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

OBJECTIVE: To prove equivalence of individual, clinically titrated basal insulin doses of glargine 300 units ⋅ mL-1 (Gla-300) and degludec 100 units ⋅ mL-1 (Deg-100) under steady state conditions in a single-blind, randomized, crossover study, on the glucose pharmacodynamics (PD) in people with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Subjects with T1D (N = 22, 11 men, age 44.3 ± 12.4 years, disease duration 25.5 ± 11.7 years, A1C 7.07 ± 0.63% [53.7 ± 6.9 mmol ⋅ mL-1], BMI 22.5 ± 2.7 kg · m-2), naïve to Gla-300 and Deg-100, underwent 24-h euglycemic clamps with individual clinical doses of Gla-300 (0.34 ± 0.08 units ⋅ kg-1) and Deg-100 (0.26 ± 0.06 units ⋅ kg-1), dosing at 2000 h, 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 versus baseline. Clamp average plasma glucose (0-24 h) was euglycemic with both insulins. The area under curve of glucose infused (AUC-GIR[0-24 h]) was equivalent for the two insulins (ratio 1.04, 90% CI 0.91-1.18). Suppression of endogenous glucose production, free fatty acids, glycerol, and ß-hydroxybutyrate was 9%, 14%, 14%, and 18% greater, respectively, with Gla-300 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 versus Deg-100 (ratio 0.77, 90% CI 0.63-0.92). CONCLUSIONS: In T1D, 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 compared with Deg-100 are higher and associated with quite similar even 24-h distribution of PD and antilipolytic effects.

Greater Suppression of Glucagon, Lipolysis, and Ketogenesis with Insulin Glargine U300 as Compared with Glargine U100 in Type 1 Diabetes Mellitus.

The aim of this study was to establish the effects of clinical doses of Gla-300 versus Gla-100 on suppression of glucagon, lipolysis, and ketogenesis in type 1 diabetes mellitus (T1DM). Eighteen persons with T1DM (age 40 ± 12 years, diabetes duration 26 ± 12 years, body mass index 23.4 ± 2 kg/m2, A1C 7.19% ± 0.52% [55 ± 6 mmol/mol]) were studied after 3 months of titration with Gla-300 and Gla-100 (randomized, crossover design) with a 24-h euglycemic clamp (s.c. injection of individual insulin daily doses used by subjects for previous 2 weeks, Gla-300 0.35 ± 0.08 and Gla-100 0.28 ± 0.07 U/kg). Gla-300 resulted in (1) less increase in insulin concentration for 0-12 h, but greater insulin concentration in 12-24 h (no differences for 24 h); (2) greater glucagon suppression; (3) greater prehepatic insulin-to-glucagon molar ratio, primarily in 12-24 h (ratio 1.78, 90% confidence intervals [CIs] 1.5-2.1); and (4) lower 24-h free fatty acid (0.81; 90% CI 0.73-0.89), glycerol (0.78; 90% CI 0.65-0.94), and ß-hydroxybutyrate (0.72; 90% CI 0.58-0.90). Over the 24 h postinjection, as compared with Gla-100, clinical doses of Gla-300 exhibit greater suppressive effects on glucagon, lipolysis, and ketogenesis, whereas the effects on glucose metabolism are equivalent.

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.

