Paola Lucidi

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes A double-blind, randomized, crossover study

OBJECTIVE—To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 ± 10 years, BMI 22.4 ± 1.6 kg/m2, and A1C 7.2 ± 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study). RESEARCH DESIGN AND METHODS—Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was >150 mg/dl). RESULTS—With glargine, plasma glucose remained at 103 ± 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose <180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P < 0.001). Estimated total insulin activity (GIR area under the curve [AUC]0–end of GIR) was 1,412 ± 662 and 915 ± 225 mg/kg (glargine vs. detemir, P < 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P < 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids0–24 h 11 ± 1.7 vs. 8 ± 2.8 mmol/l, respectively, P < 0.001). CONCLUSIONS—Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12–24 h.

Contribution of Amino Acids and Insulin to Protein Anabolism During Meal Absorption

The contribution of dietary amino acids and endogenous hyperinsulinemia to prandial protein anabolism still has not been established. To this end, leucine estimates ([1- 14C]leucine infusion, plasma α-ketoisocaproic acid [KIC] specific activity [SA] as precursor pool SA) of whole-body protein kinetics and fractional secretory rates (FSRs) of albumin, fibrinogen, antithrombin III, and immunoglobulin G (IgG) were measured in three groups of healthy volunteers during intragastric infusion of water (controls, n = 5), liquid glucose–lipid–amino acid (AA) meal (meal+AA, n = 7), or isocaloric glucose–lipid meal (meal-AA, n = 7) that induced the same insulin response as the meal+AA. The results of this study demonstrate that 1) by increasing (P < 0.01) whole-body protein synthesis and decreasing (P < 0.01) proteolysis, dietary amino acids account for the largest part (∼90%) of postprandial protein anabolism; 2) the ingestion of an isocaloric meal deprived of amino acids exerts a modest protein anabolic effect (10% of postprandial protein anabolism) by decreasing amino acid oxidation and increasing (P < 0.01) albumin synthesis; 3) albumin FSR is increased (∼20%) by postprandial hyperinsulinemia (meal–AA) and additionally increased (∼50%) by amino acid intake (meal+AA); 4) IgG FSR is stimulated (∼40%) by amino acids, not by insulin; and 5) fibrinogen and antithrombin III FSR are not regulated by amino acids or insulin.

Physiological Increments in Plasma Insulin Concentrations Have Selective and Different Effects on Synthesis of Hepatic Proteins in Normal Humans

These studies tested the hypothesis that physiological increments in plasma insulin concentrations have selective effects on the synthesis of hepatic proteins in humans. Leucine kinetics and fractional synthetic rates of albumin, fibrinogen, antithrombin III, and apoB-100 were determined in 6 normal subjects, on two different occasions during either the infusion of saline (control study) or a euglycemic-hyperinsulinemic (0.4 mU.kg−1 · min−1 for 240 min) clamp, by a primed-constant infusion of [1-14C]Leu. The insulin infusion significantly decreased the rates of nonoxidative Leu disposal (1.70 ± 0.10 vs. control 2.06 ± 0.09 mol.kg−1 · min−1), increased the albumin (7.2 ± 0.4 vs. 6.2 ± 0.6%/day), decreased the fibrinogen (18 ± 1 vs. 23 ± 2%/day), and antithrombin III (28 ± 3 vs. 40 ± 4%/day) fractional synthetic rate, whereas it did not affect the total apoB-100 (49 ± 5 vs. 52 ± 6%/day) fractional synthetic rate. Thus, the insulin-induced decrement in the estimates of whole-body protein synthesis (nonoxidative Leu disposal) represents the mean result of opposite effects of hyperinsulinemia on the synthesis of proteins with different functions. The positive effect of insulin on albumin synthesis may play an important anabolic role during nutrient absorption by promoting the capture of a relevant amount of dietary essential amino acids into the protein, whereas the negative effect of insulin on fibrinogen synthesis might, at least partially, account for the increased plasma fibrinogen concentrations previously reported in poorly controlled diabetic patients.

Effects of whole-body vibration exercise on the endocrine system of healthy men.

Whole-body vibration is reported to increase muscle performance, bone mineral density and stimulate the secretion of lipolytic and protein anabolic hormones, such as GH and testosterone, that might be used for the treatment of obesity. To date, as no controlled trial has examined the effects of vibration exercise on the human endocrine system, we performed a randomized controlled study, to establish whether the circulating concentrations of glucose and hormones (insulin, glucagon, cortisol, epinephrine, norepinephrine, GH, IGF-1, free and total testosterone) are affected by vibration in 10 healthy men [age 39±3, body mass index (BMI) of 23.5±0.5 kg/m2, mean±SEM]. Volunteers were studied on two occasions before and after standing for 25 min on a ground plate in the absence (control) or in the presence (vibration) of 30 Hz whole body vibration. Vibration slightly reduced plasma glucose (30 min: vibration 4.59±0.21, control 4.74±0.22 mM, p=0.049) and increased plasma norepinephrine concentrations (60 min: vibration 1.29±0.18, control 1.01±0.07 nM, p=0.038), but did not change the circulating concentrations of other hormones. These results demonstrate that vibration exercise transiently reduces plasma glucose, possibly by increasing glucose utilization by contracting muscles. Since hormonal responses, with the exception of norepinephrine, are not affected by acute vibration exposure, this type of exercise is not expected to reduce fat mass in obese subjects.

