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Year : 1968  |  Volume : 16  |  Issue : 3  |  Page : 109-115

Diabetic retinopathy - Concepts based on experimental data

1 Department of Ophthalmology, All-India Institute of Medical Sciences, New Delhi-16, India
2 Department of Pathology, All-India Institute of Medical Sciences, New Delhi-16, India

Date of Web Publication24-Dec-2007

Correspondence Address:
P K Agrawal
Department of Ophthalmology, All-India Institute of Medical Sciences, New Delhi-16
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Source of Support: None, Conflict of Interest: None

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How to cite this article:
Agrawal P K, Agarwal L P, Tandon H D. Diabetic retinopathy - Concepts based on experimental data. Indian J Ophthalmol 1968;16:109-15

How to cite this URL:
Agrawal P K, Agarwal L P, Tandon H D. Diabetic retinopathy - Concepts based on experimental data. Indian J Ophthalmol [serial online] 1968 [cited 2021 Jun 14];16:109-15. Available from: https://www.ijo.in/text.asp?1968/16/3/109/37531

Since the rediscovery of microa­neurysms in diabetic retinopathy by Bellantyne and Loewenstein many hypothesis and theories have been advanced to explain the pathogenesis of micro-aneurysm formation.

The following is a list of such hypo­thesis:

A Systemic factors:


2. Hyperlipoproteiniemia: KEID­ING, MANN, ROOT, LAWRY AND MARBLE [23] ; BERKMAN, RIFKIN AND ROSS [14] .

3. Pituitary adrenal hyperactivity: BECKER [12] , BECKER, MAENGWYN-DAVIES, ROSEN, FRIEDEN­WALD AND WINTER [13] .

4. Formation of microthrombi: ASHTON [7] .

5. Hypercoagulability of blood: GORMSEN [19] .

6. Increased venous pressure (BALLANTYNE [9] .

B. Local factors:

1. Ectasia and weakening of the ca­pillary wall: BALLANTYNE [9],[10] .

2. Herniation of fat through the wall: POPE [27] .

3. Pathological alteration in the centrifugal nerves: WOLTER [29] .

4. Anoxia of the retina: WISE [28] .

5. Anoxic swelling of the retina and traction on the retinal vessels by mesodermal strands: (ASHTON [7] ).

6. Primary degeneration of the mural cells and the shunt mecha­nism: COGAN AND KUWABARA. [16] COGAN, TOUSSAINT AND KUWABARA [17] .

It can be seen from this list, the confused state of affairs as to the zetiogenesis of such microaneurysms. It is but natural that it should be so, because production of diabetic reti­nal lesions in any of the experimen­tal animals has been hitherto unsatis­factory and unconvincing.- PATZ AND MAUMENEE, [26] HAUSLER, SIBAY, AND STACKOWSKA [21] HAUSLER, SIBAY AND CAMPBELL, [20] ENGERMANN, AND BLOODWORTH [18] .

The purpose of this communication is to report diabetic retinal lesions produced for the first time in albino rats, simulating human retinal micro­aneurysms. A possible morpho-phy­siopathological basis of microaneu­rysm formation is also being discus­sed.

Previous Work: We have reported on our studies on retinal capillaries, their development with special refer­ence to the cellular structure and the retraction phenomenon of capillaries (AGRAWAL [2],[3] ). In another commu­nication we have reported on the re­action of retinal capillaries and their cellular elements to experimentally induced ischaemia (AGRAWAL [4] ).

It was concluded from these stud­ies that in the capillary walls there are two types of cells, the endothe­lial and the mural cells both having derived from the same parent cell. [Figure - 1],[Figure - 2] The endothelial cells are large, oval with pale staining nuclei and situated along the long axis of the blood vessels. The mural cells have a rounded hyperchromatic nucleus and are enclosed within the basement membrane. Connecting the capillaries are intercapillary bands [Figure - 1], which may appear complete or incomplete, depending upon the degree of atrophy to which they are reduced after the process of retraction.

The mural cells are found at the junction of these capillary bands with the interconnected capillaries, as if guarding the entrance to these bands. [Figure - 1] A mural cell without an in­tercapillary band indicates the pre­sence of a primitive capillary which has completely been absorbed.

The studies on experimental is­chaemia indicate that the endothelial cells are first affected while the mural cells resist ischemia for a longer time, being enclosed in the basement membrane (Plate 3, a, b, c.)

  Methods and materials Top

Albino rats were used as experi­mental animals and the retinal ves­sels were studied by trypsin (KUWABARA and COGAN, [24],[25] ) or pepsin trpsin (ASHTON [9] ) digestion techni­ques.

