completely the Kidneys (Table 5) Dogs. The lesions in the kidneys islet cells; in others, it surrounded remnants of more of the diabetic dogs were very irregular. Many dogs or less degenerated, hydropic B cells. with a diabetes of fairly long duration showed no or In one of the cats with hyaline changes, a dense only minor changes. Often these did not differ from inflammatory infiltrate consisting of small lympho- those that have been described in the kidneys of Vol. 3, No. 2, 1967 W. GEPTS and D. TOUSSAI~: Spontaneous Diabetes in Dogs and Cats 255

Fig. 5. Diabetic Cat (No. 70). Islet of Langerhans. Severe hyalinosis. Chromium hematoxylin-phloxine. 400 x aging non-diabetic dogs. The most frequent change Table 6. Retinal vascular changes in spontaneously diabetic consisted in a mesangial thickening resulting from the dogs and cats deposition of a PAS-positive substance (Fig. 7). This Normal Abnormal Abnormal Dilatation of mesangial thickening often appeared continuous with retinal mural endothelial cells capillaries lumen a thickening of the wall of the afferent arteriole. Only vessels cells Focal. Gene- Fusi- Micro- rarely did it extend in the peripheral part of the raliz, form. aneur. glomerular capillaries, evoking the diffuse type of human diabetic glomernlosclerosis (Fig. 8). Lesions Dogs resembling, but not identical to the nodular type of (29) 7 1O 6 9 5 4 human diabetic glomerulosclerosis, were found in a Cats very few glomeruli in 2 dogs (Fig. 9). In one dog, the (5) 3 1 1 o 1 o glomerular capillaries had a wide lumen (Fig. 10), as if distended by some material that had been dissolved in 2 cats. tIydropic change in the epithelium of the out from the sections during the embedding process. ascending loop of ttenle was recorded in 3 cats. Unfortunately, wet tissue no longer being available, Retinas (Table 6) staining for fat could not be performed. Before reporting on the changes in the retinas of Foci of interstitial nephritis, probably of pyelone- our diabetic dogs and eats it may be worth while to phritic origin, were found in 2 dogs. tIydropic change describe briefly the characteristics of the retinal due to glycogen deposition (Armani-Ebstein change) capillaries in these species. Their wall contains two was observed in the ascending limbs of tIenle's loop types of cells: endothelial cells and pericytes (Fig. 11). in 7 dogs. Except for the thickening of the wall of the The endothelial cells have an elongated nucleus. The afferent arterioles, already mentioned together with pericytes ("mural cells" of Kuwabara and Cogan) the glomernlar lesions, no vascular lesions were found. have a more spherical nucleus; they often protrude Cats. Only minor changes were found in the kidneys on the outer side of the capillary wall. In the cat (Fig. of the diabetic cats. Pyelonephritie sears were present 14), the nuclei of the pericytes may appear spherical,

Diabctologia, Vol. 3 17 256 W. GE]?TS and D. TOUSSAINT: Spontaneous Diabetes in Dogs and Cats Diabetologia

Fig. 6. Diabetic Cat (No. 47). Dense lymphocytic infiltration in an islet of Langerhans with hydropic B cells. Hemalum-erytrosine-saffron. 400 x

but their darker staining and their location within the 9 dogs; it was not seen in the cats. Non-functional, basement membrane are helpful in their recognition. acellular capillaries can be found, but in smaller num- The pericytes in the retinal capillaries of normal dogs ber, in non-diabetic dogs and cats. and cats appear less numerous than in the retina of the 4. Irregularities in the width of retinal capillaries, human. without true aneurysms, were seen in 5 dogs and i cat. Most of the abnormalities that we shall describe, They have not been found in non-diabetic dogs or cats. were discovered in retinas studied with the trypsin Liver digestion method. Very few lesions could be detected The major abnormality observed in the liver was in flat-mounted, whole retinas. The following changes fatty change of the parenchymal liver cells. It was have been recorded: present in 14 dogs and in 2 cats. It was severe in 6 1. Typical microaneurysms (Fig. 13) located in the dogs, moderate in 5 and slight in 3. In cats it was posterior part of the retina in 4 dogs. We want to moderate. In 4 dogs with steatosis, the liver also stress the fact that in each of these dogs only very few showed early cirrhosis. Marked centro-lobular con- microaneurysms could be discovered. No mieroaneur- gestion, probably related to a terminal circulatory ysms were found in the diabetic cats. Neither have collapse, was present in nearly all the dogs and cats. they been found in non-diabetic dogs and cats. Adrenals 2. Degeneration of the perieytes presenting as The adrenals were available in 20 dogs and in 3 mural ghost cells (Fig. 12) was observed in 10 dogs cats. Cortical hypertrophy with adenomatous nodules, and in 1 cat. It has not been observed in the non-dia- was found in 14 dogs and in all 3 cats. The adenomas betic dogs or cats. were composed of large spongiocytes. In some of them 3. Aeellularity of the capillary walls (Fig. 15), foci of necrosis and calcification were present. resulting from loss of pericytes and endothelial cells, Pituitary was seen focally in 6 dogs and 1 cat. Generalized The pituitary was available in 7 of the diabetic acellularity of the retinal capillaries was observed in dogs. A small adenoma was discovered in 2 of these Fig. 7. Diabetic Cat (STo. 70). Kidney. Moderate thickening of the mesangial stalk, t)AS 400 x

