Objective
BioKier’s goal is to develop a non-prescription supplement to be used by type 1 diabetes patients as adjuvant therapy to standard insulin treatment to offer improved metabolic health and easier glucose management. The concept of delivery of signaling nutrients to the lower part of the digestive track has demonstrated activity in type 2 diabetes patients and the next step is to test butyrate formulated in colon-targeted, sustained-release tablets in a clinical trial in type 1 diabetes patients. The tablets, named BKR-017, are designed to mimic the metabolic effects of bariatric surgery and -glucosidase inhibitors.
Specifically, an improvement in insulin sensitivity, lowering of triglycerides, and reduction of glucose variability as measured by frequency of hypo- and hyper-glycemic episodes are potential benefits of treatment with BKR-017 in type 1 diabetes patients. The improvement of gut hormone secretion, as seen in metabolic surgery and in the use of -glucosidase inhibitors, is expected to improve metabolic health and provide better glucose control in type 1diabetes patients. BioKier is completing the process of formulation development of these tablets which are designed to capitalize on the ability of butyrate to stimulate secretion of gut hormones from the colon.
BioKier’s clinical study will recruit type 1 diabetes patients at the Mayo Clinic in Rochester, Minnesota (ranked No. 1 for diabetes and endocrinology in the U.S. News & World Report Best Hospitals rankings) for four weeks treatment with BioKier’s oral butyrate tablets to investigate the effects on control of glucose and metabolic endpoint.
Endpoints to be measured in the clinical study of BKR-017 are:
- Improved insulin sensitivity (as measured by estimated Glucose Disposal Rate, eGDR)
- Lowering of fasting and post-prandial triglycerides
- Reduction in glucose variability including frequency of hypoglycemic episodes
- Reduced time when glucose is highly elevated (glucotoxicity) as measured by 1,5AG
- Reduction of insulin dose
The objective is to demonstrate an improvement in one or more of these parameters, which will constitute an advance in the treatment options for type 1 diabetes patients.
Presently there are few options for type 1 diabetes patients to manage glucose. BKR-017 provides an opportunity for patients to better manage their glucose excursions and reduce their insulin dose. This clinical study is designed to prove the concept that butyrate can be delivered orally to the colon and that it can be as effective as the previous methods which are not amenable to widespread adoption.
Background Rationale
It was initially observed, and is now documented in prospective clinical trials, that bariatric surgery, initially developed for weight loss, which shifts digestion of food from the upper small intestine to the lower part of the small intestine, improves type 1 diabetes and resolves type 2 diabetes within days. This effect is so pronounced that this type of surgery is now called metabolic surgery. There is strong evidence that the mechanism of this effect results from expedited delivery to the lower gut of specific natural nutrients, derived from food.
BioKier is proposing to mimic this benefit by demonstrating the effects of colon-targeted, sustained-release butyrate tablets on insulin sensitivity, glucose variability, insulin dose, and triglycerides levels in type 1 diabetes patients. As demonstrated in published clinical studies, butyrate produced by fermentation of saccharides that enter the colon as a result of use of α-glucosidase inhibitors (acarbose and miglitol) reduces glucose variability and use of insulin. Furthermore, it has been demonstrated that these increased levels of butyrate in the colon lead to augmented GLP-1 secretion. This increased GLP-1 secretion after miglitol in type 1 diabetes patients is associated with improved glucose control, lower frequency of hypoglycemic episodes, and lower insulin dose.
In earlier clinical trials in diabetes patients, BioKier has shown that direct infusion of butyrate to the colon results in increased GLP-1 secretion. BioKier would now like to investigate whether butyrate delivered via a tablet to the colon of type 1 diabetes patients has a similar effect. Such a tablet would represent a novel, convenient way to deliver butyrate to the colon and improve GLP-1 secretion without the complications of surgery, fermentation, and direct infusion. Because BioKier’s tablets are able to deliver amounts of butyrate to the colon comparable to the highest effective dose of -glucosidase inhibitors, we expect similar beneficial effects on glucose control, insulin dose, and triglyceride levels.
