Journal of Clinical Endocrinology & Metabolism, 1998
This study was designed to establish the lower dose of effective GH replacement therapy in severe... more This study was designed to establish the lower dose of effective GH replacement therapy in severe GH-deficient (GHD) adults. Whole body protein and lipid kinetics were determined in six GHD men in the basal state (B) and after 1 week of treatment with placebo (PL) or 3.3 (GH3.3) or 2 (GH2) micrograms/kg.day recombinant human GH (rhGH). The rates of whole body proteolysis, oxidation, and synthesis were estimated by infusing [1-13C]leucine (prime, 1 mg/kg; infusion rate, 1 mg/kg.h); those of lipolysis (measured in four of the six patients) were estimated by infusing [1,1,2,3,3-D5]glycerol (prime, 1.8 mumol/kg; infusion rate, 0.06 mumol/kg.min). Serum insulin-like growth factor I (IGF-I) concentrations (picograms per mL; mean +/- SE) similarly increased from the basal level (39 +/- 7) after 3.3 (108 +/- 18) or 2 (109 +/- 24) microgram/kg.day rhGH (P < 0.001 vs. basal), whereas they did not change with placebo (41 +/- 8). Leucine Ra was unaffected by the treatments. GH3.3 reduced by 30% the rate of leucine oxidation (P = 0.0069 vs. basal) and increased by 11% nonoxidative leucine disposal (P = 0.0095 vs. basal) and by 21% glycerol Ra (0.0035 vs. basal); GH2 and placebo had no significant effect. In conclusion, 1) at least 3.3 micrograms/ kg.day rhGH are required to increase whole body protein synthesis and lipolysis in male GHD adults; 2) 2 micrograms/kg.day rhGH normalize serum IGF-I concentrations, but do not modify protein and lipid metabolism; and 3) a normal serum IGF-I concentration does not guarantee that rhGH treatment is also effective on intermediate metabolism.
OBJECTIVEdTo assess the role of adiposity on the pharmacodynamics of basal insulins NPH, detemir,... more OBJECTIVEdTo 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 METHODSdWe 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).
At present, the duration of the effect of recombinant human growth hormone (rhGH) on the rates of... more At present, the duration of the effect of recombinant human growth hormone (rhGH) on the rates of protein synthesis and lipolysis in GH deficient (GHD) adults is unknown. This study was designed to establish the frequency of rhGH administration necessary to provide the beneficial metabolic effects of the hormone in GHD adults. Two different studies (A and B) were performed in two groups of five GHD men. In study A, whole body protein and lipid kinetics was determined in the basal state (Bas), 12 (GH12h) and 36 (GH36h) h after the last of seven injections of rhGH (3.3 microg/kg), given at bedtime on alternate days. In study B, the same parameters were determined in the basal state (Bas), 60 (GH60h) and 84 (GH84h) h after the last of seven injections of rhGH (3.3 microg/kg), given at bedtime at 3 day intervals. The rates of protein metabolism were estimated by infusing [1-13C]leucine, and those of lipolysis by infusing [1,1,2,3, 3-D5]glycerol. Leucine oxidation decreased (P < 0.01) by approximately 30% after GH12h and GH36h but did not change after GH60h and GH84h. Non-oxidative leucine disposal increased after GH12h and GH36h by approximately 13% (P < 0.05) whereas it did not change after GH60h and GH84h. Glycerol appearance increased (P < 0. 01) by approximately 45% after GH12h and GH36h but did not change after GH60h and GH84h. The effects on protein and lipid metabolism following the injection of rhGH last longer than 36 and less than 60 h. In fact, rhGH administration on alternate days induced a sustained increase in the rates of protein synthesis and lipolysis of GHD adults, whereas a longer interval of administration (3 days) had no effect by 60 h.