OBJECTIVE: This study characterized the pharmacokinetics (PK), pharmacodynamics (PD), and endogenous (hepatic) glucose production (EGP) of clinical doses of glargine U300 (Gla-300) and glargine U100 (Gla-100) under steady-state (SS) conditions in type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: T1DM subjects (N = 18, age 40 ± 12 years, T1DM duration 26 ± 12 years, BMI 23.4 ± 2 kg/m2, A1C 7.19 ± 0.52% [55 ± 5.7 mmol · mol-1-1]) were studied after 3 months of Gla-300 or Gla-100 (evening dosing) titrated to fasting euglycemia (random, crossover) with the euglycemic clamp using individualized doses (Gla-300 0.35 ± 0.08, Gla-100 0.28 ± 0.07 units · kg-1). RESULTS: Plasma free insulin concentrations (free immunoreactive insulin area under the curve) were equivalent over 24 h with Gla-300 versus Gla-100 (point estimate 1.11 [90% CI 1.03; 1.20]) but were reduced in the first 6 h (0.91 [90% CI 0.86; 0.97]) and higher in the last 12 h postdosing (1.38 [90% CI 1.21; 1.56]). Gla-300 and Gla-100 both maintained 24 h euglycemia (0.99 [90% CI 0.98; 1.0]). The glucose infusion rate was equivalent over 24 h (1.03 [90% CI 0.88; 1.21]) but was lower in first (0.77 [90% CI 0.62; 0.95]) and higher (1.53 [90% CI 1.23; 1.92]) in the second 12 h with Gla-300 versus Gla-100. EGP was less suppressed during 0-6 h but more during 18-24 h with Gla-300. PK and PD within-day variability (fluctuation) was 50% and 17% lower with Gla-300. CONCLUSIONS: Individualized, clinical doses of Gla-300 and Gla-100 resulted in a similar euglycemic potential under SS conditions. However, Gla-300 exhibited a more stable profile, with lower variability and more physiological modulation of EGP compared with Gla-100.

Pharmacokinetics and Pharmacodynamics of NPH Insulin in Type 1 Diabetes: The Importance of Appropriate Resuspension Before Subcutaneous Injection.

OBJECTIVE: Crystalline NPH insulin comes in a two-phase solution with either a solvent or a rapid-acting insulin (in premixed formulations) and needs adequate mixing for complete resuspension before injection. The aim of this study was to establish pharmacokinetics (PK) and pharmacodynamics (PD) after injection of appropriately resuspended versus nonresuspended NPH insulin. RESEARCH DESIGN AND METHODS: PK and PD were assessed after subcutaneous injection of NPH insulin 0.35 units/kg at steady state by pen either resuspended (R+, tipping of insulin pen 20 times) or nonresuspended (pen maintained in fixed position either horizontally [R- horizontal] or vertically with tip up [R- up] or tip down [R- down]). Eleven subjects with type 1 diabetes (age 31.5 ± 12 years, diabetes duration 17.5 ± 7.7 years, BMI 22.9 ± 1.5 kg/m2, A1C 7.2 ± 0.4% [55.2 ± 4.4 mmol/mol]) were studied (euglycemic clamp) with a randomized crossover design. RESULTS: Compared with resuspended NPH insulin (R+), nonresuspended NPH insulin resulted in profound PK/PD differences with either reduced (R- horizontal and R- up) or increased (R- down) plasma insulin concentrations [FIRI_AUC(0-end of study) (free immunoreactive insulin area under the concentration-time curve between 0 and end of study)] and PD activity [glucose infusion rate (GIR)_AUC(0-end of study)] (all P < 0.05). Duration of NPH insulin action was shorter in R- up (9.4 ± 1.7 h) but longer in R- down (15.4 ± 2.3 h) compared with R+ (11.8 ± 2.6 h) (P < 0.05). Within-subject variability (percent coefficient of variation) among studies was as high as 23% for PK [FIRI_AUC(0-end of study)] and 62% for PD [GIR_AUC(0-end of study)]. CONCLUSIONS: Compared with resuspended NPH insulin, lack of resuspension profoundly alters PK/PD and may importantly contribute to day-to-day glycemic variability of type 1 diabetes.

Pharmacokinetics and pharmacodynamics of insulin glargine given in the evening as compared with in the morning in type 2 diabetes.