In a recently completed four-week clinical study conducted by BioKier in type 2 diabetes patients with colon-targeted glutamine capsules, there was significant improvement in insulin sensitivity in two-thirds of the insulin-resistant patients as well as a reduction of elevated triglycerides. Although glutamine was used as a GLP-1 secretagogue in that study, BioKier now has data that indicate that butyrate is likely to be a more effective active ingredient than glutamine for chronic treatment.
The colo-targeted butyrate tablet would represent a novel adjuvant therapy to insulin for type 1 diabetes patients. Key benefits would be improved glucose control, lower frequency of hypoglycemic episodes, and lower insulin dose. Other potential benefits include a reduction in triglycerides, the levels of which correlate with cardiovascular risk, and decrease in insulin resistance which correlates with increased incidence of major cardiovascular events. Reduction of hypo-glycemic episodes is especially important for those patients at risk of associated falls that can result in bone fractures and hospital visits. It will also be important for overnight hypo-glycemic episodes in young type 1 diabetes patients.
Description of Project
Type 1 diabetes patients suffer from poor glucose control which is mostly the result of disfunction of beta-cells and insulin resistance. One of the causes of these problems is an impairment in the signaling mechanism that sends hormone signals from the gut to the glucose-regulating tissues such as the pancreas, liver, fat, brain, and muscle. The stimulus for the gut to send these hormone signals is the arrival of nutrients in the upper gut after a meal. From observations of patients having gastric bariatric surgery for weight loss, it has become apparent over the past few decades that increasing the delivery of nutrients to the lower sections of the gut, colon in particular, restores the generation of the hormone signals to near-normal levels. This has resulted in an improvement in insulin sensitivity, non-insulin dependent glucose disposal and a lowering of blood lipids.
A direct way to delivered nutrients to the colon is by directly diverting them past the upper gut with gastric bypass surgery. A second method is by ingesting non-digestible carbohydrates that are fermented in the colon to butyrate. Use of drugs from the a-glucosidase inhibitor class result in similar effect to food, producing butyrate in the colon. These approaches are either expensive and drastic, in the case of surgery, or very unpleasant, in the case of ingesting non-digestible carbohydrates or use of a-glucosidase inhibitors, because the fermentation process produces large volumes of hydrogen gas which cause side effects including diarrhea, bloating, and flatulence. Although these methods work well in improving the gut hormone responses and the regulation of glucose, the expense or side effects have limited their broad acceptance and use. More acceptable approaches have been sought by the diabetes community.
BioKier has invented a natural, yet innovative, solution to the problem of delivering nutrients to the lower gut without the complications of the earlier methods (surgery or intolerable indigestion). BioKier’s invention is to package one of the most active nutrients in a tablet that reaches the colon intact, where it releases nutrient. This method is simple in its concept and avoids the need for surgery or the uncomfortable fermentation process. Furthermore, because the active ingredient is a nutrient found in food, it is safe and without unpleasant side effects. Recently, BioKier has shown in a clinical trial in type 2 diabetes patients that this approach improves insulin sensitivity without side effects.
Correspondingly, Type 1 diabetes patients also show improved gut hormone responses and improved glucose control after bariatric surgery and fermentation of carbohydrates in the colon. Based on the results of its trial in type 2 diabetes, BioKier now intends to test an improved version of its tablet in a clinical trial in type 1 diabetes patients. Type 1 patients stand to benefit greatly from reduced glucose variability including reduced frequency of hypoglycemic episodes. This is the result of an improvement in insulin sensitivity which is expected to lead to lower insulin use in those patients. Other benefits would be weight loss in patients with metabolic obesity and lowered triglycerides which are a factor in cardiovascular risk.
BioKier has the technical expertise for the manufacture of the butyrate tablets and will team with a nationally regarded diabetologist at the Mayo Clinic to conduct the clinical trial. BioKier wishes to receive funding from JDRF to help with the cost of the clinical trial.
