Pharmacokinetics, Pharmacodynamics, and Modulation of Hepatic Glucose Production With Insulin Glargine U300 and Glargine U100 at Steady State With Individualized Clinical Doses in Type 1 Diabetes

The model proposed by Steele (Ann. NY Acad. Sci. 82: 420-430, 1959) to compute rates of appearance and disappearance in non-steady state is subjected to theoretical analysis. It is shown that this model introduces an error with two components, one dependent on the volume of the compartment, the other related to the complex configuration of the system. The errors depend on the time course of specific activity, change differently with time, and may take the opposite sign but they do not, in general, cancel each other. Corollaries of this analysis are the following: there is no single pool-fraction value satisfactory under all non-steady-state situations; keeping tracer specific activity as constant as possible during the experiment minimizes both errors; and non-steady-state analysis demands proper modeling of the system. Tracer experiments were carried out in five normal volunteers. Plasma [3-3H]glucose concentration was first brought to equilibrium by means of a primed constant 2-h infusion, and then the steady state was perturbed by a 2-h euglycemic insulin (1 mU X min-1 X kg-1) clamp, realizing a transition between a basal and a euglycemic hyperinsulinemic steady state. These data were analyzed with Steele's equation, the two compartment models of Radziuk et al. [Am. J. Physiol. 234 (Endocrinol. Metab. Gastrointest. Physiol. 3): E84-E93, 1978], and a new model based on a study on glucose kinetics carried out in the two steady states separately. Steele's equation yielded negative values for hepatic glucose production already 40 min into the clamp and throughout the study. The average value of glucose production during the 2nd h was -0.88 mg X min-1 X kg-1; the suppression of basal release over the 2-h period was 115%. In contrast, the new model calculated a mean glucose production of 0.37 mg X min-1 X kg-1 during the 2nd h and an overall suppression of 62%; no negative values were obtained.

Download Full-text

Pharmacokinetic and Pharmacodynamic Head-to-Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 units/mL and Insulin Degludec 100 units/mL in Type 1 Diabetes

10.2337/figshare.13103027.v1 ◽

2020 ◽

Author(s):

Paola Lucidi ◽

Paola Candeloro ◽

Patrizia Cioli ◽

Anna Marinelli Andreoli ◽

Chiara Pascucci ◽

...

Keyword(s):

Type 1 Diabetes ◽

Steady State ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Glucagon Suppression ◽

Bolus Insulin ◽

Design And Methods ◽

Single Blind ◽

Randomized Crossover Study

OBJECTIVE To prove equivalence of individual, clinically-titrated basal insulin doses of Gla-300 and Deg-100 under steady-state conditions in a single-blind, randomized, crossover study, on the glucodynamics (PD) in people with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS T1DM subjects [N=22, 11 males M, age 44.3±12.4 years, disease duration 25.5±11.7 years, A1C 7.07±0.63% (53.7±6.9 mmol/mol), BMI 22.5±2.7 kg/m2], naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34±0.08 U.Kg-1) and <a>Deg-100 </a>(0.26±0.06 U.Kg-1), (dosing at 20.00h), after 3 months of optimal titration of basal (and bolus) insulin. RESULTS At the end of 3 months, Gla-300 and Deg-100 reduced slightly and similarly A1C vs baseline. Clamp average plasma glucose (0-24h) was euglycemic with both insulins. The area under curve of glucose infused [AUC-GIR(0-24h)] was equivalent for the two insulins (ratio 1.04, 90% CIs 0.91, 1.18). Suppression of endogenous glucose production, free fatty acids (FFA), glycerol and b-hydroxybutyrate was 9%, 14%, 14% and 18% greater respectively, with Gla-300 as compared with Deg-100, during the first 12 h, while glucagon suppression was no different. Relative within-day PD variability was 23% lower with Gla-300 vs Deg-100 (ratio 0.77, 90% CI 0.63, 0.92). CONCLUSIONS In T1DM, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady-state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 as compared with Deg-100 are higher, and associated with quite similar even 24h distribution of PD and anti-lipolytic effects.

Download Full-text

Glucodynamics of long-acting basal insulin peglispro compared with insulin glargine at steady state in patients with type 1 diabetes: substudy of a randomized crossover trial

Diabetes Obesity and Metabolism ◽

10.1111/dom.12691 ◽

2016 ◽

Vol 18 (11) ◽

pp. 1065-1071 ◽

Cited By ~ 7

Author(s):

L. A. Morrow ◽

M. Hompesch ◽

S. J. Jacober ◽

S. Leng Choi ◽

Y. Qu ◽

...

