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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 β-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.

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 Deg-100 (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.

PK/PD of clinical doses of Glargine 300 U/mL (Gla-300) and Gla-100 differ (Diabetes Care 2019;42:85), but any clinical relevance has been difficult to demonstrate. Aim: to demonstrate that PK/PD differences of individual doses of Gla-300 vs. Gla-100 translate into clinical benefits in T1DM, as shown by interstitial glucose (IG) (CGM). Methods: 18 persons with T1DM (age 40±12 yrs, diabetes duration 26±12 yrs, A1C 7.2±0.5 %, 55±6 mmol/mol) were randomized to Gla-300 or Gla-100 titrated for 3 months, followed by 2 month washout, and alternate treatment for 3 more months. Titrated mealtime rapid-acting insulin analogs were continued with both Gla-300 and Gla-100. Blinded CGM (iPro, Medtronic) was used during last 2 weeks of each 3-month treatment period. Results: After 3 months, A1C was no different with Gla-300 vs. Gla-100 (both 6.9±0.5 %, 52±6 mmol/mol). CGM revealed lower 24 h IG (Figure); % time in range (70-180 mg/dl) was higher (82±8 vs. 72±10), whereas % time above range (>180 mg/dl, 16±7 vs. 24±8), % time below range (particularly from midnight to pre-breakfast) ( Conclusions: Titrated Gla-300 improves glucose control, reduces variability and hypoglycemia risk vs. Gla-100, as predicted from PK/PD differences of individual doses. Disclosure L. Paola: None. P. Cioli: None. P. Candeloro: None. A. Marinelli Andreoli: None. G.B. Bolli: Consultant; Self; Sanofi. C.G. Fanelli: Advisory Panel; Self; Eli Lilly and Company, Sanofi. F. Porcellati: None. Funding Sanofi

To prove equivalence of individual, clinically titrated basal insulin doses of glargine 300 units ⋅ mLSubjects with T1D (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-GIRIn 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.

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/m

Previous studies have examined variability of pharmacokinetics (PK, plasma insulin concentration) and pharmacodynamics (PD, glucose infusion rate, GIR) of basal insulins at steady-state (SS) and at fixed doses in all subjects studied. To establish within-day PK/PD variability of individual, different, doses of insulin Glargine 300 U/ml (Gla-300) vs. Glargine 100 U/ml (Gla-100) that people with T1DM use in real life. Eighteen T1DMs [age 40±11 years, diabetes duration 26±12 years, BMI 23.4±2.1 kg/m2, A1C 7.2±0.5% (55±6 mmol/mol)] were studied after 3 month treatment with Gla-300 and Gla-100 titrated to fasting euglycemia, with a 24 h euglycemic clamp (randomized, crossover). The individual basal insulin doses that subjects used (0.35±0.Gla-300, 0.28±0.07 Gla-100, U/kg) were injected s.c. in the clamp study. Prior to clamp, glycemic control was comparable with Gla-300 and Gla-100. In the clamp, the individual doses of Gla-300 and Gla-100 resulted in 24 h PK/PD bioequivalence, but in lower variability indices of PK/PD with Gla-300 vs. Gla-100 (Table). In conclusion, at clinical, individual doses used by T1DMs in real life, Gla-300 has lower PK/PD within-day variability vs. Gla-100. These results may explain the lower glycemic variability and lower risk for hypoglycaemia reported in clinical studies with Gla-300 vs. Gla-100. Disclosure C. Fanelli: Advisory Panel; Self; Sanofi. Other Relationship; Self; Menarini Group. P. Lucidi: Other Relationship; Self; Abbott, Menarini Group, Sanofi-Aventis. P. Candeloro: None. P. Cioli: None. A. Marinelli Andreoli: None. G.B. Bolli: Speaker's Bureau; Self; Menarini Group, Sanofi. Research Support; Self; Sanofi. F. Porcellati: Advisory Panel; Self; Sanofi. Board Member; Self; Sanofi. Other Relationship; Self; Medtronic. Board Member; Self; Eli Lilly and Company.

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.

