Studies of the Rate of Regression of the Glomerular Lesions in Diabetic Rats Treated with Pancreatic Islet Transplantation

Sm, Mauer; Mw, Steffes; De, Sutherland; Najarian-S,; Af, Michael; Dm, Brown

doi:10.2337/diab.24.3.280

Cited by 153 publications

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“…In 1976 our group began studies using the intraportal route of transplantation and pure isolated islets as the source of tissue in a quantity equivalent to 5% to 10% of the islets of a normal pancreas, i.e., 500-600 islets. The total amount of islets, therefore, was much lower than that used in the studies of Mauer et al [10,11]. Metabolic studies showed that, after a few days, normalization of blood glucose and of fasting insulin levels occurs and glycosuria disappears.…”

mentioning

confidence: 77%

“…After 9 to 12 months, nearly all typical signs of diabetic glomerulopathy can be observed by transplantation of isolated islets or of a complete pancreas [4][5][6][7]12]. Furthermore, it was demonstrated that early changes of the mesangial region, i.e., deposition of PAS-positive material with enlargement of this area, can be reversed by islet transplantation when performed no later than 4 to 5 months after induction of the diabetic state [11,15]. Only Gotzsche et al [18] did not find early renal lesions in the mesangium to be reversible by transplantation, although these authors used pancreatic homogenates instead of purified islets.…”

Section: Discussionmentioning

confidence: 99%

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The effect of islet transplantation on complications in experimental diabetes of the rat

Federlin

Bretzel

1984

World j. surg.

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Experimental diabetes in the rat induces secondary complications of kidney, eye, and nervous system similar to the changes observed in humans. Transplantation of a sufficient number of isolated islets from isogeneic donors inhibits or reverses those lesions. Detailed studies have been made in order to examine renal glomerular and tubular lesions in diabetic rats prior to and following transplantation. Streptozotocin-treated rats after 2 to 3 months begin to develop renal lesions with severe morphological changes, such as enlargement of the mesangial space, thickening of the capillary wall, deposition of IgG and C3, vacuolization of the tubular epithelial cells, and protein casts. Functional disturbances including increased glomular filtration rate, proteinuria, accumulation of basement membrane products (glucosyltransferase in the kidney, laminin P2, 7-S collagen in serum), and increased excretion of brush border enzymes in the urine also developed. [ntraportal islet transplantation leading to normalization of fasting blood glucose and insulin and of body weight either prevented these lesions or reversed early changes. Advanced renal changes are not reversible; however, further progression is halted. The experimental data support the view that rigid control in human diabetics may help to prolong the phase without secondary complications and that islet transplantation in the future may be a useful therapy.The effect of islet transplantation on diabetic complications has been studied in the kidney, eye, and nervous system. Because the great majority of investigations has been made in the kidney, we shall concentrate mainly on this organ. The findings in eye and nervous system are discussed briefly.Several authors including our group have reported that islet transplantation in streptozotocin-treat-

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confidence: 77%

Section: Discussionmentioning

confidence: 99%

The effect of islet transplantation on complications in experimental diabetes of the rat

Federlin

Bretzel

1984

World j. surg.

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“…The length of study for normoglycemia post advanced glomerular fibrosis in these rat studies was a maximum of 4 months in which period no reversal of glomerular fibrosis was observed. Non advanced glomerular fibrosis, however, has been shown to be at least partially reversible (56)(57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

A Mathematical Model of Glomerular Fibrosis in Diabetic Kidney Disease to Predict Therapeutic Efficacy