OBJECTIVE: To compare pharmacokinetics (PK) and pharmacodynamics (PD) of insulin glargine in type 2 diabetes mellitus (T2DM) after evening versus morning administration. RESEARCH DESIGN AND METHODS: Ten T2DM insulin-treated persons were studied during 24-h euglycemic glucose clamp, after glargine injection (0.4 units/kg s.c.), either in the evening (2200 h) or the morning (1000 h). RESULTS: The 24-h glucose infusion rate area under the curve (AUC0-24h) was similar in the evening and morning studies (1,058 ± 571 and 995 ± 691 mg/kg × 24 h, P = 0.503), but the first 12 h (AUC0-12h) was lower with evening versus morning glargine (357 ± 244 vs. 593 ± 374 mg/kg × 12 h, P = 0.004), whereas the opposite occurred for the second 12 h (AUC12-24h 700 ± 396 vs. 403 ± 343 mg/kg × 24 h, P = 0.002). The glucose infusion rate differences were totally accounted for by different rates of endogenous glucose production, not utilization. Plasma insulin and C-peptide levels did not differ in evening versus morning studies. Plasma glucagon levels (AUC0-24h 1,533 ± 656 vs. 1,120 ± 344 ng/L/h, P = 0.027) and lipolysis (free fatty acid AUC0-24h 7.5 ± 1.6 vs. 8.9 ± 1.9 mmol/L/h, P = 0.005; ß-OH-butyrate AUC0-24h 6.8 ± 4.7 vs. 17.0 ± 11.9 mmol/L/h, P = 0.005; glycerol, P < 0.020) were overall more suppressed after evening versus morning glargine administration. CONCLUSIONS: The PD of insulin glargine differs depending on time of administration. With morning administration insulin activity is greater in the first 0-12 h, while with evening administration the activity is greater in the 12-24 h period following dosing. However, glargine PK and plasma C-peptide levels were similar, as well as glargine PD when analyzed by 24-h clock time independent of the time of administration. Thus, the results reflect the impact of circadian changes in insulin sensitivity in T2DM (lower in the night-early morning vs. afternoon hours) rather than glargine per se.

Metabolism of insulin glargine after repeated daily subcutaneous injections in subjects with type 2 diabetes.

OBJECTIVE: To investigate concentration of plasma insulin glargine after its subcutaneous dosing compared with concentration of its metabolites 1 (M1) and 2 (M2) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Nine subjects underwent a 32-h euglycemic glucose clamp study (0.4 units/kg glargine after 1 week of daily glargine administration). Glargine, M1, and M2 were measured by a specific liquid chromatography-tandem mass spectrometry assay. RESULTS: Glargine was detected in only five of the nine subjects, at few time points, and at negligible concentrations. M1 was detected in all subjects and exhibited the same pattern as traditional radioimmunoassay-measured plasma insulin. M2 was not detected at all. CONCLUSIONS: After subcutaneous injection, glargine was minimally detectable in blood, whereas its metabolite M1 accounted for most (>90%) of the plasma insulin concentration and metabolic action of the injected glargine.

Differential effects of adiposity on pharmacodynamics of basal insulins NPH, glargine, and detemir in type 2 diabetes mellitus.

OBJECTIVE: To assess the role of adiposity on the pharmacodynamics of basal insulins NPH, detemir, and glargine in type 2 diabetes mellitus (T2DM), as estimated by glucose infusion rate (GIR) and endogenous glucose production (EGP) rate in the euglycemic clamp. RESEARCH DESIGN AND METHODS: We examined the variables that best predicted GIR and EGP in 32-h clamp studies after treatment with subcutaneous injection of 0.4 units/kg NPH, detemir, and glargine in 18 T2DM subjects (crossover). RESULTS: A multiple regression analysis revealed that BMI best predicted GIR variation during the clamp. BMI was inversely correlated with GIR in all three insulin treatments, but was statistically significant in detemir treatment only. BMI correlated positively with residual suppression of EGP in detemir, but not with glargine and NPH treatments. CONCLUSIONS: Adiposity blunts the pharmacodynamics of all basal insulins in T2DM. However, as adiposity increases, the effect of detemir is lower versus NPH and glargine.

Pharmacokinetics and pharmacodynamics of therapeutic doses of basal insulins NPH, glargine, and detemir after 1 week of daily administration at bedtime in type 2 diabetic subjects: a randomized cross-over study.

OBJECTIVE: To compare the pharmacokinetics and pharmacodynamics of NPH, glargine, and detemir insulins in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: This study used a single-blind, three-way, cross-over design. A total of 18 type 2 diabetic subjects underwent a euglycemic clamp for 32 h after a subcutaneous injection of 0.4 units/kg at 2200 h of either NPH, glargine, or detemir after 1 week of bedtime treatment with each insulin. RESULTS: The glucose infusion rate area under the curve(0-32 h) was greater for glargine than for detemir and NPH (1,538 ± 688; 1,081 ± 785; and 1,170 ± 703 mg/kg, respectively; P < 0.05). Glargine suppressed endogenous glucose production more than detemir (P < 0.05) and similarly to NPH (P = 0.16). Glucagon, C-peptide, free fatty acids, and ß-hydroxy-butyrate were more suppressed with glargine than detemir. All 18 subjects completed the glargine study, but two subjects on NPH and three on detemir interrupted the study because of plasma glucose >150 mg/dL. CONCLUSIONS: Compared with NPH and detemir, glargine provided greater metabolic activity and superior glucose control for up to 32 h.

