Engineering Glucose Responsiveness Into Insulin

Abstract

Insulin has a narrow therapeutic index, reflected in a small margin between a dose that achieves good glycemic control and one that causes hypoglycemia. Once injected, the clearance of exogenous insulin is invariant regardless of blood glucose, aggravating the potential to cause hypoglycemia. We sought to create a "smart" insulin, one that can alter insulin clearance and hence insulin action in response to blood glucose, mitigating risk for hypoglycemia. The approach added saccharide units to insulin to create insulin analogs with affinity for both the insulin receptor (IR) and mannose receptor C-type 1 (MR), which functions to clear endogenous mannosylated proteins, a principle used to endow insulin analogs with glucose responsivity. Iteration of these efforts culminated in the discovery of MK-2640, and its in vitro and in vivo preclinical properties are detailed in this report. In glucose clamp experiments conducted in healthy dogs, as plasma glucose was lowered stepwise from 280 mg/dL to 80 mg/dL, progressively more MK-2640 was cleared via MR, reducing by ∼30% its availability for binding to the IR. In dose escalations studies in diabetic minipigs, a higher therapeutic index for MK-2640 (threefold) was observed versus regular insulin (1.3-fold).

Clinical Evaluation of MK‐2640: An Insulin Analog With Glucose‐Responsive Properties

“…The competition of MK‐2640 binding between the insulin receptor vs. to MRC1 is modulated by blood glucose concentration. The two trials that are presented in this report sought to evaluate safety and tolerability of MK‐2640 and test for clinical translation of the glucose‐responsive PK/PD observed preclinically . In preclinical studies, in addition to glucose‐responsive PK/PD, two limitations were observed, low insulin potency and a high CL by MRC1 .…”

Superior Glycemic Control With a Glucose-Responsive Insulin Analog: Hepatic and Nonhepatic Impacts

“…One approach to creating a GRI is to synthesize insulin analogs that retain capacity to bind to the insulin receptor (IR) and additionally can bind to the mannose receptor (MR) (7)(8)(9)(10). Binding of this type of GRI to the MR is enabled by the attachment of saccharides to an insulin backbone; the result of such binding is that the GRI is delivered for lysosomal degradation.…”

“…Binding of this type of GRI to the MR is enabled by the attachment of saccharides to an insulin backbone; the result of such binding is that the GRI is delivered for lysosomal degradation. With appropriate selection of saccharides, binding to the MR can be modulated by ambient levels of blood glucose, being greatest at low and normal glucose concentrations and correspondingly reduced with higher glycemic levels (7)(8)(9)(10). Thus, clearance of the GRI will be higher at low ambient glucose, lowering its availability for IR binding and insulin action.…”

“…Conversely, these GRIs manifest a lower clearance and higher potential for insulin action under hyperglycemic conditions. Previously reported in vivo studies with GRI analogs in rodent, dog, and minipig models have examined how ambient glucose modulates systemic PK and pharmacodynamic (PD) effects on glucose metabolism (10). A key question that arises is how various tissues shape the glucose-responsive PK and PD of these GRI analogs.…”

Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia

“…Therefore, tremendous efforts have been devoted to the development of smart insulin delivery systems that mimic the glucose-dependent dynamic insulin secretion of β-cells, thereby reducing hyperglycemic condition and mitigating the risk of insulin-induced hypoglycemia associated with a miscalculated exogenous insulin dose (6,7). To this end, chemically driven synthetic closed-loop insulin delivery systems integrating phenylboronic acid (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), glucose-binding protein (17)(18)(19)(20), and glucose oxidase (21)(22)(23)(24)(25)(26) have been extensively studied. However, synthetic strategies to tightly regulate blood glucose levels with a low risk of hypoglycemia remain elusive in clinical practice (27).…”