Thomas

Versypt

2023

Preprint

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Diabetic kidney disease (DKD) is a growing health problem that affects a significant portion of the global population. With a rising global patient number of over 135 million and a yearly incident case of over 2 million, the burden of DKD is rising. Glomerular fibrosis is tissue damage that occurs within the kidney of DKD patients for which effective therapeutic treatments are lacking. One of the reasons for the lack of therapeutic efficacy is glycemic memory where even after blood glucose within diabetic patients is regulated, glomerular fibrosis due to the initial high blood glucose continues to progress. This phenomenon is readily observed in diabetic patients who receive pancreatic transplant for blood glucose regulation where the glomerular fibrosis takes 10 years for full recovery to be observed. In pursuit of determining why it takes a long time for glomerular fibrosis to be reversed, we developed a mechanistic systems biology model of glomerular fibrosis in diabetes from a previous model of interstitial fibrosis. The adapted model consists of a system of ordinary differential equations that models the complex disease etiology and progression of glomerular fibrosis in diabetes. Within the scope of the mechanism we incorporated, we found that advanced glycation end products, which are matrix proteins that are modified due to high blood glucose, are the reason for the delay in the recovery of glomerular fibrosis. The idea that advanced glycation end products are one of the key mediators of glycemic memory is well known in the broad scope of diabetes and its many complications. The mechanism for how advanced glycation end products cause a delay in the recovery of glomerular fibrosis, however, is less established. Following that, the mechanism for why therapeutics targeting glycemic memory such as aminoguanidine, and alagebrium lack efficacy is also not well established. Using our model, we postulate that glucose control, and aminoguanidine are not effective because they do not remove accumulated advanced glycation end products. Further, our model predicts that treatments breaking down advanced glycation end products, such as alagebrium, would be the most efficacious at reversing glomerular fibrosis. Our model helps explain the lack of efficacy of alagebrium at treating advanced glomerular fibrosis due to the inability of alagebrium to reduce TGF-β. There is a well-known therapeutic treatment efficacy reduction when treatment is applied to advanced glomerular fibrosis compared to early glomerular fibrosis. We postulate that two different mechanisms associated with short lived advanced glycation end products and long-lived advanced glycation end products can explain the difference in the response to treatment of glomerular fibrosis when treatment is applied to early glomerular fibrosis vs advanced glomerular fibrosis. Using our systems biology model, we illuminate mechanistic understanding of disease etiology of glomerular fibrosis in diabetes, and then we provide mechanistic explanations for the lack of efficacy of different pharmacological agents at treating glomerular fibrosis. This understanding can enable the development of therapeutics that are more efficacious at treating kidney damage in diabetes.

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“…Weight gain is restored [17] and, in the longer term, serum lipids (which are raised in diabetic rats), return to the normal range [18]. Islet transplantation also prevents and reverses the development of later complications of experimental diabetes in rats such as renal glomerular lesions [19] and neuropathy [20].…”

Section: Metabolic Effects Of Islet Transplantation In the Rodentmentioning

confidence: 99%

Prospects for pancreatic islet transplantation

Gray

Morris

1986

World j. surg.

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It is over a decade since the first description of cure of experimental diabetes in rats by transplantation of isolated adult islets of Langerhans. Despite a remarkable number of experimental studies, clinical islet transplantation is still not a reality, raising questions about the feasibility of this approach. Experiments in rodents have demonstrated the potential of isolated islet transplantation. It is possible to cure experimentally induced diabetes and restore normal glucose metabolism with prevention or even reversal of diabetic complications. The problem of allograft rejection, while formidable, is not insurmountable and a number of techniques are now available to achieve this aim.Studies in animals larger than the rodent have been less successful and no repeatable method for isolated islet transplantation has so far emerged. Attempts at clinical purified islet transplantation have also proven unsuccessful. Transplantation of unpurified dispersed pancreatic tissue has been used successfully in dogs, but the technique has proven dangerous and inefficient when applied clinically. These disappointing results suggest, superficially, that the prospects for clinical islet transplantation are bleak. In reality, the problem in all the studies conducted in large mammals and humans has been the lack of an efficient method for separation of viable purified islets from the human and large mammalian pancreas. The recent description of more efficient islet separation methods allows new hope for clinical transplantation.

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Studies of the Rate of Regression of the Glomerular Lesions in Diabetic Rats Treated with Pancreatic Islet Transplantation

Cited by 153 publications

References 0 publications

The effect of islet transplantation on complications in experimental diabetes of the rat

The effect of islet transplantation on complications in experimental diabetes of the rat

A Mathematical Model of Glomerular Fibrosis in Diabetic Kidney Disease to Predict Therapeutic Efficacy

Prospects for pancreatic islet transplantation

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