Fig. 8. Diabetic Dog (No. 91). Kidney. Marked thickening of the mesangial stalk. Thickening of Bowman's capsule. PAS. 400 x 258 W. GEPTs and D. TotTsmtIN~ : Spontaneous Diabetes in Dogs and Cats Diabetologia

Fig. 9. Diabetic Dog (No. 59). ]Kidney. Diffuse thickening of the basement membranes, with tendency to formation of nodules. 400 x pituitaries. The cytological study of these pituitaries spontaneous canine diabetes. On the other hand, a is not yet completed and will be reported in a later review of the Hterature reveals, that in cats diabetes is publication. more frequent in males than in females. This fact is not born out by our personal data, since in our materi- Discussion al, 3 cats were females and 2 males. However, the General discussion. The faMy large number of dogs relatively small number of eats at our disposition does that we have been able to collect with the assistance not permit a valid conclusion on this point. of only a small number of veterinarians, confirms Nothing is known about the genetic aspect of Meier's statement that, at least in dogs, spontaneous canine or feline diabetes. In this respect the oecurenee diabetes is not a rare disease. Many more cases could of a diabetes in the mother and a female litter-mate of have been studied, were it not for the refusal of many one of our diabetic dogs is worth pointing out. Tennis- owners to donate their dog, even after euthanasia had sen and Blok-Sehuring [36] have reported a diabetes been performed. The same psychological factor is main- occuring in a female whippet and in 2 females of her ly responsible for the regrettable lack of physiological litter of 4 females and 1 male. Although a few authors and biochemical data on these diabetic dogs. Although [2, 38] have suggested that diabetes might be more purely morphological study provides only a one- frequent among smaller breeds of dogs, no such racial sided and not necessarily correct picture of the di- predisposition emerges from our material. Neither has sease, in the case of our dogs and cats it has revealed it been observed in other studies on a large number of a number of facts that throw some light on the nature dogs [9, 36]. of the diabetes in these animals. Obesity has been mentioned repeatedly in studies Concerning age, our data are similar to those from on spontaneous diabetic dogs, but was only rarely the literature: in dogs and eats, diabetes tends to appear present in our material. According to one of our con- in elderly animals. A predisposition for the female sex tributing veterinarians, it is more frequent in diabetic has also been mentioned in all previous studies on eats than in dogs. This could be of interest in view of Vol. 3, No. 2, 1967 W. GEPWS and D. TOUSSAINT: Spontaneous Diabetes in Dogs and Cats 259

Fig. 10. Diabetic Dog (No. 73). :Kidney. Thickening of the mesangial stalk. A few capillaries are distended (by fat?). 400 • the marked differences that we found in our material to those that have been described in earlier studies on in the aspect of the islet tissue between diabetic dogs spontaneous canine diabetes [26, 14, 35, 32, 4, 42, 8, and cats. 40, 41, 5, 17, 11, 28, 36, 9]. Reduction in the number Pancreatic lesions. It has been claimed by several and size of the islets, and hydropic B cells, thus appear authors [26, 35, 4, 40, 41, 17, 9], that in dogs, diabetes to be characteristic features of spontaneous diabetes is often the consequence of a widespread destruction in dogs. In cases of longer duration, the ]3 cells have of the pancreas by acute or chronic inflammatory completely disappeared, leaving behind either small lesions. For this reason, a distinction has been made islets composed of atrophic cells, or no islets at all. This in dogs between secondary diabetes, due to pancreati- sequence of events resembles what occurs in the pan- tis, and a true idiopathic type with primary lesions creas of human juvenile diabetics [10]; a similarity in the islet tissue. Although the descriptions that can which has already been pointed out by W~S~ALL be found in literature leave no doubt that the first et al. [42]. In both human diabetics and diabetic dogs, type does occur, we feel that its frequency has perhaps ]3 cells are still present when the disease breaks out been overestimated by some authors. In our study, clinically. The cytological characteristics of these the pancreas appeared grossly normal in most of the cells, clearly point to a marked secretory hyperactivity. animals. Although we did find inflammatory lesions However, the progressive destruction of the B cell in the pancreas of some of the diabetic dogs and cats, proceeds rapidly and reaches its full completion only we feel that they could not explain the severe changes short time after the clinical onset of the disease. that were present in the islet tissue. Some of the acute Irrespective of what the primary cause may be, it lesions could well represent a terminal complication appears that in human juvenile patients and in dogs, that had developed during the final stage of diabetic at the moment that diabetes appears clinically, it has metabolic decompensation. already reached the pancreatoprive stage of the disease. The changes that we have reported in the islet- From what we have observed in our material, the tissue of the diabetic dogs are in many respects similar situation might well be different in cats. In all 5 cats 260 W. GEP:rs and D. TovssAI~: Spontaneous Diabetes in Dogs and Cats Diabetologia

