7-LB: Insulin and Glucagon Coadministration in Type 1 Diabetes Prevents Hypoglycemia without Worsening Hyperglycemia

Bode, Bruce W.; Boyd, Jennifer; Shah, Anne; Parkes, David G.; Ghosh, Soumitra; Cherrington, Alan D.

doi:10.2337/db20-7-lb

Cited by 5 publications

(5 citation statements)

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“…4B; Table 1). Fortuitously, this degree of impairment would predict a favorable balance of respective glucagon-and insulin signaling activities in a FP, as extrapolated from the prior co-infusion studies (30)(31)(32) and assuming functional independence of the constituent domains (below). To provide a broader context for assessment of the selected lc-glucagon, alternative positions for the lactam-bond formation [residues 9-13, 12-16, 16-20, 20-24, or 24-28] were evaluated without achieving the desired functional properties (Table S6).…”

Section: Fibrillation-resistant Glucagon Analogmentioning

confidence: 99%

“…2A)-even in the face of a 35-fold increase in insulin concentration (29). Indeed, glucagon-stimulated hepatic glucose output has been observed to mitigate hypoglycemia following concurrent infusion of the two hormones at fixed molar ratios (30)(31)(32). Despite the elegance of this idea, its application is presently limited by the hormones' discordant pharmacokinetic/pharmacodynamic (PK/PD) properties (33,34) and incompatible formulation chemistries (31,35), necessitating separate SQ depots.…”

Section: Introductionmentioning

confidence: 99%

“…To prevent fibrillation, the glucagon moiety was protected by a central [i, i+4] side-chain lactam bridge (44,45), and the insulin moiety by an engineered connecting (C) peptide between Band A chains (46,47). Given the intrinsic 1:1 stoichiometry of the FP, relative hormonal activities were calibrated by amino acid substitutions in each domain (30)(31)(32). Following biophysical and cellbased studies, the FP was evaluated in rats by continuous intravenous (IV) infusion to emulate the PK/PD profile of a basal insulin analog.…”

Section: Introductionmentioning

confidence: 99%

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Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk

Varas,

Grabowski,

Jarosinski

et al. 2024

Preprint

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The risk of hypoglycemia and its serious medical sequelae restrict insulin replacement therapy for diabetes mellitus. Such adverse clinical impact has motivated development of diverse glucose-responsive technologies, including algorithm-controlled insulin pumps linked to continuous glucose monitors ("closed-loop systems") and glucose-sensing ("smart") insulins. These technologies seek to optimize glycemic control while minimizing hypoglycemic risk. Here, we describe an alternative approach that exploits an endogenous glucose-dependent switch in hepatic physiology: preferential insulin signaling (under hyperglycemic conditions) versus preferential counter-regulatory glucagon signaling (during hypoglycemia). Motivated by prior reports of glucagon-insulin co-infusion, we designed and tested an ultra-stable glucagon-insulin fusion protein whose relative hormonal activities were calibrated by respective modifications; physical stability was concurrently augmented to facilitate formulation, enhance shelf life and expand access. An N-terminal glucagon moiety was stabilized by an alpha-helix-compatible Lys13-Glu17 lactam bridge; A C-terminal insulin moiety was stabilized as a single chain with foreshortened C domain. Studies in vitro demonstrated (a) resistance to fibrillation on prolonged agitation at 37C and (b) dual hormonal signaling activities with appropriate balance. Glucodynamic responses were monitored in rats relative to control fusion proteins lacking one or the other hormonal activity, and continuous intravenous infusion emulated basal subcutaneous therapy. Whereas efficacy in mitigating hyperglycemia was unaffected by the glucagon moiety, the fusion protein enhanced endogenous glucose production under hypoglycemic conditions. Together, these findings provide proof of principle toward a basal glucose-responsive insulin biotechnology of striking simplicity. The fusion protein's augmented stability promises to circumvent the costly cold chain presently constraining global insulin access.

