Diabetologia 8, 274--282 (1972) by Springer-Verlag 1972

Obesity and Pancreatic Islet Hyperplasia in the *

L. Boquist Institute of Pathology, University of Umes Umes Sweden Received: February 20, 1972, accepted: April 28, 1972

Summary. In a colony of Mongolian gerbils maintained r@gime de laboratoire joue un r61e prddominant darts le on a standard laboratory diet, occasional obese d@veloppement de I'ob@sit@ et que le pancr@as endocrine were found. Obesity developed in animals of both sexes de ces animaux a une excellente eapaeit6 d'hyperplasie and was either transitory or permanent. The mean fasting qu! suffit souvent ~ maintenir la normoglycdmie ehez les blood glucose level in non-obese and obese gerbils was ammaux ob@ses, malgr6 la r6duction de la tol6rance au 83 and 105 rag/100 ml, respectively. Glucosuria and hyper- glucose. glycemia were found only in a few obese animals, whereas the glucose tolerance was decreased in most obese ger- ~]bergewieht und Hyperplasie der Pankreasinseln bei bils. -- The endocrine pancreas of the obese animals was der mongolischen Rennmaus morphologically either normal or more often hyperplastic, Zusammenfassung. In einer Zucht yon mongolischen sometimes with the appearance of adenomatous islets. Rennm/~usen nit einer Laboratoriumsstandarddigt wur- The fl-eells possessed prominent Golgi complex and den gelegentlieh iibergewichtige Tiere gefunden. Die endoplasmic reticulum, and sparse granulation. Large, Ubergewichtigkeit entwickelte sich bei beiden Ge- granule-poor cells and mitotic figures were seen in the sehlechtern und war entwecler voriibergehend oder blieb islets. Degenerative changes occurred in the fl-cells of fiir inner bestehen. Der durchschnittliche Niicbtern- diabetic animals. -- It is suggested that the maintenance blutzuckerspiegel bei nicht iibergewichtigen und iiber- of the gerbils under laboratory conditions with free access gewichtigen mongolischen Rennm/iusen lag bei 83 bzw. to laboratory diet plays a majo r role in the development 105 rag/100 ml. Glykosurie und Hyperglyegmie wurden of obesity and that the endocrine pancreas of these nur bei wenigen iibergewichtigen Tieren gefunden, w/ih- animals has a good capacity for hyperplasia that often is rend die Glucosetoleranz bei den meisten iibergewichtigen sufficient to maintain normo-glycemia in obese animals, mongolischen l~ennm~usen vermindert war. Das endokri- although the glucose tolerance is decreased. ne Pankreas yon iibergewiehtigen Tieren war morpho- logiseh entweder normal oder h/iufiger hyperplastisch, Obdsit@ et hyperplasie des ilots du panerdas chez la gerbille manchmal erschienen die Inseln adenomatSs. Bei den mongolienne fi-Zellen waren die Golgi-Komplexe und das Endoplas- Rdsumd. Dans un 61evage de gerbilles mongoliennes matische Reticulum vorspringend und es fanden sich soumises ~ un r@gime standard de laboratoire ont dr@ schwache Granulationen. In den Inseln wurden grol3e, an parfois trouvds des animaux ob@ses. L~ se dg- Granula arme Zellen und mitotische Figuren gesehen. veloppait chez les animaux des deux sexes et 6tait tantSt In den fl-Zellen diabetischer Tiere traten degenerative transitoire, tant6t permanente. Le taux moyen de glu- Veriinderungen auf. -- Es wird angenommen, dal3 das cose du sang, ~ jefin, ehez les animaux non ob@ses et ob~- Italten von mongolisehen l%ennm/iusen unter Laborato- ses 6tait respectivement de 83 et 105 mg/100 ml. La gly- riumsbedingungen mit freiem Zugang zu der Laborato- eosurie et l'hyperglycdmie n'dtaient trouvdes que ehez peu r.iumsnahrung eine gr613ere Rolle bei der Entwicklung der d'animaux ob6ses, tandis que la toldrance au glucose Ubergewiehtigkeit spielt und dal3 das endokrine Pankreas 6tait rdduite ehez la plupart des animaux ob@ses. -- Le dieser Tiere eine gute'F/ihigkeit zur Hyperplasie besitzt, pancrdas endocrine des animaux ob@ses dtait, morpho- die oft ausreieht, urn eine Normalglyk~mie bei iiberge- logiquement, normal ou plus souvent hyperplasique avec wichtigen Tieren zu erhalten, obgleich die Glucosetoleranz parfois l'apparition d'ilots adgnomateux. Les eellules /~ abf/~llt. poss@daient un eomplexe de Golgi et un rdticulum endo- plasmique pro@minents et une granulation faible. De Key words: Obesity, islet hyperplasia, Mongolian grosses eellules pauvres en granules et des figures mitoti- gerbil, pancreatic islets, fi-cells, glucosuria, hyperglycemia, ques se montraient dans les ilots. Des changements decreased glucose tolerance, hyperinsulinemia, electron d@gdndratifs se produisaient dans les cellules fl des animaux microscopy, light microscopy, adenomatous islets, mitotic diab6tiques. -- On sugg~re que le maintien des animaux activity, glycogen infiltration, cellular inclusions. darts les conditions de laboratoire avec libre acc@s au

