Glycemic Control Promotes Pancreatic Beta-Cell Regeneration in Streptozotocin-Induced Diabetic Mice

Grossman, Eric; Lee, David D.; Tao, Jingjing; Wilson, Raphael A.; Park, Soo‐Young; Bell, Graeme I.; Chong, Anita S.

doi:10.1371/journal.pone.0008749

Cited by 50 publications

(48 citation statements)

References 29 publications

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“…As previous studies show, chemically induced models of insulin-deficient diabetes retain some ability to regenerate ␤-cells (25,73). Thus, even with drastically low plasma insulin levels and pancreatic insulin content, as reported in our earlier studies (26 -28), the possibility of some contribution from insulin could not be discounted.…”

Section: Discussionmentioning

confidence: 50%

Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant

Gunawardana

Piston

2015

American Journal of Physiology-Endocrinology and Metabolism

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Gunawardana SC, Piston DW. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am J Physiol Endocrinol Metab 308: E1043-E1055, 2015. First published April 21, 2015; doi:10.1152/ajpendo.00570.2014.-Traditional therapies for type 1 diabetes (T1D) involve insulin replacement or islet/pancreas transplantation and have numerous limitations. Our previous work demonstrated the ability of embryonic brown adipose tissue (BAT) transplants to establish normoglycemia without insulin in chemically induced models of insulin-deficient diabetes. The current study sought to extend the technique to an autoimmune-mediated T1D model and document the underlying mechanisms. In nonobese diabetic (NOD) mice, BAT transplants result in complete reversal of T1D associated with rapid and longlasting euglycemia. In addition, BAT transplants placed prior to the onset of diabetes on NOD mice can prevent or significantly delay the onset of diabetes. As with streptozotocin (STZ)-diabetic models, euglycemia is independent of insulin and strongly correlates with decrease of inflammation and increase of adipokines. Plasma insulinlike growth factor-I (IGF-I) is the first hormone to increase following BAT transplants. Adipose tissue of transplant recipients consistently express IGF-I compared with little or no expression in controls, and plasma IGF-I levels show a direct negative correlation with glucose, glucagon, and inflammatory cytokines. Adipogenic and anti-inflammatory properties of IGF-I may stimulate regeneration of new healthy white adipose tissue, which in turn secretes hypoglycemic adipokines that substitute for insulin. IGF-I can also directly decrease blood glucose through activating insulin receptor. These data demonstrate the potential for insulin-independent reversal of autoimmune-induced T1D with BAT transplants and implicate IGF-I as a likely mediator in the resulting equilibrium. type 1 diabetes; brown adipose tissue; insulin independent; transplantation; insulin-like growth factor I TYPE 1 DIABETES (T1D) is characterized by autoimmune-mediated destruction of pancreatic ␤-cells, resulting in absolute deficiency of insulin and loss of glycemic control. Treatments for T1D, despite having been refined over many years, are geared mainly toward replacing insulin, which involves numerous risks and limitations. Direct insulin replacement via daily injections or insulin pump does not cure the disease and requires life-long repeated administration. In addition to the inconvenience, direct insulin therapy requires careful monitoring of dosage and blood glucose levels and can lead to potentially fatal hypoglycemic episodes. Pancreas transplantation, the only available treatment with a good chance of long-term insulin independence, requires invasive surgery and life-long immunosuppressive therapy. Islet transplantation, although less invasive, is limited by the availability of donor tissue and the need for immunosuppression, and patients often return to insulin dependence in the long...

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Section: Discussionmentioning

confidence: 50%

Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant

Gunawardana

Piston

2015

American Journal of Physiology-Endocrinology and Metabolism

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“…18 Experiments conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23).…”

Section: Animalsmentioning

confidence: 99%

AMP-Activated Protein Kinase Regulates Endothelial Cell Angiotensin-Converting Enzyme Expression via p53 and the Post-Transcriptional Regulation of microRNA-143/145

Kohlstedt

Trouvain

Boettger

et al. 2013

Circulation Research

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A ngiotensin II has been implicated in the pathobiology of atherosclerosis and in the arterial response to injury and restenosis via mechanisms that include vascular hypertrophy, extracellular matrix production, and cytokine induction. Although the angiotensin-converting enzyme (ACE) is only one of several enzymes that can generate angiotensin II, 1 the enzyme has been allocated a central role in cardiovascular disease development, mainly on the basis of the positive effects observed in response to ACE inhibitor therapy and experimental work involving protein downregulation.2 Certainly, ACE levels seem to correlate with disease development, and ACE protein has been detected in atherosclerotic human coronary 3,4 and carotid lesions. 5Relatively little is known about the signals that regulate ACE expression in vascular cells, but the exposure of vascular smooth muscle cells to fluid shear stress 6 or pulsatile pressure 7 is reported to increase expression of the enzyme. Although an identical phenomenon was initially reported in endothelial cells, 6 several other studies reported exactly the opposite, that is, that arterial levels of shear stress attenuate ACE promoter activity and decrease the expression of ACE mRNA in endothelial cells. [8][9][10] How can fluid shear stress regulate ACE expression? The first hypothesis was that the effects could be attributed to increased transcription as the genes for human, rat, and rabbit ACE all contain a number of shear stress-responsive elements in their promoter regions. These were however found to be inactive, and responsiveness to flow was then attributed to a combination of Barbie and GAGA response elements.

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“…However, some of the limitations of chemically inducing diabetes are the possible toxicity to other organs and the potential for β-cell regeneration following high-dose STZ administration. 28 Currently, the most popular choices of the T1D animal model are the spontaneous NOD mouse and the biobreeding (BB) rat. These models manifest with autoimmune diabetes similar to that observed in humans and currently dominate the literature.…”

Section: 27mentioning

confidence: 99%

Diabetes reversal via gene transfer: building on successes in animal models

Gerace¹,

Martiniello‐Wilks²,

Simpson³

2015

RRED

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Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulinproducing pancreatic β-cells. People with T1D manage their hyperglycemia using daily insulin injections; however, this does not prevent the development of long-term diabetic complications such as retinopathy, nephropathy, neuropathy, and various macrovascular disorders. Currently, the only "cure" for T1D is pancreas transplantation or islet-cell transplantation; however, this is hampered by the limited number of donors and the requirement for life-long immunosuppression. As a result, the need for alternative therapies is vital. One of the strategies employed to correct T1D is the use of gene transfer to generate the production of an "artificial" β-cell that is capable of secreting insulin in response to fluctuating glucose concentrations that normally occurs in people without T1D. The treatment of many diseases using cell and gene therapy is generating significant attention in the T1D research community; however, for a cell therapy to enter clinical trials, success and safety must first be shown in an appropriate animal model. Animal models have been used in diabetes research for over a century, have improved our understanding of the pathophysiology of diabetes, and have led to the discovery of useful drugs for the treatment of the disease. Currently, the nonobese diabetic mouse is the animal model of choice for the study of T1D as it most closely reflects disease development in humans. The aim of this review is to evaluate the success of cell and gene therapy to reverse T1D in animal models for future clinical application.

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Glycemic Control Promotes Pancreatic Beta-Cell Regeneration in Streptozotocin-Induced Diabetic Mice

Cited by 50 publications

References 29 publications

Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant

Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant

AMP-Activated Protein Kinase Regulates Endothelial Cell Angiotensin-Converting Enzyme Expression via p53 and the Post-Transcriptional Regulation of microRNA-143/145

Diabetes reversal via gene transfer: building on successes in animal models

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