Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin

Lucidi, Paola; Porcellati, Francesca; Yki‐Järvinen, Hannele; Riddle, Matthew C.; Candeloro, Paola; Andreoli, Anna Marinelli; Bolli, Geremia B.; Fanelli, Carmine G.

doi:10.2337/dc14-2662

Cited by 3 publications

(10 citation statements)

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“…In contrast, after SC injection M0 was undetectable with Gla‐300, whereas it was detectable only in two of the six dogs for the initial 3 h post‐dosing with Gla‐100. These findings are in line with those observed in humans following SC of therapeutic doses of glargine in humans, both Gla‐300 and Gla‐100, with M0 representing less than 5%‐10% of circulating insulin 14–18 …”

Section: Discussionsupporting

confidence: 89%

“…This possibly saturated the proteolytic enzymes that rapidly convert M0 to M1. Similarly, the elevated M1 concentrations in the IV experiments probably favoured conversion of M1 to M2 to a larger extent than usually observed with SC therapeutic doses in humans 14–18 …”

Section: Discussionmentioning

confidence: 61%

“…These findings are in line with those observed in humans following SC of therapeutic doses of glargine in humans, both Gla-300 and Gla-100, with M0 representing less than 5%-10% of circulating insulin. [14][15][16][17][18] However, it should be noted that in the present IV studies the insulin dose was large (0.15 U/kg) and resulted into pharmacological serum M1 concentrations (>300 μU/mL, more than 10 times higher than therapeutic concentrations). This possibly saturated the proteolytic enzymes that rapidly convert M0 to M1.…”

Section: Discussionmentioning

confidence: 62%

“…Gla‐300 contains the same glargine molecule soluble at acidic pH as Gla‐100, which becomes insoluble and forms micro‐precipitates at the neutral pH of the SC tissue injection site. In people with type 1 and type 2 diabetes, Gla‐300 and Gla‐100 undergo the same, nearly total biotransformation of glargine parent (M0) primarily to 21 A ‐Gly‐human insulin (metabolite M1) and, to a lesser extent, to 21 A ‐Gly‐des‐30 B ‐Thr‐human insulin (metabolite M2), which both drive the insulin effect of glargine in type 1 diabetes 14,15 and in type 2 diabetes 16–18 . However, as compared with 100 U/mL glargine, in 300 U/mL glargine, the same units are contained in one‐third of the volume thereby forming a smaller insulin depot after SC injection with half of the surface area and consequently slower absorption rate.…”

Section: Introductionmentioning

confidence: 99%

“…In people with type 1 and type 2 diabetes, Gla-300 and Gla-100 undergo the same, nearly total biotransformation of glargine parent (M0) primarily to 21 A -Gly-human insulin (metabolite M1) and, to a lesser extent, to 21 A -Gly-des-30 B -Thr-human insulin (metabolite M2), which both drive the insulin effect of glargine in type 1 diabetes 14,15 and in type 2 diabetes. [16][17][18] However, as compared with 100 U/mL glargine, in 300 U/mL glargine, the same units are contained in one-third of the volume thereby forming a smaller insulin depot after SC injection with half of the surface area and consequently slower absorption rate. The longer residency time in the SC tissue before absorption of Gla-300 versus Gla-100 might favour the activity of local protease enzymes with greater, local degradation of former versus latter glargine formulation.…”

mentioning

confidence: 99%

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Equipotency of insulin glargine 300 and 100 U/mL with intravenous dosing but differential bioavailability with subcutaneous dosing in dogs