Anticipated Outcome
BioKier is proposing to investigate the effect of colon-targeted, sustained-release butyrate tablets on insulin sensitivity, triglycerides, glucose variability, insulin dose, 1,5AG, and HbA1c levels in Type 1 Diabetes subjects. Success in this clinical trial followed by establishment of BioKier’s product, would lead to an improvement in the quality of life for type 1 diabetes patients resulting from expected reduced glucose variability including reduced number of hypoglycemic episodes, lower triglycerides and better weight management.
Known methods of achieving this metabolic cascade have not been widely adopted. Surgery is an expensive procedure with likely post-surgical complications and glucosidase inhibitors and fiber have undesired effect of serious and uncomfortable GI disturbances. However, the method proposed by BioKier, using colon-targeted, sustained-release butyrate tablets is devoid of those problems. Butyrate delivered by those tablets will provide an increase in colonic butyrate concentration to at least as high as the highest dose of acarbose, resulting in significant augmentation of meal related GLP-1 secretion, which will improve several metabolic functions in Type 1 Diabetes subjects.
Based on published results from various clinical studies, positive metabolic effects of BioKier product, BKR-017, are expected to include:
- Improved insulin sensitivity (as measured by estimated Glucose Disposal Rate, eGDR)
- Lowering of fasting and post-prandial triglycerides
- Reduction in glucose variability including frequency of hypoglycemic episodes
- Reduced time when glucose is highly elevated (glucotoxicity) as measured by 1,5AG
- Likely reduction of insulin dose
Additionally, based on outcomes of metabolic surgery there will be reduction of inflammatory state for those patients which can be estimated by inflammatory biomarker hs-CRP.
Additionally, improvement in insulin sensitivity and lowering of triglycerides should result in decreased incidence of Fatty Liver Disease (NAFLD), which is observed frequently in T1D patients.
Finally, several expected beneficial effects of this treatment should, over the long term, reduce the risk of cardiovascular disease. It is well documented in the medical literature that lower triglycerides and higher insulin sensitivity, among other expected benefits, results in lower frequency of Major Adverse Cardiovascular Events (MACE).
All of these expected improvements will lead to better quality of life in type 1 diabetes patients. Glucose management should be easier and a reduction in long term co-morbidities. Economically, there would be expected saving on the cost of prescription medications.
Relevance to T1D
Type 1 patients, in particular, stand to benefit greatly from BioKier’s product BKR-017, in that its goal is to reduce glucose variability and reduce frequency of hypoglycemic episodes because of better glucose control. These benefits would result from an improvement in insulin sensitivity which would also be expected to lead to lower insulin use in type 1 diabetes patients.
BKR-017 would be the first non-prescription adjuvant therapy for type 1 diabetes patients to help them improve their metabolic profile. This proposed adjuvant treatment is expected to also be relevant for patients with several metabolic diseases including type 2 diabetes, hypertriglyceridemia, and obesity.
BioKier’s therapeutic approach is based on the observations from metabolic surgery, where the documented results showed improvement in type 1 diabetes patients. The therapy is designed to capture most of beneficial effects of this surgical procedure in patients by using BKR-017. The medical literature reports very beneficial effects of a-glucosidase inhibitors, which work via the same mechanism, on glucose management in type 1 diabetes patients. And while the effects of those drugs were very encouraging, GI side effects, including diarrhea, bloating, flatulation caused low compliance.
While there are many drugs offered to patients with type 2 diabetes, most of those drugs offer very limited benefits to type 1 diabetes patients. According to published literature data in 2015 only 5% of T1D patients were using another drug in addition to insulin to help with diseases management. The majority of them, 3%, used metformin. Recently the addition of two new classes of drugs; GLP-1 agonists analogs and SGLT2 inhibitors, offer additional options. Initial data are promising but is too early to assess full benefits and potential adverse effects. In addition, GLP-1 analogs are injectable and a very expensive option for those patients and come with the FDA mandated warning about side effects. SGLT2 inhibitors, while demonstrating positive effects in type 1 diabetes patients are also known to sometimes cause Diabetic Ketoacidosis, a potentially lethal side effect.
BKR-017 would offer a safe, not uncomfortable, less expensive non-prescription supplement which could offer metabolic benefits to type 1 diabetes patients without risk of serious side effects.