Aim: to compare head-to-head pharmacokinetics (PK), pharmacodynamics (PD), glucose fluxes and lip... more Aim: to compare head-to-head pharmacokinetics (PK), pharmacodynamics (PD), glucose fluxes and lipid metabolism of clinical doses of insulin glargine U300 (Gla-300) and degludec U100 (IDeg) in real life in T1DM. Methods: 22 subjects [(11M, age 44±12, T1DM for 26±12 years, BMI 22.5±3.2 kg/m2, A1C 7.1±0.6% (53.4±7.1 mmol/mol)] on Gla-100, naïve to Gla-300 and IDeg, were studied (24h euglycemic clamp) with individual doses of Gla-300 and IDeg (dosing at 20.0h) after 3 months of optimal titration of basal-bolus insulin (random crossover). Results (at present in 14 of the 22 subjects, PD only, data in progress): preclamp A1C was similar with Gla-300 vs. IDeg. Individual basal insulin dose was greater with Gla-300 vs. IDeg (0.35±0.09 vs. 0.27±0.06 U/kg, p<0.01). Average PG (0-24h) was euglycemic on both occasions (p=NS). Area under curve of glucose infused [AUC-GIR(0-24h)] was equivalent for the two insulins (ratio 1.03, 90% C.I. 0.9, 1.22) (Figure). Within-day PD variability tended to be lower with Gla-300 vs. IDegl (CV 51% vs. 59%, p<0.051). Conclusions. In T1DM, PD of clinical doses of Gla-300 are equivalent to IDeg with a trend for lower within-day variability. Disclosure P. Lucidi: Other Relationship; Self; Abbott, Novo Nordisk A/S. F. Porcellati: Board Member; Self; AstraZeneca, Eli Lilly and Company, Sanofi. Consultant; Self; Medtronic. P. Candeloro: None. P. Cioli: None. C. Pascucci: None. G.B. Bolli: Advisory Panel; Self; Sanofi. Research Support; Self; A. Menarini Diagnostics, Medtronic. C. Fanelli: Advisory Panel; Self; Sanofi. Other Relationship; Self; Menarini Group.
OBJECTIVE-Acute, short-term hyperglycemia enhances high shear stress-induced platelet activation ... more OBJECTIVE-Acute, short-term hyperglycemia enhances high shear stress-induced platelet activation in type 2 diabetes. Several observations suggest that platelets in type 2 diabetes are resistant to inhibition by aspirin. Our aim was to assess comparatively the effect of aspirin, a nitric oxide-donating agent (NCX 4016), their combination, or placebo on platelet activation induced by acute hyperglycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS-In a double-blind, placebo-controlled, randomized trial, 40 type 2 diabetic patients were allocated to 100 mg aspirin once daily, 800 mg NCX 4016 b.i.d., both of them, or placebo for 15 days. On day 15, 1 h after the morning dose, a 4-h hyperglycemic clamp (plasma glucose 13.9 mmol/l) was performed, and blood samples were collected before and immediately after it for platelet activation and cyclooxygenase-1 (COX-1) inhibition studies. RESULTS-Acute hyperglycemia enhanced shear stress-induced platelet activation in placebo-treated patients (basal closure time 63 Ϯ 7.1 s, after hyperglycemia 49.5 Ϯ 1.4 s, Ϫ13.5 Ϯ 6.3 s, P Ͻ 0.048). Pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (Ϫ12.7 Ϯ 6.9 s, NS vs. placebo). On the contrary, pretreatment with the NO donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016 ϩ10.5 Ϯ 8.3 s; NCX 4016 plus aspirin: ϩ12.0 Ϯ 10.7 s, P Ͻ 0.05 vs. placebo for both). Other parameters of shear stress-dependent platelet activation were also more inhibited by NCX 4016 than by aspirin, despite lesser inhibition of COX-1. CONCLUSIONS-Acute hyperglycemia-induced enhancement of platelet activation is resistant to aspirin; a NO-donating agent suppresses it. Therapeutic approaches aiming at a wider platelet inhibitory action than that exerted by aspirin may prove useful in patients with type 2 diabetes.
ore than 30 years ago in Diabetes Care, Schmidt et al. (1) defined "dawn phenomenon," the nightto... more ore than 30 years ago in Diabetes Care, Schmidt et al. (1) defined "dawn phenomenon," the nightto-morning elevation of blood glucose (BG) before and, to a larger extent, after breakfast in subjects with type 1 diabetes (T1D). Shortly after, a similar observation was made in type 2 diabetes (T2D) (2),
Supplementary Table 1-Indices of insulin secretion and insulin resistance in study 1 and study 2 ... more Supplementary Table 1-Indices of insulin secretion and insulin resistance in study 1 and study 2 (clamp) at baseline (T0h) and over last 30 minutes of clamp (T3h) AM and PM in non-diabetic subjects and people with T2DM calculated according to Gastaldelli A et al. (31)
The DCCT (Diabetes Control Complication Trials) has conclusively demonstrated in 1993 that good g... more The DCCT (Diabetes Control Complication Trials) has conclusively demonstrated in 1993 that good glycaemic control prevents the micro-angiopathy caused by chronic hyperglycaemia in T1DM. The subsequent follow-up study EDIC (Epidemiology of Diabetes Interventions and Complications) has demonstrated similar results for macro-angiopathy. Taken together, DCCT and EDIC strongly indicate the need for aggressive treatment of T1DM with intensive therapy to target near-normoglycaemia since clinical onset of T1DM to prevent long-term micro- and macro-vascular complications. Today and in the years to come, this message remains and will remain as fundamental as it was 30 years ago.