Introduction aminations of their endocrine pancreas have dis- closed an intimate association between vesicular A colony of Mongolian gerbils has been bred in this particles and cilia [3], and nuclear inclusions [4]. laboratory since January 1968. UltrastructurM cx- Occasional gerbils in the colony have been found to develop obesity and islet hyperplasia with or without * Supported by grants from the Swedish Medical associated glucosuria, hyperglycemia and decreased Research Council (Projects No. B71-12X-718-060 and glucose tolerance. Such alterations have not previously B71-12X- 718-07A) and the Swedish Diabetes Association. been reported in this species and since studies of * A preliminary report was given at the 7th Annual Meeting of the European Association for the Study of syndromes might be of value for the understanding of Diabetes, Southampton, September 15--17, 1971. human diabetes mellitus, this study was undertaken. L. Boquist : Obesity and Islet ttyperplasia in the Mongolian Gerbil 275

Its main aim was to get further information about the For electron microscopic examinations pancreatic association between obesity and the morphology and specimens were either fixed in 2.5 per cent glutaraldehyde in 0.34 1V[ Veronal acetate buffer adjusted to pH 7.4, function of the pancreatic islets. followed by postfixation in 1 per cent osmium tetroxide in the same buffer, or directly in 1 per cent osmium tetroxide in the same buffer. After fixation the specimens Materials and Methods were rinsed, dehydrated and embedded in Epon 812. The sections were cut on an Ultrotome III and thick sections stained with toulidine blue were used for light micro- Animals scopic identification of islets and other structures of interest. After staining with uranyl acetate and lead The colony consists of inbred Mongolian gerbils citrate the sections were examined in a Siemens Elmi- ( ungiculatus) which are kept in standard labor- scope 1A and/or 101. atory animal cages under constant temperature (22~ and illumination (7 a.m.- 8 p.m.). They have free access to food and water. The diet is of commercially available Results pelleted type that is obtained from A.B. Ewes, S6der- tglje, Sweden, and has the following composition (per cent): whey powder 5; expanded cereals 72; soybean oil Obesity meal 8; defatted fish meal 8; yeast 2; soybean oil 2; lime stone 1 ; vitamin concentrate 1 ; trace elements 1. Average The frequency of obese animals in the colony was dry matter analysis : crude protein 20 ; crude fat 4 ; ash 3 ; (Ca 0.8; P 0.6; NaC1 0.6); fiber 3; nitrogen-free, extract- about 10 per cent. Obesity developed in both sexes but able substances 68. Water content: 8. Trace elements there was a male preponderance in a ratio of about added (per cent): Fe 0.0017; Cu 0.00017; Co 0.00017; 8:2. Gerbils with obvious external signs of obesity Mn 0.0017; I 0.00006; Zn 0.0125. Vitamins added: weighed more than 80-90 g and weights up to 140 g vitamin A 360 IU; vitamin Da 40 IU; vitamin E 4.2 rag; vitamin B 1 0.15 rag; vitamin B2 0.30 rag; Ca-pantothenate were recorded. The weight of the non-obese controls 0.50 rag. did not exceed 80 g. The first signs of obesity appeared From the colony, animals were taken which developed when the animals were 4--28 months old, with a mean obvious external signs of obesity, for weighing and age of 9 months. The obesity was either transitory or morphological and functional studies. In all, 42 obese gerbils were investigated. Twenty non-obese, adult permanent. In the former ease the duration of the gerbils from the colony were used as controls. All animals obese state varied from about 1 month to 10 months. were weighed once a week. The data obtained so far do not suggest any familial accumulation of obese animals. Apart from obesity no Functional studies other clinical