l~ig. 11. :Normal Dog. 1%etinal vessels. Trypsinic digestion. Pericytes (P). Endothelial cells (E). l%ed blood cells (tiC). PAS-Toluidine blue that we have been able to study, the islets and the be able to fulfill better than that of the dog the in- ]3 cells were still numerous. It is true that in all but creased requirements of insulin by producing new one case the B cells appeared markedly vacuolated. islets and new B cells for a longer time. The interest of However, LAZARUS and VOLK [20] have demonstrated a comparative physiological and biochemical study that this type of change does not necessarily represent of diabetes in these two species appears clearly from a degenerative lesion. Only in cells with an extreme our findings. degree of swelling and vacuohsation ("ballooning Hyalin deposits in the islet stroma have been degeneration"), with nuclear pyenosis, did they find reported repeatedly in spontaneously diabetic cats ultramieroscopical evidence of damage to the cell [26, 35, 39, 34, 33]. They have also been found in organelles. A distinction between hydropie change due experimental diabetes produced by growth-hormone. to glycogen deposition only, and true ballooning de- As far as we know they have never been described in generation is not always easy to make with the light spontaneously diabetic dogs. In man, they are rare in microscope. juvenile diabetics but are present in about 45% of None of the authors that previously reported on the maturity-onset diabetics. The pathogenesis of islet islet tissue in spontaneously diabetic cats, seem to hyalinosis has not yet been elucidated. There is an have been impressed, as we were by the large number almost general agreement that the hyalin substance has of islets and B cells present. It may be that their cases the same staining characteristics as amyloid; however, were studied in a later stage of the disease. Neverthe- amyloid has not been found in organs other than the less, in our material a striking difference exists in pancreas. In the human, the same hyalin substance regard to the islet tissue between dogs and cats with occurs in some islet tumors, but only in those that an equivalent duration of diabetes. This could well secrete insulin. This fact suggests that the hyalin represent an expression of a stronger resilience of the deposits could be related to a prolonged local hyper- cat pancreas against an extra-pancreatic diabetogenic secretion of insulin, damaging the stroma of the islet factor. It is possible that the pancreas of the cat might tissue. That it never occurs in spontaneously diabetic Vol. 3, No. 2, 1967 W. GEPTS and D. ToussAINW: Spontaneous Diabetes in Dogs and Cats 261

Fig. 12. Diabetic Dog (No. 83). Retinal vessels. Trypsinic digestion. Ghost cells (GC). PAS-Toluidine blue dogs and only rarely in human juvenile diabetics, may viral infectious diseases, such as mumps. The auto- be explained by the fact that in these forms of diabetes immune hypothesis has received considerable support the survival of the B cells, in the newly formed islets, from recent experimental work [21, 30, 12]. Several is too short for the deposits to develop. groups of authors have succeeded in reproducing these Another finding of considerable importance is a lesions experimentally with procedures involving an dense inflammatory infiltrate in an islet in one diabetic immuno-pathological reaction. LECoMfTE et al. [21] cat. To the best of our knowledge, this is the first time point out that these two theories are not necessarily that such a lesion has been reported in eats. Inflam- exclusive, since it appears that many post-infectious matory infiltrates in and around the islets are present complications of viral infections involve a late auto- in about 60% of human juvenile diabetics dying less immune reaction. than 1 year after the clinical onset of the disease [10]. From earlier publications, and from our own They have also been described in a case of spontaneous observations, it is evident that striking abnormalities diabetes in a cow [3]. Although the significance of our are present in the islet tissue in almost every spon- finding in a diabetic cat is diminished by the fact that taneously diabetic dog or cat. In our material, 3 cases we were able to detect it in only one islet and in one appear to be exceptions to this rule. In 2 dogs (35, 68) animal, it cannot be ignored in view of the striking and in 1 cat (62), the islets appeared almost normal, similarity between this lesion and those that have except for some degranulation in the 2 dogs. We have been seen in human juvenile diabetics and reproduced no straightforward explanation of these cases. One experimentally in cows, sheep and rabbits. The possib- possibility is that they were not really diabetic. Where- le etiology and significance of inflammatory lesions as this explanation could eventually hold for cat 62, in the islet tissue have been thoroughly discussed in it appears unlikely for the 2 dogs. In dog 35, 2 glycemias a recent paper by LECo~PTE et al. [21]. The two most had been performed (3.36 g/1 and 4.4I g/l). In dog 68 appealing hypotheses are: 1. an infectious etiology, only one glycemia (2.30 g/l) was performed, but 2. an auto-immune reaction. The first hypothesis is glycogen was present in the ascending limb of the loops supported by the occurence of eases of diabetes after of Itenle, a finding almost specific for diabetes. Another 262 W. G]~PTs and D. TovssAr~: Spontaneous Diabetes in Dogs and Cats Diabetologia