Journal of Endocrinological Investigation, Oct 1, 2006
This randomized controlled study was designed to test the efficacy and safety of percutaneous ult... more This randomized controlled study was designed to test the efficacy and safety of percutaneous ultrasound (US)-guided laser photocoagulation (PLP) for treatment of subjects with compressive symptoms due to benign thyroid nodules and/or at high surgical risk. Twenty six subjects were randomized to the intervention (no. 13, age 68+/-3 yr, mean+/-SEM) or observation (no. 13, age 71+/-2 yr) groups. In the control group, the volume of nodules did not significantly change over the 30 week period of observation. In the intervention group, median nodule volume at baseline was 8.2 ml (range 2.8-26.9) and was not significantly different from that of the control group. Nodules decreased significantly (p<0.0001) by 22% after 2 weeks (6.5 ml; range 2.4-16.7) and by 44% after 30 weeks (4.6 ml; range 0.69-14.2). Energy given was correlated (p<0.05) with the reduction of thyroid nodule volume. All patients tolerated the treatment well and reported relief from compressive and cosmetic complaints (p<0.05). At the time of enrolment 7/13 (54%) and 6/13 (46%) of patients in the intervention and control groups, respectively, had sub clinical hyperthyroidism. PLP normalized thyroid function at 6 and 30 weeks after treatment. In conclusion, PLP is a promising safe and effective procedure for treatment of benign thyroid nodules in patients at high surgical risk.
It was January 23, 1922, when the first successful subcutaneous injection of a pancreatic extract... more It was January 23, 1922, when the first successful subcutaneous injection of a pancreatic extract, prepared by Banting and purified by Collip, was administered to Leonard Thompson, a young boy in diabetic ketoacidosis, at the Toronto General Hospital. That day is the birth of insulin therapy which over the years has saved tens of millions of lives of people. Animal extracted insulin has been continuously purified until human insulin and the insulin analogs have been obtained with the rDNA technique to substitute insulin according to physiology. Today basal-bolus insulin therapy in type 1 diabetes, and basal insulin in type 2 (possibly in combination with GLP-1 RA) remain the consolidated gold standards of insulin therapy in diabetes.
Journal of Clinical Endocrinology & Metabolism, 1998
This study was designed to establish the lower dose of effective GH replacement therapy in severe... more This study was designed to establish the lower dose of effective GH replacement therapy in severe GH-deficient (GHD) adults. Whole body protein and lipid kinetics were determined in six GHD men in the basal state (B) and after 1 week of treatment with placebo (PL) or 3.3 (GH3.3) or 2 (GH2) micrograms/kg.day recombinant human GH (rhGH). The rates of whole body proteolysis, oxidation, and synthesis were estimated by infusing [1-13C]leucine (prime, 1 mg/kg; infusion rate, 1 mg/kg.h); those of lipolysis (measured in four of the six patients) were estimated by infusing [1,1,2,3,3-D5]glycerol (prime, 1.8 mumol/kg; infusion rate, 0.06 mumol/kg.min). Serum insulin-like growth factor I (IGF-I) concentrations (picograms per mL; mean +/- SE) similarly increased from the basal level (39 +/- 7) after 3.3 (108 +/- 18) or 2 (109 +/- 24) microgram/kg.day rhGH (P < 0.001 vs. basal), whereas they did not change with placebo (41 +/- 8). Leucine Ra was unaffected by the treatments. GH3.3 reduced by 30% the rate of leucine oxidation (P = 0.0069 vs. basal) and increased by 11% nonoxidative leucine disposal (P = 0.0095 vs. basal) and by 21% glycerol Ra (0.0035 vs. basal); GH2 and placebo had no significant effect. In conclusion, 1) at least 3.3 micrograms/ kg.day rhGH are required to increase whole body protein synthesis and lipolysis in male GHD adults; 2) 2 micrograms/kg.day rhGH normalize serum IGF-I concentrations, but do not modify protein and lipid metabolism; and 3) a normal serum IGF-I concentration does not guarantee that rhGH treatment is also effective on intermediate metabolism.
OBJECTIVEdTo assess the role of adiposity on the pharmacodynamics of basal insulins NPH, detemir,... more OBJECTIVEdTo 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 METHODSdWe 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).
