Pierpaolo De Feo

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.

Comparison of Glucose Counterregulation During Short-Term and Prolonged Hypoglycemia in Normal Humans

To compare glucose counter regulatory mechanisms during short-term hypoglycemia and prolonged hypoglycemia, insulin was infused either intravenously (160 mil · M−2 · min) for 10 min or subcutaneously (15 mU · M−2 · min) for 12 h in normal volunteers. With each type of insulin infusion, hypoglycemia (∼50 mg/dl) was either allowed to develop or was prevented (control experiments) by the glucose-clamp technique. During prolonged hypoglycemia, both increased glucose production (1.55 ± 0.05 versus 0.33 ± 0.14 mg · kg−1 · min in control experiments at 12 h, P < 0.01) and suppressed glucose utilization (1.55 ± 0.06 versus 3.17 ± 0.15 mg · kg−1 · min in control studies at 12 h, P < 0.01) were involved in counterregulation. During short-term hypoglycemia, only increased glucose production (3.23 ± 0.33 versus 0.06 ± 0.03 mg · kg−1 · min in control experiments at 60 min) was involved, since glucose clearance actually increased (3.99 ± 0.20 versus 2.88 ± 0.02 ml · kg−1 · min in control experiments at 60 min, P < 0.01). Estimated portal venous insulin concentrations decreased 40% (basal 24 ± 3 versus 14 ± 1 mU/ml at 60 min, P < 0.01) in the short-term hypoglycemia experiments but remained at basal levels (basal 25 ± 1 versus ∼26 μU/min between 1 and 12 h) during prolonged hypoglycemia. Despite the fact that hypoglycemia was more gradually induced in the prolonged hypoglycemia model, peak counterregulatory hormone responses were at least as great as those during short-term hypoglycemia. Plasma free fatty acids and ketone bodies increased 150–200% above basal (both P < 0.01) with counterregulation during prolonged hypoglycemia but did not increase above basal levels with counterregulation during short-term hypoglycemia. Finally, plasma alanine remained unchanged during short-term hypoglycemia but decreased nearly 40% during prolonged hypoglycemia (basal 327 ± 20 versus 208 ± 21 μM at 12 h, P < 0.01). We conclude that glucose counterregulatory mechanisms differ during short-term and prolonged hypoglycemia. In the former, only an increase in glucose production mediated by suppression of insulin secretion and increased glucagon secretion is involved, whereas during prolonged hypoglycemia, both a suppression of glucose utilization, and an increase in glucose production are important. These latter changes in glucose production and utilization may be influenced by changes in circulating nonglucose substrates (e.g., alanine, free fatty acids, and ketone bodies) as well as by hormonal factors acting on both hepatic and extrahepatic tissues.