Fig. 13. Diabetic Dog (No. 28). Flat mounted retina embedded in paraffin. N[icroaneurysm in the ganglion cell layer. 3lIasson triehromic stain possible explanation could be that, as in the human, been reported [32, 42, 28, 27]. PATZ eta]. [27, 28] two types of diabetes exist in dogs and cats. In ma- examined kidneys from diabetic dogs and controls, by turity-onset human diabetes, it occurs fairly often, light and electron microscopy. They found a signi- that, in spite of a persisting hyperglycemia and the ficantly greater incidence and severity of diffuse absence of insulin treatment, the individual islets look glomerulosclerosis and thickening of the basement qualitatively normal, with well granulated B cells. It membrane in diabetic dogs than in the controls. has been suggested that in these eases the B cells do Focal, occasionally generalized, thickening of the not react normally to the stimulus of hyperglycemia. glomerular intercapillary stroma, and of the capillary This secretory inertia of 13 cells in human maturity wall proper, was also observed in long-term experimen- onset diabetics, has been confirmed by biological tal diabetes in dog [22, 31]. That the lesions, which observations [29, 43]. Contrary to what exists in man, have been described in spontaneously or experimentally the severe and rapidly progressing type of the disease diabetic dogs, are identical to those in the glomeruli would be the prevailing type in dogs, and would present of human diabetics is difficult to prove. It could well itself at a later age in life. However, as far as we know, be that these lesions merely represent an accentuation no survey of the incidence of diabetes in a large po- of the aging changes encountered in the kidneys of pulation of living dogs h~s been performed up to now. non-diabetic dogs. It may well be, that only the more severe cases have Hyalinosis of the afferent and efferent arterioles, come to our attention, while many more benign cases a characteristic feature in the kidney of many human go on unnoticed. diabetics, has not been observed in our dogs or eats. Kidneys. No exact counterpart of human diabetic Thickening of the wall of the afferent arteriole was glomerulosclerosis, either of the diffuse or the nodular well pronounced in many of our cases, and this finding type has been found in our dogs or eats. In earlier has also been reported by DIxo~ and SA~FOI~D [5]. studies on spontaneous canine or feline diabetes, These authors point out that this lesion is not patho- glomerular changes simulating the human lesions have gnomonic of diabetes mellitus since it is also present Vol. 3, No. 2, 1967 W. GEP~s and D. TOUSSAIk#T: Spontaneous Diabetes in Dogs and Cats 263