Short-term effects of the long-acting insulin analog detemir and human insulin on plasma levels of insulin-like growth factor-I and its binding proteins in humans.

OBJECTIVE: The objective of the study was to compare responses of plasma levels of IGF-I and IGF binding proteins (IGFBP-1 and IGFBP-3) induced by human regular insulin (HI) and the long-acting insulin analog detemir (IDet) at doses equivalent with respect to the glucose-lowering effect. EXPERIMENTAL DESIGN: Ten nondiabetic subjects (six males, four females; age, 36 +/- 7 yr; body mass index, 22.9 +/- 2.6 kg/m(2)) were studied on four randomized occasions with iv infusion of IDet (2 mU/kg . min for 4 h, followed by 4 mU/kg . min for 1 h) or HI (1 mU/kg . min for 4 h, followed by 2 mU/kg . min for 1 h) in euglycemia [plasma glucose (PG), 90 mg/dl] or during stepped hypoglycemia (PG, 90, 78, 66, 54, and 42 mg/dl). RESULTS: PG was maintained at preselected plateaus, without any significant difference between IDet and HI (P > 0.2). Plasma insulin concentrations were on average approximately nine times greater with IDet than HI (749 +/- 52 vs. 83 +/- 19 muU/ml, respectively). Plasma IGF-I concentrations did not change from baseline during insulin infusion in euglycemia (IDet, 147 +/- 16 ng/ml; HI, 155 +/- 15 ng/ml) and hypoglycemia (IDet, 163 +/- 14 ng/ml; HI, 165 +/- 14 ng/ml) with no differences between the two insulins (P > 0.2). A similar pattern was observed for plasma IGFBP-3 levels. Insulin infusion resulted in a suppression of plasma IGFBP-1 concentrations with no differences between IDet (baseline, 16.6 +/- 3.8 ng/ml; endpoint, 2.0 +/- 0.6 ng/ml) and HI (baseline, 16.6 +/- 4.1 ng/ml; endpoint, 2.6 +/- 1.4 ng/ml) (P > 0.2) and study conditions (P > 0.2). CONCLUSIONS: The greater plasma insulin concentrations obtained with IDet exert effects on plasma levels of IGF-I, IGFBP-1, and IGFBP-3 similar to those of HI. Additional studies are needed to confirm these short-term results in patients with diabetes mellitus on long-term treatment with IDet.

Portal vein glucose sensors do not play a major role in modulating physiological responses to insulin-induced hypoglycemia in humans.

OBJECTIVE: Experimental data from animal studies indicate that portal vein glucose sensors play a key role in the responses to slow-fall hypoglycemia. However, their role in modulating these responses in humans is not well understood. The aim of the present study was to examine in humans the potential role of portal vein glucose sensors in physiological responses to insulin-induced hypoglycemia mimicking the slow fall of insulin-treated diabetic subjects. RESEARCH DESIGN AND METHODS: Ten nondiabetic subjects were studied on two different occasions during intravenous insulin (2 mU . kg(-1) . min(-1)) plus variable glucose for 160 minutes. In both studies, after 60 min of normal plasma glucose concentrations, hypoglycemia (47 mg/dl) was induced slowly (60 min) and maintained for 60 min. Hypoglycemia was preceded by the ingestion of either oral placebo or glucose (28 g) given at 30 min. RESULTS: Plasma glucose and insulin were not different with either placebo or glucose (P > 0.2). Similarly, counterregulatory hormones, substrates, and symptoms were not different with either placebo or glucose. The Stroop color and colored words subtest of the Stroop test deteriorated less (P < 0.05) with glucose than placebo. CONCLUSIONS: In contrast to animals, in humans, prevention of portal hypoglycemia with oral glucose from the beginning of insulin-induced slow-fall hypoglycemia has no effect on sympathoadrenal and symptomatic responses to hypoglycemia.