Ulrich

Tennagels

Fanelli

et al. 2020

Diabetes Obesity Metabolism

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Aims Insulin glargine 300 U/mL (Gla‐300) contains the same units versus glargine 100 U/mL (Gla‐100) in three‐fold lower volume, and higher subcutaneous (SC) doses are required in people with diabetes. To investigate blood glucose (BG) lowering potency, Gla‐300 and Gla‐100 were compared after intravenous (IV, for 4 h) and SC (for 24 h) injection in healthy Beagle dogs. Materials and methods The dose of 0.15 U/kg Gla‐300 and Gla‐100 was injected IV in 12 dogs. BG, C‐peptide, glucagon and the active metabolite 21A‐Gly‐human insulin (M1; liquid chromatography‐tandem mass spectrometry method) were measured. Twelve other dogs were studied after SC injection of 0.3 U/kg Gla‐300 and Gla‐100. Results After IV injection, Gla‐300 and Gla‐100 were equally potent [BG_AUC0‐4 h ratio 1.01 (95% confidence interval, 0.94; 1.09)]. After SC injection, BG decreased slower and less with Gla‐300. Similar metabolism of Gla‐300 and Gla‐100 to M1 occurred with IV dosing [M1_AUC0‐1 h ratio 0.99 (95% confidence interval, 0.82; 1.22)], but with SC dosing M1_Cmax and AUC0‐24h were 44% and 17% lower; mean residency time and bioavailability were 32% longer and 50% lower, with Gla‐300. Conclusions IV Gla‐300 and Gla‐100 have the equivalent of BG‐lowering potency and M1 metabolism. SC Gla‐300 has lower M1 bioavailability with a reduced BG‐lowering effect and need for greater doses versus Gla‐100.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Equipotency of insulin glargine 300 and 100 U/mL with intravenous dosing but differential bioavailability with subcutaneous dosing in dogs

Ulrich

Tennagels

Fanelli

et al. 2020

Diabetes Obesity Metabolism

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Assessment of circulating insulin using liquid chromatography‐mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β‐cell function

Seegmiller

Schmit

Arends

et al. 2023

Diabetes Obesity Metabolism

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Aim: To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and β-cell measures in people with type 2 diabetes.Materials and Methods: Using liquid chromatography-mass spectrometry (LC-MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose).Results: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC-MS; however, the analogue and its metabolites crossreacted by less than 100% in the insulin immunoassay. This incomplete crossreactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose.Conclusions: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased.

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Molecular Modeling and Bioinformatics Analysis of Drug-Receptor Interactions in the System Formed by Glargine, Its Metabolite M1, the Insulin Receptor, and the IGF1 Receptor

González-Beltrán

Gómez-Alegría

2021

Bioinform Biol Insights

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Introduction: Insulin and insulin-like growth factor type 1 (IGF1) regulate multiple physiological functions by acting on the insulin receptor (IR) and insulin-like growth factor type 1 receptor (IGF1R). The insulin analog glargine differs from insulin in three residues (GlyA21, ArgB31, ArgB32), and it is converted to metabolite M1 (lacks residues ArgB31 and ArgB32) by in vivo processing. It is known that activation of these receptors modulates pathways related to metabolism, cell division, and growth. Though, the structures and structural basis of the glargine interaction with these receptors are not known. Aim: To generate predictive structural models, and to analyze the drug/receptor interactions in the system formed by glargine, its metabolite M1, IR, and IGF1R by using bioinformatics tools. Methods: Ligand/receptor models were built by homology modeling using SWISSMODEL, and surface interactions were analyzed using Discovery Studio® Visualizer. Target and hetero target sequences and appropriate template structures were used for modeling. Results: Our glargine/IR and metabolite M1/IR models showed an overall symmetric T-shaped conformation and full occupancy with four ligand molecules. The glargine/IR model revealed that the glargine residues ArgB31 and ArgB32 fit in a hydrophilic region formed by the α-chain C-terminal helix (αCT) and the cysteine-rich region (CR) domain of this receptor, close to the CR residues Arg270-Arg271-Gln272 and αCT residue Arg717. Regarding IGF1R, homologous ligand/receptor models were further built assuming that the receptor is in a symmetrical T-shaped conformation and is fully occupied with four ligand molecules, similar to what we described for IR. Our glargine/IGF1R model showed the interaction of the glargine residues ArgB31 and ArgB32 with Glu264 and Glu305 in the CR domain of IGF1R. Conclusion: Using bioinformatics tools and predictive modeling, our study provides a better understanding of the glargine/receptor interactions.

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Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin

Cited by 3 publications

References 5 publications

Equipotency of insulin glargine 300 and 100 U/mL with intravenous dosing but differential bioavailability with subcutaneous dosing in dogs

Equipotency of insulin glargine 300 and 100 U/mL with intravenous dosing but differential bioavailability with subcutaneous dosing in dogs

Assessment of circulating insulin using liquid chromatography‐mass spectrometry during insulin glargine treatment in type 2 diabetes: Implications for estimating insulin sensitivity and β‐cell function

Molecular Modeling and Bioinformatics Analysis of Drug-Receptor Interactions in the System Formed by Glargine, Its Metabolite M1, the Insulin Receptor, and the IGF1 Receptor

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