Anna Marinelli Andreoli

Università degli Studi di Perugia, Perugia, Umbria, Italy

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Publications (12)78.67 Total impact

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    ABSTRACT: 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/m(2), 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.
    No preview · Article · Sep 2015 · Diabetes care
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    Preview · Article · Jul 2015 · Diabetes care
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    ABSTRACT: Severe hypoglycemia (SH) is the most dangerous complication of diabetes treatment and the limiting factor in blood glucose (BG) management. This study retrospectively analyzed the clinical characteristics, causal factors, and medical costs of type 2 diabetic patients (T2DM) admitted for severe hypoglycemia to the emergency department (ED) of Perugia hospital, Italy, from 1 July 2005 to 30 June 2011. SH was defined as an event requiring assistance from another person administering carbohydrates or glucagon to correct hypoglycemia, identified on the basis of capillary BG measured by the ambulance crew or at the ED, using the ICD-9-CM discharge diagnosis code. There were 205 admissions, half of whom (107, 50.5%) were treated in the ED and discharged the same day. The other 98 (49.5%) required hospital admission. The characteristics of these latter were: age 78 ± 10 yrs (mean ± SD), duration of diabetes (15 ± 12 yrs), HbA1c (6.8 ± 1.5%; 51 ± 11,2 mmol/mol), renal function (estimated glomerular filtration rate 56 ± 32 ml/min/1.73 m2), associated comorbid conditions (Charlson Comorbidity Index 5.4 ± 2.1), use of more than three different medications (86%). More than half (57.1%) were using insulin, 41.8% oral agents; of the latter, more than half (61.7%) were taking a sulphonylurea, mainly glibenclamide. SH induced by SU was associated with a longer average length of stay (ALOS) (3.0 vs. 6.0 days) and the estimated average cost per ALOS was greater than that due to insulin (€4,500 vs. €2,250, not including the costs of the emergency telephone service and ambulance). In conclusion, these findings indicate that half of SH events in T2DM presenting to the ED require hospital admission and almost half are due to inappropriate use of SU, with a significant impact on patients’ health and healthcare costs.
    No preview · Article · Jun 2015 · Giornale Italiano di Diabetologia e Metabolismo
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    ABSTRACT: 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.
    Preview · Article · Dec 2014 · Diabetes Care
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    ABSTRACT: 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-1 R and greater mitogenetic effects. The present study was specifically designed to establish the dose-response metabolism of glargine over 24 hours 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 (AUC0-24 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 (AUC0-24h – 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-1 R binding and mitogenesis.
    No preview · Article · Jul 2014 · Nutrition, metabolism, and cardiovascular diseases: NMCD
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    ABSTRACT: 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.RESULTSGlargine 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.
    Full-text · Article · Oct 2012 · Diabetes care
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    ABSTRACT: 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. 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). 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. Adiposity blunts the pharmacodynamics of all basal insulins in T2DM. However, as adiposity increases, the effect of detemir is lower versus NPH and glargine.
    Full-text · Article · Dec 2011 · Diabetes care
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    ABSTRACT: To compare the pharmacokinetics and pharmacodynamics of NPH, glargine, and detemir insulins in type 2 diabetic subjects. 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. 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 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. Compared with NPH and detemir, glargine provided greater metabolic activity and superior glucose control for up to 32 h.
    Full-text · Article · Jun 2011 · Diabetes care
  • Geremia B Bolli · Anna Marinelli Andreoli · Paola Lucidi
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    ABSTRACT: 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.
    No preview · Article · Jun 2011 · Diabetes Technology & Therapeutics
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    ABSTRACT: 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. 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-(2)H(2)]-Glucose was infused to measure glucose fluxes. 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 micromol/kg/min, respectively, P < 0.001). The effect was largely removed by blockade of lipolysis during hypoglycemia in study 3 (28.9 +/- 2.6 micromol/kg/min, P > 0.2 vs. study 1) and largely reproduced by replacement of FFA in study 4 (22.3 +/- 2.8 micromol/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 micromol/kg/min, P < 0.05) and increased glucose utilization (16.9 +/- 1.85 vs. 28.5 +/- 2.7 micromol/kg/min, P < 0.05). In study 4, GIR fell by approximately 23% (22.3 +/- 2.8 micromol/kg/min, vs. study 3, P = 0.058), indicating a role of acipimox per se on insulin action. Lipolysis induced by hypoglycemia counterregulation largely mediates posthypoglycemic insulin resistance in healthy subjects, with an estimated overall contribution of approximately 39%.
    Full-text · Article · Mar 2010 · Diabetes
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    ABSTRACT: 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. 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). 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). 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.
    No preview · Article · Jun 2009 · The Journal of Clinical Endocrinology and Metabolism
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    Full-text · Article · Jun 2007 · Diabetes care