Experimental diabetes was pro­duced in two groups of animals (1) Alloxan diabetes (2) Diabetes by growth hormone and hydrocortisone (AGRAWAL AGARWAL and TAN­DON [6] ).


Alloxan diabetic rats failed to re­veal any retinal changes in the rats. It was only in animals with growth hormone and hydrocortisone that re­tinal changes were seen after six months of diabetes. Several inter­esting findings were seen. [Figure - 5],[Figure 6],[Figure 7],[Figure 8],[Figure 9],[Figure 10],[Figure 11],[Figure 12]. The first change was a loss of mural cells which was characteristic. [Figure - 5],[Figure 6]. They were preferentially lost from the capillaries giving rise to micro-aneurysms and from vessels over a considerable area in the sur­rounding neighbourhood. At quite a number of places a large number of ghost cells were present. [Figure 7],[Figure 8]. The microaneurysms came from vessels having normal or hyperplas­tic endothelial lining but they bor­dered on and were oriented towards areas in which the capillaries had lost all their cells. (Plate 4E, F). The endothelial population of vessels in which microaneurysms developed, increased while the capillaries which had lost all the cells did not show any aneurysmal dilatation. (Plate 4G, H). At the intercapillary bands when the mural cells were destroyed, there was an aggregation of endothelial cells. At places there was sugges­tion of the opening of the defunct bands. A multitude of microaneu­rysms were seen in all phases of de­velopment. (Plate 4 G. H).

The picture so described has not been seen in any of the experiment­ally produced diabetic retinal lesions. However most of the components have been described in this series of observations.

Thus we can see that while in ex­perimental ischemia, the endothelial cells are first affected, in diabetes the cells to suffer first are the mural cells. The selective loss of mural cells in diabetes (COGAN and KUWABA­RA, [16] ) have led to great speculations about this selective action, for which no satisfactory explanation has yet been advanced.

The histochemical studies of dia­betic retinal tissue indicate a de­pressed metabolic activity and pro­duction of a state of anoxia in the retinal tissues. This results in a pri­mary involvement of the basement membrane of the retinal capillaries (BLOODWORTH [15] ). The mural cells cannot survive without the base­ment membrane in which they are enclosed and so we get a focal dege­neration of mural cells in diabetic re­tinopathy. (AGRAWAL et al [6] ). As has already been shown the mural cells guard the intercapillary bands and once they degenerate, the control over the bands is lost. Under un­regulated hydrodynamics due to the loss of mural cells these bands start opening and dilating. The type of aneurysm formation depends upon the type of band which has been opened up. An incomplete band will give rise to only a dilatation of the capillary while a complete one will give rise to neovascularization. (Ex­plained in [Figure - 1]. Migration of en­dothelial cells in the opened up bands results in increased endothlial popu­lation in early micro-aneurysms. The degeneration and secondary deposits of hyaline results in obliteration of these aneurysms.

  Summary Top

Experimental diabetic retinopathy was produced for the first time in al­bino rats by administration of growth hormone and hydrocortisone.

The histopathological changes so produced are described, and hypo­thecated (Agarwal's hypothesis) to explain the earlier degeneration of the basement membrance which en­closes the mural cells. The subse­quent changes, neovascularization, microaneurysm formation and aggre­gation of endothelial cells will result from the loss of the function of the valvular action of such mural cells which guard the entrance of interca­pillary bands.[30]