signs of any disease were recorded. Glucose oxidase paper strips were used for urine glucose analysis. Blood was obtained by the orbital Urine and Blood Glucose, Glucose Tolerance, and bleeding technic from either the right or left orbital venous Serum Insulin plexus. Fasting blood glucose was determined by means of a glucose oxidase method (A.B. I~2abi, Stockholm, Sweden). The glucose tolerance was investigated after Glueosuria was found at one or more observation intraperitoneal injection of 2 g/kg body weight of glucose. times in 14 of the obese gerbils. Three of them were Urinanalysis was carried out on all animals once a week, permanently glucosuric from about 1--4 months after whereas the blood glucose and glucose tolerance was the development of obesity ("diabetic animals"), assayed in a varying number of animals every other week. The latter determinations were performed in each animal whereas the rest possessed transitory or intermittent at least at two different occasions. glucosuria. The diabetic animals were 2 males and Serum insulin assays were performed in some (14 i female ; 5, 7 and 11 months old at the first appearance obese and 15 non-obese) gerbils by Dr. A. Lernmark, of glueosuria. No glucosuria was observed in the non- Department of Histology, Ume&, using the double anti- body radioimmunological technic (method C) of Hales obese animals. and Randle [ 13J with crystalline ox insulin (Vitrum A. B.e The mean fasting blood glucose level of the non- Stockholm, Sweden) as standard. obese animals was 83 • 4 rag/100 ml (~ S. E.M.). The approximate limit values for normo-glycemia were Morphologic studies calculated to be 40 and 125 rag/100 ml. All the blood glucose values in the non-obese animals fell within the Pancreatic specimens for light microscopic examination were fixed in Bouin's fluid or 10 per cent formalin. The normal range. following stains were used: hematoxylin-eosin, van The mean fasting blood glucose level of the obese Gieson, Maske's aldehyde fuehsin, chrome alum hema- animals was 105~5 mg/100 ml (~S.E.M.). Thus, toxylin, alkaline Congo red, Sudan black, and the staining although the mean fasting blood glucose level in the procedures of I-IellerstrSm and Hellman, and Grimelius. It was not the aim of the present study to perform an obese animals fell within the normal range, it was extensive quantitative determination of the islet volume. higher than in the controls. I-Iyperglycemia was re- I-towever, by rough estimation of light microscopic corded at one or more observation times in 15 obese sections from the head, body and tail of the pancreas animals. Three of these were permanently hyper- from obese and non-obese gerbils, differentiation could rather easily he made between animals with and those glycemic, whereas the others showed transitory or without islet hyperplasia, intermittent hyperglycemia. 276 L. Boquist: Obesity and Islet I-Iyperplasia in the Mongolian Gerbil Diabetologia

The glucose tolerance was decreased in most of the sparse granulation. Only a few ~i- and ~-cells were obese gerbils as compared with that of the non-obese seen as a peripheral rim. ones. The mean values of the glucose tolerance tests Some islets contained a varying amount of large performed in the 42 obese and 20 non-obese animals cells without or with very faint cytoplasmic granula- are given in Fig. 1 that is based upon the mean values tion, probably representing degranulated, hypertrophic of the two or more tests performed in each animal. The present study included only some preliminary determinations of the serum immunoreactive insulin level. As far as can be concluded from these determina- tions, most obese animals were hyperinsulinemic. The mean value of the obese gerbils was 5.7 :~ 1.9 mFg / ml and that of the non-obese ones 1.1 • 0.8 mFg/ml.

