Anna Marinelli Andreoli

Università degli Studi di Perugia, Perugia, Umbria, Italy

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Publications (8)50.87 Total impact

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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.
    Nutrition, metabolism, and cardiovascular diseases: NMCD 07/2014; · 3.52 Impact Factor
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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.
    Diabetes care 10/2012; · 7.74 Impact Factor
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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.
    Diabetes care 12/2011; 34(12):2521-3. · 7.74 Impact Factor
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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.
    Diabetes care 06/2011; 34(6):1312-4. · 7.74 Impact Factor
  • 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.
    Diabetes Technology &amp Therapeutics 06/2011; 13 Suppl 1:S43-52. · 2.21 Impact Factor
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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%.
    Diabetes 03/2010; 59(6):1349-57. · 7.90 Impact Factor
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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.
    The Journal of Clinical Endocrinology and Metabolism 06/2009; 94(8):3017-24. · 6.31 Impact Factor
  • Diabetes care 06/2007; 30(5):1261-3. · 7.74 Impact Factor