Growth Hormone, Sorbitol, and Diabetic Capillary Disease

Beaumont, Paul; Schofield, PJ; Hollows, Fred; Williams, Tracy; Steinbeck, A. W.

doi:10.1016/s0140-6736(71)91170-6

Cited by 43 publications

(8 citation statements)

References 27 publications

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“…A similar pathogenic basis of diabetic peripheral neuropathy has been snggested (Gabbay, Merola and Field, 1966;Stewart, Sherman, Kurien, Moonsammy and Wisgcrhof, 1967) and a hypothesis relating diabetic smalt vessel disease of the retina to changes in the activity of the sorbitol pathway in retina (Beaumont, Hollows, Schofield, Williams and Steinbeck, 1971) is currently under investigation in this laboratory.…”

Section: Introductionmentioning

confidence: 74%

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Sorbitol Metabolism in the Retina: Accumulation of Pathway Intermediates in Streptozotocin Induced Diabetes in the Rat

Hutton

Schofield

Williams

et al. 1974

Aust J Exp Biol Med

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Summary. The capacities of rat lens and retina to accumulate sorbitol pathway intemiediates in streptozotocin induced diabetes were inve.stigated. The experiments performed were of two types:(i) investigations of the time course of the appearance of the pathway intermediates in lens and retina following the induction of diabetes, and (ii) investigation of the relationship of scirbitol pathway intermediate accumulations to varying doses of .strt'ptozotocin. The experimental objectives were to investigate the factors which control the activity of the pathway in vivo, and to a.ssfss the proposed relation.ship between sorbitol metabolism in the retina and the pathogenesis of diabetic small vessel disease in this tissue.The sorbitol which accumulated in the retina of the diabetic animal (approximately 1-5 iimolc/g protein) was formed by the intrinsic metabolic activity of the tissne and was not attributed to transport from an external metabolic site. The accunmlation of this intermediate was directly related to the plasma gincose concentration and could not be related to other parameters of the diabetic state, e.g. plasma free fatty acid concentration, ketonaemia.It was confirmed that the rat lens accumulated sorbitol (approximately 80 (imole/g protein) and fructose (approximately 20 n'Tiole/g protein) in diabetes, and that such accumulations were related to the glucose concentration of the aqueous humour. The possibility that factors associated with kctoacidosis aflected the relati\e concentration.s of lens sorbitol and fructose was suggested by the results.An hypothesis which invoked sorbitol iiccuninlation to osmotically signifieant concentrations within the retina as a pathogenic agent in diabetic small ve.ssel disease in this tissue conld not be directly supported by the results. Alternate mechanisms by which low concentrations of sorbitol iu diabetic retina could act as a pathogenic stimulus are discussed.

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Section: Introductionmentioning

confidence: 74%

“…The present commuuication reports the results of parallel studies conducted on the lens and retina of diabetic rats aimed at initially assessing the hypothesis (Beaumont et al., 1971) and investigating factors which may control the activity of the sorbitol pathway in retina and lens in vivo.…”

Section: Introductionmentioning

confidence: 99%

Sorbitol Metabolism in the Retina: Accumulation of Pathway Intermediates in Streptozotocin Induced Diabetes in the Rat

Hutton

Schofield

Williams

et al. 1974

Aust J Exp Biol Med

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“…The basement membrane changes rest in turn on a metabQlic abnormality of smooth muscle mural cells, and in the renal glomerulus on the epithelial cells (Walker, 1968) but whether this is due to insulin lack or excess (Jackson, Van Mieghem & Van Keller, 1972), a relative excess of growth hormone (Lundback et al, 1970;Beaumont et al, 1971) or an associated genetic defect (Siperstein, 1970) is not known.…”