3OO o o Obese gerbiks

A A N0n-obese gerbils

E o

(D) 200 E

LO 03 O O J O

C) O O m 100 <

i i .i 0 3 60 120 180

MINUTES AFTER INJECTION Fig. 1. Glucose tolerance tests (glucose was injected intra- Fig. 2. Transverse section of the body of the pancreas from peritoneally at a dose of 2 g/kg bodyweight) in 42 obese obese gerbil showing islet hyperplasia with a great num- and 20 non-obese Mongolian gerbils. Mean values • ber of normal-sized and enlarged islets, some of them seem S.E.M. to be fused. Two adenornatous islets (A) with associated cell buds are also seen. Aldehyde-fuchsin stain. • 15 Light microscopic findings fl-cells (Fig. 4). These cells occurred both in the central The general appearance of the exo- and endocrine and peripheral portion of the islets. They had one or portion of the pancreas in the non-obese gerbils was sometimes two large nuclei that often were peripherally essentially similar to that of other species; situated and possessed one or two prominent nucleoli fl- (B), ~i- (D) and ~- (A) cells were identified. (Fig. 5). The endocrine pancreas of the obese gerbils was Occasional mitotic figures were seen in the fi-eells either similar to that of the non-obese animals, or more of hyperplastic islets (Fig. 5). Glycogen accumulation often it exhibited signs of hyperplasia of varying was found in the cytoplasm of the fl-cells, and in dia- degree. In the latter ease both the number and size of betic gerbils there was so-called hydropie degeneration the islets were increased (Fig. 2) and irregular islets in some islets (Fig. 6). The diabetic animals possessed occurred in addition to the ordinary rounded and oval also pyknosis and signs of cytoplasmic degeneration ones. Small buds of islet parenehymal cells were seen in a few fi-cells. on the larger islets and two or more islets occasionally Adenomatous giant islets were found in cases with seemed to be fused, sometimes with the appearance of marked islet hyperplasia (Fig. 2). They were sur- dumb-bell shaped islets (Fig. 3). rounded by small, normal-sized islets that often were There was a rich vascular supply in the hyper- separated from the adenomatous tissue only by a few plastic islets that mainly were composed of fl-cells with strands of collagenous connective tissue (Fig. 7). The Vol. 8, No. 6, 1972 L. Boquist: Obesity and Islet Hyperplasia in the Mongolian Gerbil 277 adenomatous islets exhibited a network of sinusoidal blood vessels between cords of parenehymal cells that were slightly polymorphous and had rounded nuclei with a coarse chromatin pattern and distinct large nueleoli. The tinctorial characteristics of these cells

Fig. 4. Pancreas from obese gerbil with islet hyperplasia showing numerous large cells with sparse granulation and often peripherally situated nuclei. Aldehyde-fuchsin stain. • 290

Fig. 3. Islet hyperplasia in obese gerbil. The islet shows a tendency to dumb-bell-shape, rich vascularization, central sparsely granulated fi-eells, and peripheral ~-eells. Portions of neighboring islets are also seen. Aldehyde- fuchsin stain. • 180 denoted that they were of /?-type. Scattered cells of ~1- and ep-type were only infrequently seen. The exocrine pancreas of the obese animals was normal. Pancreatic ductules were occasionally seen in association with normal-sized or hyperplastie islets. Peripheral nerves and ganglionic cells were seen, without any relationship to the islets.

Electron Microscopic Eindings The fine structure of the endocrine pancreas of the Fig. 5. Portion of two fused hyperplastic islets showing large cells with faint granulation, one of them has two non-obese gerbils was essentially similar to that of peripheral nuclei (C). One mitotic figure is seen (arrow). o~her rodent species. The light microscopic observation Aldehyde-fuchsin stain, • 380 of fl- (B), ~1- (D) and ~2- (A) cells was confirmed. As to the obese gerbils, signs of high cellular activity was a well developed Golgi complex (Fig. 8), a pro- were often found in the animals which light micro- minent rough-surfaced endoplasmie reticulum and a scopically had normal pancreatic islets. Thus, there moderate or large amount of mitochondria. The

