Objective
We seek to enhance the health and quality of life of individuals with T1D through the creation of novel "smart" insulin therapeutics that protect from hypoglycemic episodes ("the lows"). Hypoglycemia is a near-daily risk of insulin replacement therapy, a risk deepened by efforts to achieve tight glycemic control as monitored by hemoglobin A1c measurements or by calculation of Time-in-Range via a continuous glucose monitor. Presently, individuals with T1D often face a dilemma: whether to (a) optimize glycemic control in an effort to prevent long-term complications at the price of elevated immediate hypoglycemic risk or instead (b) moderate glycemic goals to avoid hypoglycemia but at the expense of a higher risk of long-term complications. To cut this Gordian knot, we seek to develop insulin-glucagon fusion proteins for use in insulin pumps carefully designed to enable effective control of hyperglycemia ("the highs") while minimizing the risk of moderate or severe hypoglycemia. Our strategy builds on a new paradigm in endocrine physiology whereby the blood-glucose level controls how the liver responds to insulin versus glucagon, when faced with both hormones. When the blood-glucose concentration is high, insulin "wins," and so upward excursions are effectively treated; but when the blood-glucose concentration is low, glucagon wins--and the liver responds to secreting glucose to protect the patient from any further decrease in blood-glucose level. In this new paradigm, insulin and glucagon are regarded as co-regulatory hormones instead of strictly counter-regulatory hormones. Thus, instead of an emergency use of glucagon as a rescue agent for severe hypoglycemia, we envision day-in and day-out use of a single fusion protein that contains both hormones to achieve the best of both worlds. Such a new type of insulin product could be used in insulin pumps to advance the safety and effectiveness of automated insulin deliver. In essence, the function of the control algorithm (connected to a continuous glucose monitor) would be improved by the "smart" nature of the liver to further improve Time-in-Range while keeping mild hypoglycemia from ever deepening. By mitigating the risk of moderate or severe hypoglycemia, we envision that individuals with T1D can achieve both improved glycemic control and lower risk of the lows--truly the best of both worlds.
Background Rationale
In past decades insulin and glucagon were regarded as "counter-regulatory" hormones with opposite actions. Insulin would lower the level of glucose in the blood whereas glucagon would raise the level of glucose in the blood. This concept underlies the use of insulin injections day-in and day-out to control blood-glucose concentrations and the separate use of glucagon injections as an emergent treatment of severe hypoglycemia (i.e., as a rescue kit). Investigational dual-hormone insulin-glucagon pumps built on this treatment paradigm in an effort to improve Time-in-Range in automated insulin delivery. Here, we exploit a new physiological paradigm wherein insulin and glucagon can function as "co-regulatory" hormones: respective responsiveness of the liver to these hormones depends on the blood-glucose concentration and in fact glucagon can assist the signaling of insulin in the face of hyperglycemia. This new paradigm provides the key Background/Rationale for our proposal. We seek to replace independent injections of insulin or glucagon by injection of a single protein molecule that contains both hormones, carefully calibrated in relative signaling activities to provide effective treatment of hyperglycemia (the highs) while minimizing the risk of moderate or severe hypoglycemia (the lows). In essence, the glucagon portion of the "fusion protein" will instruct the liver to secrete more glucose when the blood-glucose concentration is mildly low, preventing any further decrease, even as the "smart" liver cells know to disregard the glucagon portion when the blood-glucose is high--or even to respond to the glucagon portion by enhancing the effectiveness of the insulin portion. Thus, the Background provided by the new paradigm of co-regulatory hormones immediately motivates the proposed design of insulin-glucagon fusion proteins. We envision that the use of an appropriately calibrated fusion protein in an insulin pump, as part of an automated insulin delivery system, would enhance the safety and effectiveness of the control algorithm to enable individuals with T1D to achieve better glycemic control with a lower risk of symptomatic hypoglycemia. This would truly be the best of both worlds.