Keyword(s):

Type 1 Diabetes ◽

Steady State ◽

Insulin Glargine ◽

Basal Insulin ◽

Crossover Trial ◽

Randomized Crossover Trial ◽

Long Acting

Download Full-text

Performing resistance exercise before versus after aerobic exercise influences growth hormone secretion in type 1 diabetes

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2013-0329 ◽

2014 ◽

Vol 39 (2) ◽

pp. 262-265 ◽

Cited By ~ 11

Author(s):

Jane E. Yardley ◽

Ronald J. Sigal ◽

Michael C. Riddell ◽

Bruce A. Perkins ◽

Glen P. Kenny

Keyword(s):

Growth Hormone ◽

Resistance Exercise ◽

Hepatic Glucose Production ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Glucose Production ◽

Lipid Mobilization ◽

Gh Secretion ◽

Hepatic Glucose

We compared growth hormone (GH) and plasma glucose (PG) levels in type 1 diabetic individuals performing aerobic before resistance exercise (AR) to when resistance exercise was performed first (RA). In AR, GH secretion declined in late exercise while it rose throughout exercise in RA, resulting in higher GH in RA versus AR at exercise completion. Higher GH during RA may support PG by increasing hepatic glucose production and lipid mobilization.

Download Full-text

LY2605541 (LY) exhibits a Flatter Glucodynamic profile than insulin Glargine (GL) at steady state in subjects with Type 1 Diabetes (T1D)

Diabetologie und Stoffwechsel ◽

10.1055/s-0034-1374973 ◽

2014 ◽

Vol 9 (S 01) ◽

Cited By ~ 1

Author(s):

L Morrow ◽

M Hompesch ◽

S Jacober ◽

SL Choi ◽

Y Qu ◽

...

Keyword(s):

Type 1 Diabetes ◽

Steady State ◽

Insulin Glargine

Download Full-text

Pharmacokinetic and Pharmacodynamic Head-to-Head Comparison of Clinical, Equivalent Doses of Insulin Glargine 300 units/mL and Insulin Degludec 100 units/mL in Type 1 Diabetes

10.2337/figshare.13103027 ◽

2020 ◽

Author(s):

Paola Lucidi ◽

Paola Candeloro ◽

Patrizia Cioli ◽

Anna Marinelli Andreoli ◽

Chiara Pascucci ◽

...

Keyword(s):

Type 1 Diabetes ◽

Steady State ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Glucagon Suppression ◽

Bolus Insulin ◽

Design And Methods ◽

Single Blind ◽

Randomized Crossover Study

OBJECTIVE To prove equivalence of individual, clinically-titrated basal insulin doses of Gla-300 and Deg-100 under steady-state conditions in a single-blind, randomized, crossover study, on the glucodynamics (PD) in people with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS T1DM subjects [N=22, 11 males M, age 44.3±12.4 years, disease duration 25.5±11.7 years, A1C 7.07±0.63% (53.7±6.9 mmol/mol), BMI 22.5±2.7 kg/m2], naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34±0.08 U.Kg-1) and <a>Deg-100 </a>(0.26±0.06 U.Kg-1), (dosing at 20.00h), after 3 months of optimal titration of basal (and bolus) insulin. RESULTS At the end of 3 months, Gla-300 and Deg-100 reduced slightly and similarly A1C vs baseline. Clamp average plasma glucose (0-24h) was euglycemic with both insulins. The area under curve of glucose infused [AUC-GIR(0-24h)] was equivalent for the two insulins (ratio 1.04, 90% CIs 0.91, 1.18). Suppression of endogenous glucose production, free fatty acids (FFA), glycerol and b-hydroxybutyrate was 9%, 14%, 14% and 18% greater respectively, with Gla-300 as compared with Deg-100, during the first 12 h, while glucagon suppression was no different. Relative within-day PD variability was 23% lower with Gla-300 vs Deg-100 (ratio 0.77, 90% CI 0.63, 0.92). CONCLUSIONS In T1DM, individualized, clinically titrated doses of Gla-300 and Deg-100 at steady-state result in similar glycemic control and PD equivalence during euglycemic clamps. Clinical doses of Gla-300 as compared with Deg-100 are higher, and associated with quite similar even 24h distribution of PD and anti-lipolytic effects.

Download Full-text