Diabetologia, Vol. 8 19 278 L. Boquist: Obesity and Islet Hyperplasia in the Mongolian Gerbil Diabetologia

granules. The cytoplasm of the fi-cells showed varying density and contained numerous free ribosomes and occasional microtubules. Some fl-cells exhibited an abundant amount of mitochondria that often were elongated and curved. The adenomatous islets were composed of cells with a varying number of secretory granules of fl-type. Other, rather infrequent findings in the /?-cells were large cytoplasmic vacuoles and marked de- generative changes with the appearance of pyknotic nuclei, swollen and distintegrated mitochondria, condensed cytoplasm, and disorganized Golgi complex and endoplasmic reticulum. Lysosomes with incor- porated secretory granules could be seen. The de- generative alterations were mainly confined to the diabetic animals. Fig. 6. Islet of diabetic obese gerbil, showing so-cMled The cells that light microscopically were large, hydropic degeneration, van Gieson's stain. • 120 granule-poor, and interpreted as hypertrophic fl-cells,

Fig. 7. Portion of adenomatous islet demonstrating cords of parenehymal cells and rich vascular supply. A normal- sized islet is separated from the adenomatous one only by a few strands of connective tissue. Aldehyde-fuchsin stain. X 90 number of secretory granules in these cells varied. were ultrastructurally found to have low cytoplasmic Signs of emiocytosis were occasionally observed. electron density, a prominent Golgi complex and The obese gerbils with light microscopic evidence endoplasmic reticulum, and a moderate amount of of islet hyperplasia, were ultrastructurally found to free ribosomes, smooth-surfaced vesicles and mito- possess /?-cells with similar signs of high cellular chondria. Only a few secretory granules of fl-type were activity as mentioned above. The Golgi complex often found in these cells (Fig. 10). contained numerous prosecretory granule cores (Fig. 9). Some mitochondria of undamaged fl-cells possessed The number of secretory granules in these cells varied ; longitudinal cristae and parallel, electron dense, rod- often, they were degranulated. A variation in granule shaped structures (Fig. 11). size was also observed; some fl-cells possessed rather The ~l-cells that were characterized by numerous large granules, whereas others had numerous small secretory granules of low density, were unaffected, Vol. 8, No. 4, 1972 L. Boquist : Obesity and Islet Hyperplasia in the Mongolian Gerbil 279

Some ~2-cells contained lipoid bodies and lysosomes -- the Chinese hamster [2] -- obesity is a component with incorporated secretory granules. Lipoid bodies of the syndrome. Obesity, with or without associated occurred also in large amount in the cytoplasm of some hyperglycemia, often develops when the animals are fi-cells. transferred from their wild environment to laboratories. Dilated intercellular spaces and microvilli on the This is most often the ease when their normal habitat surrounding /?-cell membranes were found in hyper- is desert or semi-desert regions [17]. Hereditary factors plastic islets. In the dilated spaces cilia could be seen, may be involved in the development of obesity in some of them were swollen and contained vesicular laboratory . Furthermore, dietary factors may

Fig. 8. Electron mierograph of/?-cell from obese gerbil showing Fig. 9. Prominent fl-cell Golgi complex containing a well developed Golgi complex with an enclosed granule core, numerous prosecretory granules. • 13500 secretory granules, mitochondria, and a so-called nuclear body (arrow). • 19000 particles (Fig. 12). Intranuclear rods and so-cMled play a role, e.g. in sandrats [9, 10], KK-mice [13], and nuclear bodies (Fig. 8) were seen in the fl-cells. The Wellesley hybrid mice [8]. Desert regions are the cilia and nuclear inclusions were similar to those seen natural habitat of the Mongolian gerbil. It belongs to in non-obese animals [3, 4]. the same subfamily (Gerbillinae) as the sandrat. In this laboratory, the gerbils are maintained on a labora- tory diet which has a composition and calorie value Discussion apparently quite different from that of the diet avail- able in the regions from which the animals originally Syndromes associated with hyperglycemia and/or came. It is believed that the altered environmental and obesity are known to occur in about a dozen different dietary conditions brought about by the transfer of kind of laboratory rodents [16]. In all but one of these the gerbils to the laboratory are the most important

19" 280 L. Boquist: Obesity and Islet ttyperplasia in the Mongolian Gerbil Diabetologia