Effect of oral amino acids on counterregulatory responses and cognitive function during insulin-induced hypoglycemia in nondiabetic and type 1 diabetic people.

OBJECTIVE: Amino acids stimulate glucagon responses to hypoglycemia and may be utilized by the brain. The aim of this study was to assess the responses to hypoglycemia in nondiabetic and type 1 diabetic subjects after ingestion of an amino acid mixture. RESEARCH DESIGN AND METHODS: Ten nondiabetic and 10 diabetic type 1 subjects were studied on three different occasions during intravenous insulin (2 mU . kg(-1) . min(-1)) plus variable glucose for 160 min. In two studies, clamped hypoglycemia (47 mg/dl plasma glucose for 40 min) was induced and either oral placebo or an amino acid mixture (42 g) was given at 30 min. In the third study, amino acids were given, but euglycemia was maintained. RESULTS: Plasma glucose and insulin were no different in the hypoglycemia studies with both placebo and amino acids (P > 0.2). After the amino acid mixture, plasma amino acid concentrations increased to levels observed after a mixed meal (2.4 +/- 0.13 vs. placebo study 1.7 +/- 0.1 mmol/l, P = 0.02). During clamped euglycemia, ingestion of amino acids resulted in transient increases in glucagon concentrations, which returned to basal by the end of the study. During clamped hypoglycemia, glucagon response was sustained and increased more in amino acid studies versus placebo in nondiabetic and diabetic subjects (P < 0.05), but other counter-regulatory hormones and total symptom score were not different. Beta-OH-butyrate was less suppressed after amino acids (200 +/- 15 vs. 93 +/- 9 micromol/l, P = 0.01). Among the cognitive tests administered, the following indicated less deterioration after amino acids than placebo: Trail-Making part B, PASAT (Paced Auditory Serial Addition Test) (2 s), digit span forward, Stroop colored words, and verbal memory tests for nondiabetic subjects; and Trail-Making part B, digit span backward, and Stroop color tests for diabetic subjects. CONCLUSIONS: Oral amino acids improve cognitive function in response to hypoglycemia and enhance the response of glucagon in nondiabetic and diabetic subjects.

Different brain responses to hypoglycemia induced by equipotent doses of the long-acting insulin analog detemir and human regular insulin in humans.

OBJECTIVE: The acylated long-acting insulin analog detemir is more lipophilic than human insulin and likely crosses the blood-to-brain barrier more easily than does human insulin. The aim of these studies was to assess the brain/hypothalamus responses to euglycemia and hypoglycemia in humans during intravenous infusion of equipotent doses of detemir and human insulin. RESEARCH DESIGN AND METHODS: Ten normal, nondiabetic subjects (six men, age 36+/-7 years, and BMI 22.9+/-2.6 kg/m(2)) were studied on four occasions at random during intravenous infusion of either detemir or human insulin in euglycemia (plasma glucose 90 mg/dl) or during stepped hypoglycemia (plasma glucose 90, 78, 66, 54, and 42 mg/dl steps). RESULTS: Plasma counterregulatory hormone response to hypoglycemia did not differ between detemir and human insulin. The glycemic thresholds for adrenergic symptoms were higher with detemir (51 +/- 7.7 mg/dl) versus human insulin (56 +/- 7.8 mg/dl) (P = 0.029). However, maximal responses were greater with detemir versus human insulin for adrenergic (3 +/- 2.5 vs. 2.4 +/- 1.8) and neuroglycopenic (4 +/- 3.9 vs. 2.7+/-2.5) symptoms (score, P < 0.05). Glycemic thresholds for onset of cognitive dysfunction were lower with detemir versus human insulin (51 +/- 8.1 vs. 47 +/- 3.6 mg/dl, P = 0.031), and cognitive function was more deteriorated with detemir versus human insulin (P < 0.05). CONCLUSIONS: Compared with human insulin, responses to hypoglycemia with detemir resulted in higher glycemic thresholds for adrenergic symptoms and greater maximal responses for adrenergic and neuroglycopenic symptoms, with an earlier and greater impairment of cognitive function. Additional studies are needed to establish the effects of detemir on responses to hypoglycemia in subjects with diabetes.