At present, the duration of the effect of recombinant human growth hormone (rhGH) on the rates of... more At present, the duration of the effect of recombinant human growth hormone (rhGH) on the rates of protein synthesis and lipolysis in GH deficient (GHD) adults is unknown. This study was designed to establish the frequency of rhGH administration necessary to provide the beneficial metabolic effects of the hormone in GHD adults. Two different studies (A and B) were performed in two groups of five GHD men. In study A, whole body protein and lipid kinetics was determined in the basal state (Bas), 12 (GH12h) and 36 (GH36h) h after the last of seven injections of rhGH (3.3 microg/kg), given at bedtime on alternate days. In study B, the same parameters were determined in the basal state (Bas), 60 (GH60h) and 84 (GH84h) h after the last of seven injections of rhGH (3.3 microg/kg), given at bedtime at 3 day intervals. The rates of protein metabolism were estimated by infusing [1-13C]leucine, and those of lipolysis by infusing [1,1,2,3, 3-D5]glycerol. Leucine oxidation decreased (P < 0.01) by approximately 30% after GH12h and GH36h but did not change after GH60h and GH84h. Non-oxidative leucine disposal increased after GH12h and GH36h by approximately 13% (P < 0.05) whereas it did not change after GH60h and GH84h. Glycerol appearance increased (P < 0. 01) by approximately 45% after GH12h and GH36h but did not change after GH60h and GH84h. The effects on protein and lipid metabolism following the injection of rhGH last longer than 36 and less than 60 h. In fact, rhGH administration on alternate days induced a sustained increase in the rates of protein synthesis and lipolysis of GHD adults, whereas a longer interval of administration (3 days) had no effect by 60 h.
Aim: to compare head-to-head pharmacokinetics (PK), pharmacodynamics (PD), glucose fluxes and lip... more Aim: to compare head-to-head pharmacokinetics (PK), pharmacodynamics (PD), glucose fluxes and lipid metabolism of clinical doses of insulin glargine U300 (Gla-300) and degludec U100 (IDeg) in real life in T1DM. Methods: 22 subjects [(11M, age 44±12, T1DM for 26±12 years, BMI 22.5±3.2 kg/m2, A1C 7.1±0.6% (53.4±7.1 mmol/mol)] on Gla-100, naïve to Gla-300 and IDeg, were studied (24h euglycemic clamp) with individual doses of Gla-300 and IDeg (dosing at 20.0h) after 3 months of optimal titration of basal-bolus insulin (random crossover). Results (at present in 14 of the 22 subjects, PD only, data in progress): preclamp A1C was similar with Gla-300 vs. IDeg. Individual basal insulin dose was greater with Gla-300 vs. IDeg (0.35±0.09 vs. 0.27±0.06 U/kg, p<0.01). Average PG (0-24h) was euglycemic on both occasions (p=NS). Area under curve of glucose infused [AUC-GIR(0-24h)] was equivalent for the two insulins (ratio 1.03, 90% C.I. 0.9, 1.22) (Figure). Within-day PD variability tended to be lower with Gla-300 vs. IDegl (CV 51% vs. 59%, p<0.051). Conclusions. In T1DM, PD of clinical doses of Gla-300 are equivalent to IDeg with a trend for lower within-day variability. Disclosure P. Lucidi: Other Relationship; Self; Abbott, Novo Nordisk A/S. F. Porcellati: Board Member; Self; AstraZeneca, Eli Lilly and Company, Sanofi. Consultant; Self; Medtronic. P. Candeloro: None. P. Cioli: None. C. Pascucci: None. G.B. Bolli: Advisory Panel; Self; Sanofi. Research Support; Self; A. Menarini Diagnostics, Medtronic. C. Fanelli: Advisory Panel; Self; Sanofi. Other Relationship; Self; Menarini Group.
OBJECTIVE-Acute, short-term hyperglycemia enhances high shear stress-induced platelet activation ... more OBJECTIVE-Acute, short-term hyperglycemia enhances high shear stress-induced platelet activation in type 2 diabetes. Several observations suggest that platelets in type 2 diabetes are resistant to inhibition by aspirin. Our aim was to assess comparatively the effect of aspirin, a nitric oxide-donating agent (NCX 4016), their combination, or placebo on platelet activation induced by acute hyperglycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS-In a double-blind, placebo-controlled, randomized trial, 40 type 2 diabetic patients were allocated to 100 mg aspirin once daily, 800 mg NCX 4016 b.i.d., both of them, or placebo for 15 days. On day 15, 1 h after the morning dose, a 4-h hyperglycemic clamp (plasma glucose 13.9 mmol/l) was performed, and blood samples were collected before and immediately after it for platelet activation and cyclooxygenase-1 (COX-1) inhibition studies. RESULTS-Acute hyperglycemia enhanced shear stress-induced platelet activation in placebo-treated patients (basal closure time 63 Ϯ 7.1 s, after hyperglycemia 49.5 Ϯ 1.4 s, Ϫ13.5 Ϯ 6.3 s, P Ͻ 0.048). Pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (Ϫ12.7 Ϯ 6.9 s, NS vs. placebo). On the contrary, pretreatment with the NO donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016 ϩ10.5 Ϯ 8.3 s; NCX 4016 plus aspirin: ϩ12.0 Ϯ 10.7 s, P Ͻ 0.05 vs. placebo for both). Other parameters of shear stress-dependent platelet activation were also more inhibited by NCX 4016 than by aspirin, despite lesser inhibition of COX-1. CONCLUSIONS-Acute hyperglycemia-induced enhancement of platelet activation is resistant to aspirin; a NO-donating agent suppresses it. Therapeutic approaches aiming at a wider platelet inhibitory action than that exerted by aspirin may prove useful in patients with type 2 diabetes.