Fig. 14. normal Cat. l~ctinal vessels. Trypsinic digestion. Pericytcs (l~). Endothelial cells (E) ~esodermic tract (~[). PAS-Toluidine blue in many non-diabetic aged dogs and in dogs made retinopathy, in an alloxan-diabetic dog and in two hypertensive experimentally for periods of several dogs with growth hormone diabetes. ]~ISKET~rS et el. years. [32, 31] failed to detect retinal changes in dogs with Although the duration of the diabetes exceeded long standing spontaneous or experimental diabetes. one year only in a few of our dogs and in none of our However, this failure may at least partly be due to cats, we feel inclined to believe that in these species the fact that the retinas were examined with the the lesions in the kidney are much less pronounced and whole mount technique, before the development of the characteristic than in human diabetics. trypsin digestion method. Retinal vascular changes. The same impression The paucity of microaneurysms and other changes has been gained from the study of the retinal vessels typical of diabetic retinopathy, may well be related in our diabetic dogs and cats. A number of changes, to the relatively short duration of the diabetes in such as focal or diffuse loss of endothelial cells and many of our dogs and cats. This would suggest that pericytes, mural ghost cells, are undoubtedly much the duration required for the diabetic condition to more frequent in diabetic dogs than in non-diabetic produce retinal vascular complications, must be cal- controls. However, microaneurysms have been found culated in an absolute number of years, and not in small numbers and in 3 dogs only. Convincing relatively to the duration of life. However, it cannot examples of diabetic retinopathy have been described be excluded that the retinal capillaries of dogs and by PATZ et el. [27, 9] in 2 dogs, with a respective cats are less susceptible to develop degenerative duration of diabetes of 1 year and 21/2 years, ttAUSLER changes than in the human. In a large group of non- [13] described microaneurysms and hemorrhages in a diabetic patients, who for some reason or other had metasomatotrophin-diabetic dog, that had remained been submitted to a prolonged cortisone treatment, in the diabetic state for a period of ten years; there TO~SSAINT and FAI~ [37] observed large numbers were reasons to believe that the retinal lesions had of micro-aneurysms in those patients that had develop- developed during the final two years. E~GEI~_A~ and ed hyperglycemia. On the other hand, no retinal chang- BLOODWORTH [6] described typical lesions of diabetic es whatsoever were found in dogs and cats, rendered 264 W. GEPTs and D. ToussAin~: Spontaneous Diabetes in Dogs and Cats Diabetologia

Fig. 15. Diabetic Cat (36). I~etinal vessels. Trypsinic digestion. Ghos~ cells (GC). Non-functional capillary (NfC). l~ed blood cells (I~C). l~cd blood cells (lZC) PAS-Toluidine blue hyperglycemic by a prolonged administration of Acknowledgement. The authors are very grateful to the veterinarians who contributed diabetic dogs and cats : cortisone. Dr. 1~. DUFAIT (Antwerp), Dr. A. GIZlCl~AUx and Dr. Liver. Fatty change was present in the liver of LO~BA (Brussels). -- The skflful technical assistance of many dogs and cats. In 4 dogs the liver also showed Mr. A. DEMEIRE, 1Virs A. DElVIEIlZE-M]~,DA:Et~,Mrs.. M.L. incipient cirrhosis. Similar changes have been mention- POECKEN8 and Miss D. DERYCKE is also acknowledged. ed in earlier reports on diabetic dogs and eats. The pathogenesis of these lesions cannot be deduced from A~fe~nG88 their histological aspect. Numerous metabolic distur- bances can lead to accumulation of fat in the liver [1] .dmLAlV,F.l%., D.J. BOWIE, J. J.l%. MeL]~OD and W.L. cells. Severe steatosis develops in the liver of pan- l~o~Inso~: Behaviour of depancreatized dogs kept alive with insuline. Brit. J. exp. Path. 5, 75--83 createctomised dogs maintained with insulin [1, 7]. (1924). Adrenals. The high incidence of cortical hyperplasia [2] APEL, S. : Klinische Erfahrungen beim Diabetes Mel- and adenomas seems impressive at first sight. However litus des Fleischfressers. Berl. Miinch. tiers Wschr. "12, 295 (1959) (quoted from G/~nEt~, K.). similar changes have been reported, with the same [3] CmzlsTEnsEn, lq. O., and P. SCl~AVlBYE: On diabetes frequency, in non-diabetic aging dogs [17, 9]. mellitus hos kvaeg. Nord. Vet.-Med. 2, 863--900 Pituitary. The changes in the pituitary of diabetic (i950). [4] CoFFIn, D.L., and A. TltOl~DA~-CI~I~IS~NsEn: The dogs will be discussed when the results of the cytologi- clinical and some pathological aspects of pancreatic cal study, now under progress, are reported. The pre- disease in dogs. Vet. Med. 48, 193--196 (1953). sence of an adenoma in 2 of the 7 pituitaries that were [5] DIxon, J.B., and J. S~FOI~D : Pathological features available is worth pointing out, since the literature of spontaneous canine diabetes. J. comp. Path. 72, i53--i64 (1962). contains at least 2 other cases of spontaneous animal [6] ENG]~lZ~An, l%.L., and J.M.B. B~ooDwol~: Ex- diabetes existing together with a pituitary tumor perimental diabetic retinopathy in dogs. Arch. [19]. Ophthal. "/3, 205--210 (1965). Vol. 3, No. 2, 1967 W. GEPTS and D. TOUSSAINT: Spontaneous Diabetes in Dogs and Cats 265

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