Nocturnal Blood Glucose Control in Type I Diabetes Mellitus

A major problem in replacing insulin in type I diabetes mellitus is that currently no depot preparation exists that is capable of mimicking the background insulin secretion of the healthy pancreas. Because all of the currently available intermediate- or long-acting insulin preparations have a peaked-action profile, excess insulin action at midnight and insulin waning at dawn occur whenever such an insulin preparation is given at supper time. If the target fasting plasma glucose is the ambitious near-normoglycemia of intensive insulin therapy, intermediate-acting insulin at suppertime easily results in hypoglycemia in the early evening hours and hyperglycemia in the fasting state. The problems of overnight glycemia in type I diabetes are further complicated by the dawn phenomenon and the Somogyi phenomenon. The dawn phenomenon is the combination of an initial decrease in insulin requirements between ∼2400 and ∼0300, followed by an increase in the insulin needs between ∼0500 and ∼0800. The dawn phenomenon is the result of changes in hepatic (and extrahepatic) insulin sensitivity, which are best attributed to nocturnal growth hormone secretion. The dawn phenomenon is a day-to-day reproducible event that occurs in nearly all diabetic patients. Its contribution to fasting hyperglycemia correlates with diabetes duration (inversely) and the HbAlc percentage (directly). Overall, it is estimated that the specific contribution of the dawn phenomenon to fasting hyperglycemia is ∼2 mM (∼35 mg/dl), but it may be much greater because of the waning of the depot-insulin preparation injected the previous evening. The Somogyi phenomenon, strictly speaking, refers to fasting hyperglycemia that occurs after inducement of nocturnal hypoglycemia by regular insulin. Because the present therapeutic regimens of NPH/Lente insulin given at suppertime cause overnight hyperinsulinemia, excessive fasting hyperglycemia rarely follows nocturnal hypoglycemia, except when excessive glucose is ingested to correct hypoglycemia. However, nocturnal hypoglycemia may easily deteriorate glycemic control later in the day, because it induces prolonged posthypoglycemic insulin resistance, which results in postbreakfast and late-morning hyperglycemia. With nocturnal insulin therapy, it is important to consider the problems of insulin pharmacokinetics, the dawn phenomenon, and the Somogyi phenomenon to prevent both nocturnal hypoglycemia and excessive fasting hyperglycemia. In programs of intensive insulin therapy aiming at a goal of near-normoglycemia in the fasting state, intermediate-acting insulin should be given at bedtime and should not be combined with regular insulin at suppertime. In programs of nonintensive insulin therapy, intermediateacting insulin can be injected with regular insulin at supper, but the fasting plasma glucose goal should be increased to 10–12 mM to prevent nocturnal hypoglycemia. In conclusion, insulin deficiency is the most important cause of fasting hyperglycemia in type I diabetes mellitus. However, insulin excess around midnight, which results from depot-insulin administration at suppertime, is the cause of frequent nocturnal hypoglycemia in type I diabetic patients. Correction of abnormal insulin pharmacokinetics by either splitting the evening insulin administration (intensive insulin therapy) or by increasing the targeted fasting plasma glucose (nonintensive insulin therapy) is the key to preventing nocturnal hypoglycemia and decreasing fasting hyperglycemia, thus improving overnight glycemic control in type I diabetes mellitus.

The importance of determining irreversibly glycosylated hemoglobin in diabetics.

The concentration of glycohemoglobins (HbA1(a+b+c), HbA1,) was measured before and after incubation of normal and diabetic erythrocytes for 6 h at 37°C in saline. This procedure removes as much as 80-90% of the labile glucose-HbA0 adduct (labile HbA1,), thus allowing accurate estimation of irreversibly glycosylated hemoglobin (stable HbA1,). The concentration of HbA1 measured before such an incubation is total HbA1, (stable + labile). We determined the concentration of total, stable, and labile HbA1, in the same blood samples used to measure fasting plasma glucose (FPG) every day, for 4 consecutive days, in two groups of hospitalized insulin-treated diabetics. Group A subjects (N = 7) were type I, C-peptide negative, unstable diabetics, while group B subjects (N = 15) were type II, C-peptide positive, stable diabetics. Individual day-to-day variations of total HbA1, were wide in group A (Δ = 1.58 ± 0.14%), and slight in group B (Δ = 0.12 ± 0.01%; P < 0.001), paralleling similar plasma glucose fluctuations. Day-to-day variations of stable HbA1, were virtually absent not only in group B subjects with stable glycemic values (Δ = 0.08 ± 0.01%), but also in those of group A with marked glycemic instability (Δ = 0.07 ± 0.01%; P = NS). Day-to-day variations of labile HbA1, were marked in group A (Δ = 1.31 ± 0.14%), but negligible in group B (Δ = 0.15 ± 0.03%; P < 0.001). On admission, FPG correlated with labile HbA1, in group A (r = 0.89) and B (r = 0.71). FPG correlated with stable HbA1, in group B (r = 0.73) but not in group A subjects and with total HbA1, more closely in group B (r = 0.73) than in A (r = 0.61). A very close correlation was found between the concentration of total and labile HbA1 in subjects of group B (r = 0.82). In group B, fasting, post-breakfast, and mean daily plasma glucose values, determined every 3-6 days during the 2 mo before admission, significantly correlated both with total and stable HbA1 determined on admission, while in group A they did not. In group A, the correlation was significant when stable instead of total HbA1 was considered. We conclude that the significant fluctuations of total HbA1 reduce its value as an index of long-term control in unstable diabetics. On the other hand, a single determination of stable HbA1, totally independent of simultaneous blood glucose values, closely reflects blood glucose control over the previous 2 mo. We propose routine estimation of stable HbA1, which is simple and straightforward, to carry out follow-up studies of unstable diabetics.