Fig. 10. Portion of large, degranulated fi-cell showing low cytoplasmic electron density, Golgi complex, mitochondria and one secretory granule (arrow). • 10000

Fig. 11. ~-cell mitochondrion possessing longitudinal Fig. 12. Cilium extending from a fi-cell into a dilated inter- cristae and parallel electron dense, rod-shaped structures. cellular space. Vesicular particles of varying size and shape • 28000 are enclosed within the dilated ciliary membranes, • 26000 Vol. 8, No. 4, 1972 L. Boquist: Obesity and Islet Hyperplasia in the Mongolian Gerbil 281 factors in the development of obesity in some of these to be a result of the high hyperplastic activity of the animals. However, inasmuch as they have been inbred, endocrine pancreas. The occurrence in these islets of genetic factors might also have some pathogenetie granulated fi-eells and a rich vascular supply denotes significance. that they may be hormonally active and not merely Obese-hyperglycemic syndroms in laboratory ro- represent a neoplastic "degeneration". dents may be of transitory nature. In obese mice The results indicate that the Mongolian gerbil has a Westman [20] found a significantly higher body-weight good capacity for new formation of islet cells and that already at an age of 26 days, after which time the the hyperplasia of the endocrine pancreas often is weight gain continued until the animals were about sufficient to establish an adequate insulin production 5--6 months old. The obesity in the Mongolian gerbil for the maintenance of normo-glycemia in obese was in some eases transitory. No clear association of gerbils. Only in a few cases does the functional capacity the symptoms to the age was found in the gerbils of the pancreatic islets of obese animals seem to be although most of them were young when they began insufficient to meet the increased demands associated to develop obesity. with obesity, in which eases glucosuria and hyper- Many rodent species in which obesity develops, do glycemia occur (diabetic animals). Marked degenerative also exhibit hyperglycemia and glucosuria. However, changes of the fl-cells were observed only in diabetic normo-glycemia may occur in the sandrat [9] although animals suggesting that their E-cells are exhausted. the glucose tolerance is decreased. In the Mongolian gerbils there were only a few cases of hyperglycemia and glucosuria, whereas the glucose tolerance was References decreased in most obese animals. It is, however, worth 1. Boquist, L. : Alloxan administration in the Chinese to note that the mean level of fasting blood glucose hamster. I. Blood glucose variations, glucose toleranee, was higher in the obese than in the lean animals. Using and light microscopical changes in pancreatic islets an undefined method, Mays [14] found a blood glucose and other tissues. Virch. Arch. Abt. B Zellpath. 1, 157-168 (1968). level of approximately 94:~25 rag/100 ml in normal 2. - Pancreatic islet morphology in diabetic Chinese Mongolian gerbils. hamsters. A light and electron microscopic study. There are numerous reports on hyperinsulinemia Acta Path. Mierobiol.Scand. 75, 399--414 (1969). and altered peripheral sensitivity to insulin in obese 3.- Cilia and vesicular particles in the endocrine pancreas of the Mongolian gerbil. J. Cell. Biol. 45, animals, e.g. in obese hyperglycemic mice [12] and 532--541 (1970). KK-mice [7]. In the sandrat there is an initial in- 4. -- Some peculiar fine structures in the pancreatic crease and a subsequent fall of the serum insulin level islets of diabetic and non-diabetic rodents. Acta attributed to pancreatic exhaustion [15]. Obesity Diabetol. Lat. 7, 590--615 (1970). 5.- Tubular cytoplasmic bodies in pancreatic islet decreases the insulin sensitivity of adipose tissue also B-cells of mice. Z. Zellforseh. 106, 69--78 (1970). in Wellesley hybrid mice [6] and human subjects [18]. 6. Cahill, G.F., Jr., Jones, E.E., Lauris, V., Steinke, J., Preliminary studies denoted that hyperinsulinemia Soeldner, J.S.: Studies on experimental diabetes in occurs also in obese gerbils. Wellesley hybrid mouse. II. Serum insulin levels and response of peripheral tissues. Diabetologia 3, 171-- The ~-eells of the obese gerbils were often sparsely 174 (1967). granulated denoting an intense and rapid release of 7. Dulin, W.E., Wyse, B.M. : Diabetes in the KK mouse. insulin with no or only a slight tendency to hormone Diabetologia 6, 317--323 (1970). storage in secretory granules. Consistent with this are 8. Gleason, R.E., Lauris, V., Soeldner, J.S.: Studies on the presence of secretory granules in the Golgi regions experimental diabetes in Wellesley hybrid mouse. III. Dietary effects and similar changes in a commer- and signs of high cellular activity, and the occurrence cial Swiss-I-Iauschka strain. Diabetologia 3, 175--178 of seemingly hypertrophic fl-eells. The mitochondrial (1967). rod-shaped structures occurring in some/~-cells beared 9. Hackel, D.B., Lebovitz, tI.E., Frohman, L.A., some resemblance to the tubular bodies previously Mikat, E., Schmidt-Nielsen, K:. : Effect of calorie re- striction on the glucose tolerance and plasma insulin observed in mitochondria of E-cells in mice [5]. Their of the sandrat. Metabolism 16, 1133-- 1139 (1967). significance remains doubtful. 10. I-Iaines, H., Hackel, D.B., Schmidt-Nielsen, K.: In most obese gerbils there were signs of hyper- Experimental diabetes mellitus induced by diet in plasia of the endocrine pancreas, sometimes of con- the sand rat. Amer. J. Physiol. 208, 297--300 (1965). 11. Hales, C.M., Randle, P.J. : Immunoassay of insulin siderable degree. The finding of mitotic figures in the with insulin-antibody precipitate. Biochem. J. 88, fl-eells denote that the hyperplasia, at least partly, was 137--146 (1963). achieved by division of mature #-cells. The occasionally 12. Hellerstrhm, C., Westman, S., Herb.a.i, G., Petersson, observed association between ductules and islets might B., Westman, J., Borglund, E., Ostensson, C.G.: Pathogenetic aspects of the obese-hyperglycemic indicate a new formation of endocrine cells also from syndrome in mice (Genotype obob): II. Extrapanere- ductules. atic factors. Diabetologia 6, 284--291 (1970). Adenomatous islets have occasionally been ob- 13. Matsuo, T., Shine, A., Iwatsuka, H., Suzuoki, Z.: served in alloxan-treated Chinese hamsters [1] and Induction of overt diabetes in t(K mice by dietary means. Endoerinol. Japon. 17, 477--488 (1970). streptozotocin-treated rats [19]. The presence of 14. Mays, A., Jr.: Baseline hematological and blood such islets in the pancreas of obese gerbils is believed biochemical parameters of the Mongolian gerbil 282 L. Boquist : Obesity and Islet I-typerplasia in the Mongolian Gerbil