  References Top

ADLERSBERG, D., WANG, CH. 1., RIFKIN H., BERKMAN J., ROSS, G. AND WEINSTEIN, C.: Serum Lipids and Polysaccharides in Diabetes Mellitus. Diabetes, 5, 116 (1956).  Back to cited text no. 1
AGRAWAL, P. K.: Cellular Structure of the Hyaloid System of the Rat Orient. Arch. Ophth. 2, 279 (1964).  Back to cited text no. 2
AGRAWAL, P. K.: The Cellular Structure and Development of the Re­tinal Vessels of the Rat. Orient. Arch. Ophth. 3, 23, (1965).  Back to cited text no. 3
AGRAWAL, P. K.: The Effect of Ex­perimental Ischemia on the Retinal Blood-vessels of the Rat. Orient. Arch. Ophth. ; Chicago) 3, 184 (1965).  Back to cited text no. 4
AGRAWAL P. K.: Histochemical Studies of the Retinal Blood-vessels. I (Normal Adult Rats) Orient Arch. Ophth. 3, 184 (1965).  Back to cited text no. 5
AGRAWAL P. K., AGARWAL L. P. AND TANDON H. D. Experimental Diabetic Retinopathy in Albino Rats. Orient. Arch. Ophth. 4, 68, (1966).  Back to cited text no. 6
ASHTON N.: Lancet ii, 625, (1959).  Back to cited text no. 7
ASHTON N.: Studies of the Retinal Capillaries in relation with Diabetic and other Retinopathies. Brit. J. Ophth. 47, 521, (1963).  Back to cited text no. 8
BALLANTYNE, A. J.: Retinal Chan­ges associated with Diabetes and Hypertension. Arch. Ophth. (Chicago) 33, 97, (1945).  Back to cited text no. 9
BALANTYNE, A. J.: The State of the Retina in Diabetes Mellitus. Trans. Oph. Soc. U.K. 66, 503, (1946).  Back to cited text no. 10
BALLANTYNE, A. J. AND LOWEN­STEIN, A.: Retinal micro-aneurysms and Retinal Haemorrhages. Brit. J. Ophth. 28, 593, (1944).  Back to cited text no. 11
BECKER, B.: Diabetic Retinopathy. Ann. Intern. Med. 37, 273, (1952).  Back to cited text no. 12
BECKER, B., MAENGWYN - DA­VIES, GERTRUDE S., ROSEN, D., FRIEDENWALD, J. S., AND WIN­TER F. C.: The Adrenal Cortex and B. Vitamins in Diabetic Retinopathy. Diabetes, 3, 175, (1954).  Back to cited text no. 13
BERKMAN J., RIFKIN H. AND ROSS G.: Serum Polysaccharides in Diabetic Patients, with and without degenerative Vascular Disease: J. Clin. Invest. 32, 415, (1953).  Back to cited text no. 14
BLOODWORTH J. M. B. Jr.: Diabe­tic Microangiopathy. Diabetes. 12, 99, (1963).  Back to cited text no. 15
COGAN D. G., KUWABARA T.: Ca­pillary Shunts in the Pathogenesis of Diabetic Retinopathy. Diabetes, 12, 293, (1963).  Back to cited text no. 16
COGAN D. G., TOUSSAINT D., KU­WABARA T.: Retinal Vascular Pat­tern (IV Diabetic Retinopathy). Arch. Ophth. (Chicago) 66, 366, (1965).  Back to cited text no. 17
ENGERMAN, R. L. AND BLOOD­WORTH J. M. B. Jr.; Experimental Diabetic Retinopathy in Dogs Arch. Ophth. (Chicago) 75, 205, (1965).  Back to cited text no. 18
GORMSEN J. Danish Soc. ?For Int. Med. Nov. 14 (1958).  Back to cited text no. 19
HAUSLER H. R., SIBEY, T. M. AND CAMPBELL J.; Retinopathy in a Dog following Diabetes induced by Growth Hormones. Diabetes, 13, 122 (1964).  Back to cited text no. 20
HAUSLER, H. R., SIBEY, T. M. AND STACKOWSKA B.: Observation of retinopathy in metahypophyseal dia­betic Chinese hamsters. Invest. Ophth. 2, 378, (1963).  Back to cited text no. 21
IANNACONNE, A. AND KORNE­RUP, T. Acta Med. Scand. 148, 411, (1954).  Back to cited text no. 22
KEIDING, N. R., MANN G. V., ROOT, H. F., LAWREY E. Y. AND MARBLE A.: Serum Lipoproteins and Cholestrol levels in normal subjects and in young Patients with Diabetes in relation to Vascular Complications. Diabetes, 1, 434, (1952).  Back to cited text no. 23
KUWABARA T. AND COGAN D. G. Studies of Retinal Vascular Pattern. Arch. Ophth. (Chicago) 64,904, (1961).  Back to cited text no. 24
KUWABARA T. AND COGAN D. G.: Retinal Vascular Pattern (VI Mural of Retinal Capillaries) Arch. Ophth. (Chicago) 69, 492, (1963).  Back to cited text no. 25
PATZ., A. AND MAUMENEE A. E.: Studies on Diabetic Retinopathy Amer. J. Ophth. 54, 532, (1962).  Back to cited text no. 26
POPE, C. H.: Retinal Capillary Mi­croaneurysms. A. Concept of Patho­genesis. Diabetes. 9, 9, (1960).  Back to cited text no. 27
WISE G. N.: Retinal Microaneurysms. Arch. Ophth. (Chicago) 57, 151, (1957).  Back to cited text no. 28
WOLTER, J. R.: Diabetic Capillary Microaneurysms of Retina. Arch. Ophth. (Chicago) 65, 847 (1961).  Back to cited text no. 29
WOLTER, J. R.: The Nature of Ca­pillary Microaneurysms in Diabetic Retinopathy. Diabetes, 11, 136, (1962).  Back to cited text no. 30


  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]


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