Aims This study measured the insulin concentration (Ins [C] ) of NPH insulin in vials and cartridges from different companies after either resuspension (R+) or not (R−; in the clear/cloudy phases of unsuspended NPH). Methods Measurements included Ins [C] in NPH(R+) and in the clear/cloudy phases of NPH(R−), and the time needed to resuspend NPH and time for NPH(R+) to separate again into clear/cloudy parts. Results In vials of NPH(R+) (assumed to be 100%), Ins [C] in the clear phase of NPH(R−) was [C] in the clear phase of NPH(R−) was P =0.022). Time required for 50% separation into cloudy and clear parts of NPH was longer with Novo (60±7min) vs. Lilly (18±3min) in vials ( P =0.021), and affected by temperature, but not by the different diameter sizes of the vials. With pen cartridges, separation into clear and cloudy parts was significantly faster than in vials ( P Conclusion Ins [C] in NPH preparations varies depending on their resuspension or not. Thus, subcutaneous injection of the same number of units of NPH in patients with diabetes may deliver different amounts of insulin depending on its prior NPH resuspension.

OBJECTIVE Changes in glucose metabolism occurring during counterregulation are, in part, mediated by increased plasma free fatty acids (FFAs), as a result of hypoglycemia-activated lipolysis. However, it is not known whether FFA plays a role in the development of posthypoglycemic insulin resistance as well. RESEARCH DESIGN AND METHODS We conducted a series of studies in eight healthy volunteers using acipimox, an inhibitor of lipolysis. Insulin action was measured during a 2-h hyperinsulinemic-euglycemic clamp (plasma glucose [PG] 5.1 mmo/l) from 5:00 p.m. to 7:00 p.m. or after a 3-h morning hyperinsulinemic-glucose clamp (from 10 a.m. to 1:00 p.m.), either euglycemic (study 1) or hypoglycemic (PG 3.2 mmol/l, studies 2–4), during which FFA levels were allowed to increase (study 2), were suppressed by acipimox (study 3), or were replaced by infusing lipids (study 4). [6,6-2H2]-Glucose was infused to measure glucose fluxes. RESULTS Plasma adrenaline, norepinephrine, growth hormone, and cortisol levels were unchanged (P > 0.2). Glucose infusion rates (GIRs) during the euglycemic clamp were reduced by morning hypoglycemia in study 2 versus study 1 (16.8 ± 2.3 vs. 34.1 ± 2.2 μmol/kg/min, respectively, P < 0.001). The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 ± 2.6 μmol/kg/min, P > 0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 ± 2.8 μmol/kg/min, P < 0.03 vs. study 1). Compared with study 2, blockade of lipolysis in study 3 decreased endogenous glucose production (2 ± 0.3 vs. 0.85 ± 0.1 μmol/kg/min, P < 0.05) and increased glucose utilization (16.9 ± 1.85 vs. 28.5 ± 2.7 μmol/kg/min, P < 0.05). In study 4, GIR fell by ∼23% (22.3 ± 2.8 μmol/kg/min, vs. study 3, P = 0.058), indicating a role of acipimox per se on insulin action. CONCLUSION Lipolysis induced by hypoglycemia counterregulation largely mediates posthypoglycemic insulin resistance in healthy subjects, with an estimated overall contribution of ∼39%.

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; β-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.

Glargine metabolism has been studied in insulin-treated people with type 2 diabetes (T2D) at usual glargine doses of 0.4–0.8 units/kg/day (1,2). In some obese subjects with insulin-resistant T2D, higher basal insulin doses are needed, and the question of safety of glargine (3) is therefore still relevant. Epidemiological studies indicate that the risk of cancer is especially elevated in obese individuals with insulin-resistant diabetes requiring high insulin doses (4). Unmodified insulin glargine has been suggested to confer a higher risk of cancer (3), but prior studies have shown that, at usual doses, an active metabolite (M1) with actions similar to human insulin is the main circulating molecule after glargine injection (1,2). The aim of the current study was to establish the plasma levels of insulin glargine (M0) and its metabolites M1 and M2 (1,2) in subjects with T2D treated long-term with glargine dose ≥1.2 units/kg/day. Blood samples of 10 subjects with T2D (male/female 5/5, age 56 ± 10 years, BMI 37.9 ± 7.9 kg/m2, A1C 8.9 ± 1.3% …

OBJECTIVECrystalline 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 METHODSPK 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.RESULTSCompared 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)].CONCLUSIONSCompared 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.

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 curve0–32 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 β-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.