ore than 30 years ago in Diabetes Care, Schmidt et al. (1) defined "dawn phenomenon," the nightto... more ore than 30 years ago in Diabetes Care, Schmidt et al. (1) defined "dawn phenomenon," the nightto-morning elevation of blood glucose (BG) before and, to a larger extent, after breakfast in subjects with type 1 diabetes (T1D). Shortly after, a similar observation was made in type 2 diabetes (T2D) (2),
Supplementary Table 1-Indices of insulin secretion and insulin resistance in study 1 and study 2 ... more Supplementary Table 1-Indices of insulin secretion and insulin resistance in study 1 and study 2 (clamp) at baseline (T0h) and over last 30 minutes of clamp (T3h) AM and PM in non-diabetic subjects and people with T2DM calculated according to Gastaldelli A et al. (31)
The DCCT (Diabetes Control Complication Trials) has conclusively demonstrated in 1993 that good g... more The DCCT (Diabetes Control Complication Trials) has conclusively demonstrated in 1993 that good glycaemic control prevents the micro-angiopathy caused by chronic hyperglycaemia in T1DM. The subsequent follow-up study EDIC (Epidemiology of Diabetes Interventions and Complications) has demonstrated similar results for macro-angiopathy. Taken together, DCCT and EDIC strongly indicate the need for aggressive treatment of T1DM with intensive therapy to target near-normoglycaemia since clinical onset of T1DM to prevent long-term micro- and macro-vascular complications. Today and in the years to come, this message remains and will remain as fundamental as it was 30 years ago.
Journal of Endocrinological Investigation, Oct 1, 2006
This randomized controlled study was designed to test the efficacy and safety of percutaneous ult... more This randomized controlled study was designed to test the efficacy and safety of percutaneous ultrasound (US)-guided laser photocoagulation (PLP) for treatment of subjects with compressive symptoms due to benign thyroid nodules and/or at high surgical risk. Twenty six subjects were randomized to the intervention (no. 13, age 68+/-3 yr, mean+/-SEM) or observation (no. 13, age 71+/-2 yr) groups. In the control group, the volume of nodules did not significantly change over the 30 week period of observation. In the intervention group, median nodule volume at baseline was 8.2 ml (range 2.8-26.9) and was not significantly different from that of the control group. Nodules decreased significantly (p<0.0001) by 22% after 2 weeks (6.5 ml; range 2.4-16.7) and by 44% after 30 weeks (4.6 ml; range 0.69-14.2). Energy given was correlated (p<0.05) with the reduction of thyroid nodule volume. All patients tolerated the treatment well and reported relief from compressive and cosmetic complaints (p<0.05). At the time of enrolment 7/13 (54%) and 6/13 (46%) of patients in the intervention and control groups, respectively, had sub clinical hyperthyroidism. PLP normalized thyroid function at 6 and 30 weeks after treatment. In conclusion, PLP is a promising safe and effective procedure for treatment of benign thyroid nodules in patients at high surgical risk.
It was January 23, 1922, when the first successful subcutaneous injection of a pancreatic extract... more It was January 23, 1922, when the first successful subcutaneous injection of a pancreatic extract, prepared by Banting and purified by Collip, was administered to Leonard Thompson, a young boy in diabetic ketoacidosis, at the Toronto General Hospital. That day is the birth of insulin therapy which over the years has saved tens of millions of lives of people. Animal extracted insulin has been continuously purified until human insulin and the insulin analogs have been obtained with the rDNA technique to substitute insulin according to physiology. Today basal-bolus insulin therapy in type 1 diabetes, and basal insulin in type 2 (possibly in combination with GLP-1 RA) remain the consolidated gold standards of insulin therapy in diabetes.
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