Important Role of Adrenergic Mechanisms in Acute Glucose Counterregulation Following Insulin-induced Hypoglycemia in Type I Diabetes: Evidence for an Effect Mediated by Beta-Adrenoreceptors

During hypoglycemia induced by an i.v. insulin infusion for 60 min, rates of plasma glucose (PG) decrease and recovery, PG nadir, and plasma counter-regulatory hormone and free fatty acid responses were studied in eight type I uncomplicated diabetic subjects and eight nondiabetic subjects. Each subject was tested three times at two different rates of insulin infusion (25 and 32 mU/m2/min): (1) during infusion of saline, (2) during infusion of phentolamine + propranolol (combined alpha, beta-blockade), and (3) during infusion of propranolol alone (isolated beta-blockade) for 150 min. At the time of the studies, the diabetic subjects had been made euglycemic by an overnight i.v. insulin infusion. During infusion of insulin (25 mU/m2/min) and saline, the rates of PG decrease and recovery were slower (P < 0.01) and PG nadir was delayed in the diabetic subjects. Moreover, their plasma glucagon response was blunted while plasma epinephrine, norepinephrine, growth hormone, and cortisol responses were similar in both groups. Infusion of insulin at 32 mU/m2/min caused larger decreases in PG than had been observed when insulin was infused at 25 mU/m2/min. Plasma glucagon responses increased in the nondiabetic subjects (P < 0.05) but not in the diabetic subjects. However, in the diabetic subjects, plasma epinephrine increased more than in the nondiabetic subjects (P < 0.05). There was an inverse correlation between the individual plasma epinephrine responses and the plasma glucagon responses in the diabetic subjects (r = −0.72) but not in the nondiabetic subjects. Alpha, beta-adrenergic blockade decreased the plasma glucose nadir and impaired the rate at which normoglycemia was restored in the diabetic subjects (P < 0.005 vs. saline) but not in the nondiabetic subjects. Plasma catecholamine and growth hormone responses were increased and plasma FFA recovery was suppressed in both groups (P < 0.05 vs. saline), while the cortisol responses were unaltered. During isolated beta-adrenergic blockade, changes in plasma glucose, counterregulatory hormones and FFA were essentially identical to those observed during combined alpha, beta-adrenergic blockade in both groups except that the augmented plasma norepinephrine responses were no longer apparent. Conclusions although epinephrine is not essential for prompt restoration of normoglycemia in normal man following insulin-induced hypoglycemia, it plays a major role in glucose counterregulation in diabetics who have an impaired glucagon secretion in response to hypoglycemia. These counterregulatory effects of epinephrine are mediated by beta-adrenoreceptors.

Administration of recombinant human growth hormone on alternate days is sufficient to increase whole body protein synthesis and lipolysis in growth hormone deficient adults

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.

Ultrasound-guided interstitial laser ablation for thyroid nodules is effective only at high total amounts of energy: results from a three-year pilot study.