Metabolic response to exercise

At the beginning, the survival of humans was strictly related to their physical capacity. There was the need to resist predators and to provide food and water for life. Achieving these goals required a prompt and efficient energy system capable of sustaining either high intensity or maintaining prolonged physical activity. Energy for skeletal muscle contraction is supplied by anaerobic and aerobic metabolic pathways. The former can allow short bursts of intense physical activity (60-90 sec) and utilizes as energetic source the phosphocreatine shuttle and anaerobic glycolysis. The aerobic system is the most efficient ATP source for skeletal muscle. The oxidative phosporylation of carbohydrates, fats and, to a minor extent, proteins, can sustain physical activity for many hours. Carbohydrates are the most efficient fuel for working muscle and their contribution to total fuel oxidation is positively related to the intensity of exercise. The first metabolic pathways of carbohydrate metabolism to be involved are skeletal muscle glycogenolysis and glycolysis. Later circulating glucose, formed through activated gluconeogenesis, becomes an important energetic source. Among glucose metabolites, lactate plays a primary role as either direct or indirect (gluconeogenesis) energy source for contracting skeletal muscle. Fat oxidation plays a primary role during either low-moderate intensity exercise or protracted physical activity (over 90-120 min). Severe muscle glycogen depletion results in increased rates of muscle proteolysis and branched chain amino acid oxidation. Endurance training ameliorates physical performance by improving cardiopulmonary efficiency and optimizing skeletal muscle supply and oxidation of substrates. 2003, Editrice Kurtis

A randomized controlled trial to evaluate the efficacy of ultrasound-guided laser photocoagulation for treatment of benign thyroid nodules

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 (6.5ml; 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.

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 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.

Meal intake similarly reduces circulating concentrations of octanoyl and total ghrelin in humans

Several data show that meal intake and nutritional status regulate circulating ghrelin concentrations in humans. Ghrelin mainly circulates in two different forms: octanoyl and des-octanoyl ghrelin. Most circulating ghrelin is des-octanoyl ghrelin which is considered inactive because it lacks endocrine activity. However, recent evidence suggests that des-octanoyl ghrelin exerts biological activity such as stimulation of adipogenesis, cardiovascular effects and control of cell growth. In healthy humans, although the total ghrelin concentration is known to peak before meals and to be reduced by food intake, no data are available about the octanoyl ghrelin response in the absorptive state. Therefore, after an overnight fast, we compared the effects of a mixed meal ingestion (meal study) or of additional 240 min fasting (control study) on plasma concentrations of octanoyl and total ghrelin in 6 healthy subjects (body mass index: 23±0.7). At baseline, octanoyl-ghrelin accounted for 3.15±0.2% of total circulating ghrelin without differences between the two sessions. A similar ratio was maintained in the absorptive state with no differences between the studies and basal values. Compared with control, meal intake significantly suppressed (nadir at 90 min) octanoyl and total ghrelin by 38±3 and 40±3% of basal values, respectively. In the meal study, multivariate analysis of variance showed that serum insulin best predicted plasma octanoyl-ghrelin concentrations accounting for 97% of its variation (r2=−0.97, p=0.0016). In conclusion: in healthy humans, octanoyl-ghrelin represents about 3–4% of total circula-ting ghrelin and this ratio is closely maintained in post-absorptive and absorptive states.

Thirty Years of Research on the Dawn Phenomenon: Lessons to Optimize Blood Glucose Control in Diabetes

More than 30 years ago in Diabetes Care , Schmidt et al. (1) defined “dawn phenomenon,” the night-to-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), and the physiology of glucose homeostasis at night was studied in normal, nondiabetic subjects (3–5). Ever since the first description, the dawn phenomenon has been studied extensively with at least 187 articles published as of today (6). In this issue, Monnier et al. (7) report an additional observation on the dawn phenomenon in a large group of T2D subjects and quantify its role on overall BG control. Given this information and the extensive data to date, an assessment of our knowledge in this area should be determined. Specifically, what have we learned from the last 30 years of research on the dawn phenomenon? What is the appropriate definition, the identified mechanism(s), the importance (if any), and the treatment of the dawn phenomenon in T1D and T2D? Physiology of glucose homeostasis in normal, nondiabetic subjects indicates that BG and plasma insulin concentrations remain remarkably flat and constant overnight, with a modest, transient increase in insulin secretion just before dawn (3,4) to restrain hepatic glucose production (4) and prevent hyperglycemia. Thus, normal subjects do not exhibit the dawn phenomenon sensu strictiori because they secrete insulin to prevent it. In T1D, the magnitude of BG elevation at dawn first reported was impressive and largely secondary to the decrease of plasma insulin concentration overnight (1), commonly observed with evening administration of NPH or lente insulins (8) (Fig. 1). Even in early studies with intravenous insulin by the “artificial pancreas” (Biostator) (2), plasma insulin decreased overnight because of progressive inactivation …

Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis.

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%.