Pharmacokinetics and pharmacodynamics of the long-acting insulin analog glargine (1) are superior to those of insulin NPH (2–9). In the clinical setting, this translates into lower risk of nocturnal hypoglycemia (10–13), lower A1C (provided that appropriate requirements of mealtime rapid-acting insulin are met) (11–13), and the convenience of once (12), compared with multiple, administration of NPH (14). However, no study has examined subjects after several days of its use versus the “first” subcutaneous injection. The present studies were undertaken to establish the pharmacokinetics and pharmacodynamics of insulin glargine in type 1 diabetes after 1 week of its once-daily use and to compare it with those observed after the first injection. After institutional review board approval, 20 type 1 diabetic subjects (12 male subjects, age 31 ± 2 years, type 1 diabetes duration 11 ± 1 years, BMI 23.3 ± 0.4 kg/m2, fasting plasma C-peptide

Background and aims After subcutaneous injection insulin glargine is rapidly metabolized to M1 and M2. In vitro , both M1 and M2 have metabolic effects and bind to IGF-1R similarly to human insulin, whereas glargine exhibits a higher affinity for the IGF-1R and greater mitogenetic effects. The present study was specifically designed to establish the dose–response metabolism of glargine over 24 h following s.c. injection in T2DM subjects on long-term use of glargine. Methods and results Ten subjects with T2DM were studied during 24 h after s.c. injection of 0.4 (therapeutic) and 0.8 (high dose) U/kg of glargine on two separate occasions during euglycaemic clamps (cross-over design). Glargine, M1 and M2 over 24 h period were determined in appropriately processed plasma samples by a specific liquid chromatography-tandem mass spectrometry assay. Plasma M1 concentration (AUC 0–24 h ) was detected in all subjects and increased by increasing the glargine dose from therapeutic to high dose ( p = 0.008). Glargine was detectable in 6 (therapeutic dose) and 9 (high dose) out of the 10 subjects and also increased by increasing the dose ( p = 0.031). However, glargine concentration (AUC 0–24 h – high dose) represented at most only 9.7% (4.6–15%) of the total amount of insulin measured in the blood. M2 was not detected at all. Conclusion In T2DM people on long-term use of insulin glargine, even with higher doses (0.8 U/kg), glargine is nearly totally metabolized to the active metabolite M1. Glargine is often detectable in plasma, but its concentration remains well below that needed in vitro to potentiate IGF-1R binding and mitogenesis.

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.

In physiology, insulin is released continuously by the pancreas at a nearly constant rate between meals and in the fasting state (basal insulin secretion). The pivotal role of basal insulin is to restrain release of glucose from the liver and free fatty acids from adipose tissue, thus preventing hyperglycemia and ketosis. In type 1 diabetes mellitus (T1DM) (absolute insulin deficiency), the replacement of basal insulin is challenging because the currently available pharmacological preparations of long-acting insulin do not exactly reproduce the fine physiology of flat action profile of basal insulin of subjects without diabetes. NPH and NPH-based insulin mixtures no longer have a place in the treatment of T1DM because of their early peak effects and relatively short duration of action, which result into risk of nocturnal hypoglycemia and fasting hyperglycemia, respectively, after the evening injection. Only continuous subcutaneous (s.c.) insulin infusion (CSII) or long-acting analogs such as glargine (24 h in duration, once a day) and detemir (24 h in duration, once or more often twice a day) should be used as basal insulin in T1DM in combination with mealtime rapid-acting analogs. CSII and the long-acting analogs are nearly peakless and therefore reduce the risk for hypoglycemia (especially at night), blood glucose (BG) variability, and lower A1C with similar or less hypoglycemia. CSII is the "gold standard" of replacement of basal insulin because of better reproducibility of subcutaneous absorption of soluble insulin. Although CSII is not superior to multiple daily insulin injections in the general T1DM population, CSII might be indicated in subsets of T1DM (long-term T1DM with insulin "supersensitivity" and needs for low-dose insulin, some individuals with variable subcutaneous absorption of long-acting analogs) to minimize BG variability, reduce hypoglycemia, and benefit A1C.

[EN] 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., F.P., P.L., P.R., and C.G.F. received grants from various companies (sanofi-aventis, Eli Lilly, Bristol-Myers Squibb, Novartis, and Merck Sharp & Dohme) for participating at meetings and congresses. G.B.B. received honoraria for scientific advising and consulting from the following companies: sanofi-aventis, MannKind, and Eli Lilly. No other potential conflicts of interest relevant to this article were reported.