mentioning

confidence: 99%

Some chemical indices of diabetic vascular disease

Wardle

Piercy

Anderson

1973

Postgraduate Medical Journal

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Summary Some chemical indices which could be related to diabetic complications have been assessed in 105 diabetics. In juvenile (insulin-dependent) diabetics with retinopathy, cardiovascular disease or nephropathy, levels of fibrinogen, fibrin monomer, beta-lipoprotein, cholesterol and alpha-2-macroglobulin were raised. Only in part is the explanation due to a rise of fibrinogen and cholesterol with age. Among twenty-six patients with a plasma fibrinogen over 400 mg/100 ml, eleven sustained a major cardiovascular catastrophe within the next 2 years. Alpha-1-acid-glycoprotein was raised in these eleven and beta-2-glycoprotein generally in juveniles with cardiovascular disease. Triglycerides were elevated in all groups, but notably in patients with Grade I retinopathy with venous dilation. There was a suggestion that triglycerides were related inversely to dietary carbohydrate in mature onset diabetics, and serum cholesterol in juveniles was related to insulin dosage. The part of lipids in vascular disease is then discussed. An interesting positive correlation was found between fibrin monomer, itself an indication of in vivo thrombin formation, and beta-lipoprotein. Although alpha-2-macroglobulin was elevated in juveniles, especially with complications, this did not apply to maturity onset cases and therefore no direct relation to diabetic vascular disease can be suggested. Moreover, alpha-2-macroglobulin levels were normal in acromegaly.

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“…It has been suggested that these disturbances culminate in the irreversible impairment of lens cell function and finally result in colloidal swelling of the lens fibres and cellular disruption. Beaumont et al (1971) have proposed a similar mechanistic basis for the pathogenesis of diabetic small vessel disease of the retina. The concentration of sorbitol which accumulates in the retina in the diabetic state is, however, much lower than that which accumulates in the lens and would need to be confined to a small cellular compartment in the retina if it were to result in osmotic damage to the tissue (Hutton et al, 1974).…”

mentioning

confidence: 96%

“…The morphological and functional lesions characteristic of diabetic small vessel disease in the retina are found in many other tissues of the human diabetic (Bloodworth, 1963;Ditzel, 1968) and it is thus not improbable that such lesions have a common pathogenic basis. As an extension of the hypothesis of Beaumont et al (1971), an investigation was undertaken of the possibility that intracellular sorbitol accumulation in the glomerulus in diabetes may be causally related to diabetic glomerulosclerosis. This tissue was selected for investigation since it can be readily isolated, it is an almost pure specimen of vascular tissue and it is a site of diabetic small vessel disease of major clinical concern.…”

mentioning

confidence: 99%

The Localisation of Sorbitol Pathway Activity in the Rat Renal Cortex and Its Relationship to the Pathogenesis of the Renal Complications of Diabetes Mellitus

Hutton

Schofield

et al. 1975

Aust J Exp Biol Med

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Summary. A series of in vivo and in vitro investigations was perfonned to examine the localisation of sorbitol pathway activity in the rat renal cortex and to investigate the possible relation that the accumulation of sorbitol pathway intermediates in renal cortical tissue may have to the pathogenesis of renal complications in diabetes mellitus.Neither of the sorbitol pathway intermediates, sorbitol or fructose, were detected either in intact glomeruli which had been isolated from rats rendered chronically diabetic with streptozotocin, or in metabolically active glomeruli which had been incubated in vitro in high glucose media. Such data agreed with previously published observations that the enzyme aldose reductase is not present in renal glomeruli, and suggested that changes in sorbitol pathway activity cannot be directly related to the pathogenesis of diabetic glomerulosclerosis.Sorbitol was detected in low concentrations (3-1 nmol/g protein) in cortical tubules which had been isolated from the renal cortex of rats rendered chronically diabetic with streptozotocin. This concentration of sorbitol was higher than that in the intact renal cortex of the diabetic animal (0-3 nmol/g protein) or in the cortical tubules of non-diabetic animals (0 5 (imol/g protein).It is apparent that the renal cortical tubule is a major site of sorbitol pathway activity in the renal cortex. However, there is presently no obvious causal relationship between the accumulation of such relatively low concentrations of sorbitol in the renal cortical tubule and the pathogenesis of glomerulosclerosis or cortical tubular lesions in diabetes.'Present address:

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Growth Hormone, Sorbitol, and Diabetic Capillary Disease

Cited by 43 publications

References 27 publications

Sorbitol Metabolism in the Retina: Accumulation of Pathway Intermediates in Streptozotocin Induced Diabetes in the Rat

Sorbitol Metabolism in the Retina: Accumulation of Pathway Intermediates in Streptozotocin Induced Diabetes in the Rat

Some chemical indices of diabetic vascular disease

The Localisation of Sorbitol Pathway Activity in the Rat Renal Cortex and Its Relationship to the Pathogenesis of the Renal Complications of Diabetes Mellitus

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