Objective. According to cross-sectional surveys, the prevalence of nontoxic nodular goiter appears to be higher in the adult population. Surgical intervention is indicated for the following: (a) progressive goiter growth, (b) compression of organs such as the trachea and esophagus, and (c) significant aesthetic disfigurement. Ultrasound-guided laser photocoagulation for the treatment of benign thyroid nodules is a viable alternative to traditional surgery. However, studies that have appeared in literature since the introduction of ultrasound-guided laser photocoagulation for the treatment of benign thyroid nodules report contradictory data concerning the energy required for nodule ablation. The aim of the present trial was to evaluate retrospectively the efficacy of percutaneous laser thermal ablation in 2 groups of patients, one treated with low, and the other with high, total amount of energy. Design. Forty euthyroid patients were treated with 1 session of percutaneous laser photocoagulation treatment at low (median = 71 J/mL; 20 patients) and high (median = 578 J/mL; 20 patients) energy. The volume of the nodules was measured by the same investigator, blinded for treatment, using the ellipsoid formula before treatment, at 2, 4, 8, and 30 weeks, and every 6 months for 3 years thereafter. Results. Thyroid nodule ablation is effective over time only if a sufficient amount of energy (>400-500 J/mL for the nodular tissue to be treated) is given, although it incurs proportionate side effects. Conclusions. Percutaneous laser thermal ablation is a viable alternative to traditional surgery for the treatment of benign nodular thyroid disease only if a sufficient amount of energy is delivered.

A comparison of laser with radiofrequency ablation for the treatment of benign thyroid nodules: a propensity score matching analysis

Abstract Purpose: To compare technique efficacy and safety of laser ablation (LA) and radiofrequency ablation (RFA) in treatment of benign thyroid nodules. Materials and methods: Institutional review board approval was obtained, and patients’ consent was waived. 601 nodules were treated from May 2009 to December 2014 at eight centres, 449 (309 females, age 57 ± 14 years) with LA and 152 (107 females, age 57 ± 14 years) with RFA. A matched cohort composed of 138 patients from each group was selected after adjustment with propensity score matching. Factors influencing volume reduction at 6 and 12 months and complications were evaluated. Results: No significant differences were observed in the baseline characteristics between groups after propensity score matching adjustment. Mean nodule reduction at 6 and 12 months was −67 ± 19% vs. −57 ± 21% (p < 0.001) − 70 ± 19% vs. −62 ± 22% (p = 0.001) in LA group and in RFA group, respectively. Nodules with volume >30 mL had significantly higher percentage volume reduction at 6 and 12 months (−69 ± 19 vs. −50 ± 21, p = 0.001) and (−73 ± 18 vs. −54 ± 23 8, p = 0.001) in the LA group than in the RFA group, respectively. In both groups, operator’s skills affected the results. Major complications occurred in 4 cases in each group (p = 0.116) Conclusions: LA and RFA showed nearly similar outcome but LA was slightly more effective than RFA in large nodules. Operator’s skills could be crucial in determining the extent of nodule volume reduction regardless of the used technique.

Is physical exercise a core therapeutical element for most patients with type 2 diabetes

Over the last decade, growing scientific evidence has demonstrated that exercise is an effective therapeutic strategy for type 2 diabetes (1–12). According to position statements published by the American Diabetes Association, American College of Sports Medicine, and American Heart Association, exercise therapy should be part of a structured lifestyle intervention and include both aerobic and resistance training (13,14). Physical activity is defined as any bodily movement produced by skeletal muscles that results in energy expenditure beyond resting expenditure. Exercise is a subset of physical activity that is planned, structured, repetitive, and purposeful in the sense that improvement or maintenance of physical fitness is the objective. As with pharmacological therapy, for aerobic or resistance exercise therapy it is necessary to prescribe the right dose (intensity, volume, and frequency) and to carefully consider the potential side effects and contraindications. The aim of this review is to discuss a correct approach to exercise therapy and to underline the beneficial effects, precautions, and limitations of the use of exercise in type 2 diabetic subjects. Another crucial point that merits discussion is the profound gap between the exercise therapy suggested by scientific guidelines and the applicability of it in the management of type 2 diabetes. Full compliance with an exercise regimen requires high motivation and capability, both in the diabetes team operators/facilitators and in their patients, and is based on a strong therapeutic alliance. There are several obstacles in this virtuous process: lack of time and lack of confidence in the behavioral and motivation strategies of physicians and other diabetic team operators, unhealthy lifestyles of physicians who should advise exercise, and reluctance of sedentary diabetic patients to change their lifestyle, mainly due to poor self-efficacy or lack of time (15). The “no” side of this debate will discuss the evidence …