Reversing Type 1 Diabetes Without Insulin Replacement
Project Researcher: Subhadra Gunawardana, Ph.D. – Washington University, St. Louis
Type 1 diabetes (T1D) is a serious disease affecting 3 million Americans, with over 15,000 children being diagnosed each year (1). Traditional treatments involve insulin replacement, either directly or via islet/pancreas transplantation, and have numerous limitations. Exogenous insulin administration is obviously inconvenient, and can be dangerous due to potentially fatal dips in blood glucose. Pancreas transplantation, the only available long-term remedy, requires major invasive surgery. Islet transplantation is safer but less effective, as patients return to diabetes in the long term. Both islet and pancreas transplantation are limited by the availability of donor tissue and the need for life-long immunosuppression. Thus there is an ongoing need for better therapies.
The ultimate goal in treating T1D is to restore blood glucose control. We recently demonstrated an entirely novel approach to restore normal blood glucose without insulin, thereby avoiding the aforementioned complications. Transplanting healthy embryonic brown adipose tissue (BAT) under the skin of type 1 diabetic mice results in dramatic restoration of glucose control and reversal of diabetes, with no contribution from insulin. While insulin remains low as is typical with T1D, BAT transplant recipients show progressive weight gain and reversal of all clinical signs of diabetes, accompanied by an increase in healthy fat (adipose tissue) content in the body.
Adipose tissue is a versatile endocrine organ which secretes hundreds of hormones affecting all body systems, and exerts a profound influence on blood glucose regulation. Healthy adipose tissue is a powerful asset, which helps improve overall metabolism, maintain normal glucose control and prevent diabetes. Metabolic diseases such as obesity, insulin resistance and diabetes are characterized by inflamed unhealthy adipose tissue, which cannot perform its expected function, produces harmful compounds and impairs glucose regulation.
While insulin is generally necessary to maintain adipose tissue in a healthy state, our research shows that BAT transplantation is a simple and effective alternate technique to replenish healthy adipose tissue and reverse type 1 diabetes. BAT transplants stimulate regeneration of healthy fat in diabetic recipients, and a combination of hormones produced by healthy fat establishes physiological glucose regulation, compensating for the lack of insulin. As the transplants are done under the skin, there is minimal trauma to patients. Once the transplants are successful, glucose control is established by hormones produced from within the body. Thus there is no need for administration of any drugs or hormones from outside.
This technique is proven effective in long-term reversal of T1D in mouse models. To customize it for human patients, it is necessary to find suitable alternatives for embryonic tissue which is currently not practical for human use. Potential alternatives such as adult BAT or BAT stem cells cannot reverse diabetes like embryonic BAT does, most likely due to the lack of various growth factors abundant in embryonic tissue. We hypothesize that provision of specific growth factors would enable adult BAT to behave like embryonic BAT, replenish healthy adipose tissue in recipients and reverse diabetes. Thus we propose to perform transplants with adult BAT, with temporary administration of specific embryonic growth factors, which we hope would enable the transplants to replenish healthy fat and reverse T1D.
If successful, this approach will provide a cure for T1D. Even if not viable as a single treatment for T1D, utilizing BAT transplants as part of an insulin therapy regimen would provide glucose control with less intervention by patients, thus eliminating problems with insulin mono-therapy such as dangerous dips in blood glucose. It should be emphasized that this approach does not require regular administration any drugs or individual hormones, and would thus avoid the many inherent difficulties with such therapies.
Update on 7-16-17
I am happy to report that funding from DRC has enabled successful completion of this project. Our previous research had demonstrated the feasibility of reversing type 1 diabetes (T1D) without insulin in mouse models, through subcutaneous transplantation of embryonic brown adipose tissue (BAT). Euglycemia following BAT transplants is rapid and long-lasting, accompanied by decreased inflammation and regenerated healthy white adipose tissue (WAT).
The major goal of the current project was to establish better alternatives to embryonic tissue, practical for use in human patients. As previously described, BAT-derived stem cell lines or adult BAT transplants alone fail to reverse T1D, presumably due to the lack of growth factors abundant in embryonic tissue. We hypothesized that adding growth factors would enable transplants to survive and vascularize in the recipients’ subcutaneous space as well as stimulate adipogenesis and decrease inflammation in the surrounding host tissue. Preliminary data point to insulin like growth factor 1 (IGF- 1) as a possible candidate. IGF-1 is expressed more abundantly in donor embryonic BAT and in newlyformed WAT in transplant recipients than it is in the WAT of diabetic or normal controls. Plasma IGF-1 levels increase soon after transplant placement, and continue to increase in negative correlation to proinflammatory cytokines.
Here we tested the ability of adult BAT transplants to correct T1D aided by temporary supplementation with exogenous IGF-1 in nonobese diabetic (NOD) mice, a mouse model closely related to human T1D. Fresh BAT from healthy adult CB7BL/6 donors were transplanted in the subcutaneous space of NOD recipients. Exogenous IGF-1 was administered daily for a week following transplant, at 100 µg/Kg SC. Adult BAT transplants with IGF-1 supplementation resulted in rapid and long-lasting reversal of T1D at a 61% success rate, in contrast with no recovery in the control groups who received adult BAT alone, IGF-1 alone, or no treatment (Figure 1). As before, the euglycemia occurred independent of insulin. Insulin was not detectable by immuno-staining in the pancreas of the transplant recipients post-mortem, in contrast to normal non-diabetic controls (Figure 2).
Figure 1. IGF-1 suplementation enables adult BAT transplants to correct T1D in NOD mice: Nonfasting blood glucose levels before and after adult BAT (aBAT) transplants followed by temporary supplementation with exogenous IGF-1 (100 ug/Kg/day SC for 5-7 days), compared with different control groups. Adult BAT transplants combined with IGF-1 corrected T1D at a 61% success rate.
Figure 2. Effects are independent of insulin: Lack of insulin immuno-staining in the pancreata of NOD mice with or without transplants, in comparison with non-diabetic WT controls.
While more time is needed to verify whether this effect is permanent and to improve success rates, these findings provide a strong foundation for eventual translation of this approach to human patients. To that end, we now seek to reproduce the results with human adipose tissue transplants, and to document the underlying mechanisms of insulin-independent glucose regulation.
Update on 11-10-16
Update on 09-01-16
Aided by funding from DRC, we are researching suitable alternatives for embryonic tissue in order to customize the BAT-transplant technique for human patients. In the past few months, we have performed several transplants with healthy adult BAT on T1D mice, with and without temporary administration of IGF-1 (insulin-like growth factor). IGF-1 is a growth factor abundant in embryonic BAT but absent or deficient in adult adipose tissue. Preliminary results are promising, showing significant improvement of diabetes in some of the recipients who received IGF-1 supplementation. We are in the process of adjusting the dosage and duration of IGF-1 supplementation in an attempt to improve success rates. In addition, we plan to test other growth factors which may enable adult adipose tissue transplants to reverse diabetes and to investigate the molecular mechanisms underlying the insulin-independent glucose regulation produced by BAT transplants.