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Section: Fibrillation-resistant Glucagon Analogmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk

Varas,

Grabowski,

Jarosinski

et al. 2024

Preprint

Self Cite

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“…Cherrington and colleagues have reported that concurrent injection of both hormones both provides glycemic control and buffers hypoglycemia. Encouraging clinical results were presented at the 80th ADA meeting [ 193 ]. Related studies by Novo Nordisk (using different insulin/glucagon ratios) provided evidence that such dual hormone therapy can not only mitigate risk of hypoglycemia, but also insulin-induced weight gain [ 194 , 195 ].…”

Section: Next-generation Insulin Analogsmentioning

confidence: 99%

Structural principles of insulin formulation and analog design: A century of innovation

Jarosinski

Dhayalan

Chen

et al. 2021

Molecular Metabolism

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Background The discovery of insulin in 1921 and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front, from the stabilization of animal insulin formulations to the frontiers of synthetic peptide chemistry, and in turn, from the advent of recombinant DNA manufacturing to structure-based protein analog design. In each case, a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding. Scope of review Pioneering crystallographic analyses—beginning with Hodgkin's solving of the 2-Zn insulin hexamer—elucidated general features of protein self-assembly, including zinc coordination and the allosteric transmission of conformational change. Crystallization of insulin was exploited both as a step in manufacturing and as a means of obtaining protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs. Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic (PK) properties. Encouraged by clinical trials demonstrating the long-term importance of glycemic control, regimens based on such analogs sought to resemble daily patterns of endogenous β-cell secretion more closely, ideally with reduced risk of hypoglycemia. Major conclusions Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics.

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“…The interaction or relationship between insulin and diabetes is properly regulated via the insulin transduction pathway (Ho et al 2016). In diabetes patient, this pathway which is abnormally increasing the absorbance of glucose into fat and muscle cells, as well as dysfunctional glycogenesis of glycogen in liver by glucagon (McCrimmon and Sherwin 2010;Bode et al 2020).…”

Section: Diabetes Diseasementioning

confidence: 99%

Establishment of transplantation platform for delivering mouse induced pluripotent stem cell-derived insulin-producing cells (mips-ipcs) for diabetes treatment

Tran

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Pancreatic beta-cell replacement is recognized for feasible type 1 diabetes (T1D) treatment. However, in post-transplantation, the autoimmune destruction incidentally attacks the activity and survival of beta-cells are reported in animal and human. To address these concerns, the generation of immortalized, biocompatible beta-cells,�and the engraftment platform are insightfully investigated.�The stepwise chemical process was used for�in vitro�Insulin-producing cells (IPCs) production from�mouse gingival fibroblast-induced pluripotent stem cells (mGF-iPSCs). The real-time qRT-PCR, glucose stimulation C-peptide/Insulin�secretion, immunostaining, and visible cell methods were examined during IPC differentiation. The�encapsulated-IPC�beads�were�loaded into subcutaneous�pocket�space via transplantation platform. Completed blood count, blood chemistry,�C-peptide,�HOMA indexes,�intraperitoneal glucose tolerance test,�and histopathology were analyzed at pre-, post-transplantation and at termination. The 40 cytokines were explored via�antibody�array detection.�In this study,�in vitro�IPC differentiation protocol�wasperceptively dissection. IPC encapsulation achieved to the transplantable capacity.In mice, the�catheter insertion and 10%�Pluronic-F127 carrying-VEGF-165�(VP) created the�subcutaneous pocket formation (SPF), and stimulated angiogenesis and neovascularization surrounding the SPF.�Especially,�IPC-bead�engraftment�alleviated�hyperglycemia in�STZ-induced-diabetic mice-VP + IPC-bead transplantation.�In post-transplantation,�IPC-bead�transplantation�showed noimmune�response, as well as, IPC-bead maintained the health condition in diabetic mice.�The obtained results�can be�applied as a clinical transplantation protocol for T1D treatment using cell-based therapy.

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7-LB: Insulin and Glucagon Coadministration in Type 1 Diabetes Prevents Hypoglycemia without Worsening Hyperglycemia

Cited by 5 publications

References 0 publications

Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk

Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk

Structural principles of insulin formulation and analog design: A century of innovation

Establishment of transplantation platform for delivering mouse induced pluripotent stem cell-derived insulin-producing cells (mips-ipcs) for diabetes treatment

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