Description of Project
To protect individuals with T1D from hypoglycemia (“the lows”), we seek to develop a novel form of a "smart" insulin based on pump-compatible insulin-glucagon fusion proteins (FPs). The essential idea is to exploit the physiological adaptation of the liver to conditions of low- or high blood-glucose concentrations. The liver cell itself is “smart” as it can adjust its responsiveness to concurrent exposure to insulin and glucagon to appropriately regulate blood-sugar concentrations. (On a technical level, this approach is innovative by circumventing the need for a chemical glucose sensor in a traditional glucose-responsive insulin [GRI] or a traditional glucose-responsive polymer for co-formulation by exploiting an endogenous switch in the liver.) The utility of our FP-based biotechnology is based on new mechanistic insights into the hormonal control of hepatic metabolism whereby concurrent treatment with both insulin and glucagon leads to divergent outcomes depending on “glycemic status” (whether the blood-sugar concentration is low, high or in the normal range): under hypoglycemic conditions, "glucagon wins" to mitigate further hypoglycemic risk, whereas under hyperglycemic conditions, "insulin wins" to treat the insulin deficiency of T1D. Whereas the FPs bind to both insulin receptors and glucose receptors in the liver, the “smart” liver cells have built-in control mechanisms to prioritize one hormone or the other to maximize “time in range”: when the blood-sugar concentration is neither too high nor too low—the normal range. This new paradigm of the smart liver cell transforms the classical view of insulin and glucagon as "counter-regulatory hormones" to their deeper current understanding as "co-regulatory hormones." In individuals with T1D, insulin and glucagon can work jointly to maintain the blood-glucose concentration in the normal range, thereby reducing the frequency and severity of hypoglycemic episodes. Use of an ultra-stable fusion protein would in principle simplify both pharmaceutical formulation (relative to co-formulation of insulin analogs and glucagon analogs) and avoids separate injections. What's more, the FP approach is in principle amenable to both prandial (or pump) and basal implementations. Here, we focus on pump-compatible rapid-acting FPs in an effort to enhance Time-in-Range in automated insulin delivery and to minimize risk of moderate or marked hypoglycemic episodes.
Anticipated Outcome
This one-year pilot proposal seeks to develop rapid-acting insulin-glucagon fusion proteins that are compatible with insulin pumps as part of automated insulin delivery systems. The immediate technical outcome would be protein sequences of the insulin portion and glucagon portion of the fusion protein, defined as a single polypeptide that contains both hormones as linked domains. To this end, there will be a number of secondary outcomes, which provide "stepping stones" toward the identification of a candidate new insulin formulation for future clinical trials. These secondary outcomes include the respective signaling activities of the insulin portion, the glucagon portion, and the linked polypeptide. Such activities will be measured in cell-based assays and in rats. Another secondary outcome is the physical stability of the insulin portion, the glucagon portion, and the linked polypeptide, as pharmaceutical formulations must be sufficiently stable to provide an appropriate shelf-life and to maintain activity within the reservoir of a pump. Yet additional secondary outcomes pertain to the fidelity of synthesis and purification of the hormone domains, both individually and when linked in a fusion protein. Careful documentation of these intermediate steps will be essential in a future application to the U.S. Food & Drug Administration (FDA) to pursue phase-I human trials, which is our overarching objective.
Relevance to T1D
The central therapeutic goal of insulin replacement therapy in T1D is normalization of the blood-glucose concentration: the pattern of ups and downs in "blood sugar" should be as close as possible to that of individuals without diabetes mellitus. This is challenging due to the body's changing needs for insulin and glucose through meals (themselves variable in caloric content and mixture of carbohydrates, protein and fat) and amidst day-to-day and hour-to-hour variation in exercise. The historic DCCT/EDIC clinical trials have demonstrated that achieving lower mean blood-glucose concentrations can delay or prevent microvascular complications, including delayed wound healing, blindness and renal failure. Yet this therapeutic goal imposes a dilemma: the more aggressive the regimen to control blood sugar, the higher the risk of hypoglycemia--itself a dreaded complication with acute and chronic effects. We seek to resolve this dilemma by developing a new type of "smart" insulin that exploits the protective effect of glucagon as a "co-regulatory" hormone. Insulin-glucagon fusion proteins promise the best of both worlds: effective management of the highs and protection from the lows. In this way, our technology promises to enhance long-term health by enabling individuals with T1D to optimize glycemic control without added risk of hypoglycemia--the best of both worlds. Use of such fusion proteins in an automated delivery system would improve the effectiveness of the control algorithm to minimize "time below range" (i.e., hypoglycemic excursion) even with aggressive glycemic targets. We envision that reducing the risk of hypoglycemia would also enhance quality of life, as presently the 24-7 fear of hypoglycemia is ever-present for both patients and their families. The use of a "smart" insulin-glucagon fusion protein in an automated delivery system thus promises to reduce the burden of insulin therapy while maximizing its ability to protect patients from long-term microvascular and vascular complications.