(Meriones unguiculatus). Lab. Animal Care 19, 838-- in the carbohydrate intolerance of human obesity. 842 (1969). J. olin. Invest. 47, 153--165 (1968). 15. Miki, E., Like, A.A., Soeldner, J.S., Steinke, J., 19. Steiner, I~., Oelz, O., Zahnd, G., Froesch, E.1%.: Cahill, G. F., Jr. : Acute ketotic-type diabetic syndrome Studies on islet cell regeneration, hyperplasia and in sandrats (Psammomys obesus) with special refer- intrainsular cellular interrelations in long lasting ence to the pancreas. Metabolism 15, 749--760 (1966). streptozotocin diabetes in rats. Diabetologia 6, 558-- 16. l~enold, A.E. : Spontaneous diabetes and/or obesity 564 (1970). in laboratory rodents. In: Advances in Metabolic 20. Westman, S. : The development and manifestations Disorders, Levine, 1~., Luft, R., Eds. Vol. III, pp. of the obese-hyperglycemic syndrome in mice. Ab- 49--84. l~ew York and London: Academic Press 1968. stracts of Uppsala Dissertations in Medicine No. 49 17. -- Burr, I.: The pathogenesis of diabetes mellitus. (1968). Possible usefulness of spontaneous hyperglycemic Lennart Boquist, M.D. syndromes in animals. Calif. Med. 112, 23--34 (1970). Institute of Pathology 18. Salans, L.B., l~nittle, J.L., Hirsch, J.: The role of University of Ume& adipose cell size and adipose tissue insulin sensitivity S-901 87 Ume&, Sweden