Gynecomastia and drugs: a critical evaluation of the literature.

PURPOSE: A large number of medications have been implicated in the genesis of gynecomastia. However, gynecomastia is common in men, asymptomatic, increases with age, and is considered to be due to an increased estradiol/testosterone ratio. This complicates the interpretation of medication-related gynecomastia. Therefore, we have reviewed the literature in order to assess the data relating gynecomastia onset with utilization of specific medications. METHODS: The literature was searched in PubMed and the Ovid/Medline databases from the 1946 to January 2015 with the search terminology of "gynecomastia, drugs/medications." A few other articles were found and included. RESULTS: One hundred ten publications were reviewed. Sixty-three were single case reports. There were 24 population-based studies of which 8 were HIV-infected patients treated with antiretroviral agents. Among the case reports, 49 were for individual medications, and 2 were reports of antineoplastic or antiretroviral drug regimens. In the great majority, mastodynia with or without breast enlargement was present and referred to as gynecomastia. Generally, hormonal profiles could not explain the breast enlargement. The pain/tenderness and breast enlargement resolved spontaneously over time. CONCLUSION: Many different medications have been associated with the presence of "gynecomastia." Generally, it presents as a syndrome characterized by a single painful/tender breast (mastodynia) associated with breast enlargement and is transient. We suggest that these cases be referred to as an acute gynecomastia syndrome. This syndrome also occurs independent of medication use. Thus, in an individual patient, whether it is medication induced often remains uncertain. The pathogenesis remains unknown.

A Glucose-Only Model to Extract Physiological Information from Postprandial Glucose Profiles in Subjects with Normal Glucose Tolerance.

BACKGROUND: Current mathematical models of postprandial glucose metabolism in people with normal and impaired glucose tolerance rely on insulin measurements and are therefore not applicable in clinical practice. This research aims to develop a model that only requires glucose data for parameter estimation while also providing useful information on insulin sensitivity, insulin dynamics and the meal-related glucose appearance (GA). METHODS: The proposed glucose-only model (GOM) is based on the oral minimal model (OMM) of glucose dynamics and substitutes the insulin dynamics with a novel function dependant on glucose levels and GA. A Bayesian method and glucose data from 22 subjects with normal glucose tolerance are utilised for parameter estimation. To validate the results of the GOM, a comparison to the results of the OMM, obtained by using glucose and insulin data from the same subjects is carried out. RESULTS: The proposed GOM describes the glucose dynamics with comparable precision to the OMM with an RMSE of 5.1 ± 2.3 mg/dL and 5.3 ± 2.4 mg/dL, respectively and contains a parameter that is significantly correlated to the insulin sensitivity estimated by the OMM (r = 0.7) Furthermore, the dynamic properties of the time profiles of GA and insulin dynamics inferred by the GOM show high similarity to the corresponding results of the OMM. CONCLUSIONS: The proposed GOM can be used to extract useful physiological information on glucose metabolism in subjects with normal glucose tolerance. The model can be further developed for clinical applications to patients with impaired glucose tolerance under the use of continuous glucose monitoring data.

Bayesian parameter estimation in the oral minimal model of glucose dynamics from non-fasting conditions using a new function of glucose appearance.

BACKGROUND AND OBJECTIVE: The oral minimal model (OMM) of glucose dynamics is a prominent method for assessing postprandial glucose metabolism. The model yields estimates of insulin sensitivity and the meal-related appearance of glucose from insulin and glucose data after an oral glucose challenge. Despite its success, the OMM approach has several weaknesses that this paper addresses. METHODS: A novel procedure introducing three methodological adaptations to the OMM approach is proposed. These are: (1) the use of a fully Bayesian and efficient method for parameter estimation, (2) the model identification from non-fasting conditions using a generalised model formulation and (3) the introduction of a novel function to represent the meal-related glucose appearance based on two superimposed components utilising a modified structure of the log-normal distribution. The proposed modelling procedure is applied to glucose and insulin data from subjects with normal glucose tolerance consuming three consecutive meals in intervals of four hours. RESULTS: It is shown that the glucose effectiveness parameter of the OMM is, contrary to previous results, structurally globally identifiable. In comparison to results from existing studies that use the conventional identification procedure, the proposed approach yields an equivalent level of model fit and a similar precision of insulin sensitivity estimates. Furthermore, the new procedure shows no deterioration of model fit when data from non-fasting conditions are used. In comparison to the conventional, piecewise linear function of glucose appearance, the novel log-normally based function provides an improved model fit in the first 30 min of the response and thus a more realistic estimation of glucose appearance during this period. The identification procedure is implemented in freely accesible MATLAB and Python software packages. CONCLUSIONS: We propose an improved and freely available method for the identification of the OMM which could become the future standardard for the oral minimal modelling method of glucose dynamics.

Amino acid ingestion and glucose metabolism--a review.

Interest in the effect of proteins or amino acids on glucose metabolism dates back at least a century, largely because it was demonstrated that the amino acids from ingested protein could be converted into glucose. Indeed, these observations influenced the dietary information provided to people with diabetes. Subsequently it was shown that ingested protein did not raise the blood glucose concentration. It also was shown that proteins could stimulate a rise in insulin and glucagon but the response to various proteins was different. In addition, it was shown that individual amino acids also could stimulate a rise in insulin and in glucagon concentrations. When individual amino acids are ingested by normal subjects, there is an ordering of the insulin and glucagon responses. However, the order is not the same for insulin and glucagon. In addition, the metabolic response cannot be predicted based on the functional groups of the amino acids. Thus, empirical prediction of the metabolic response to ingested single amino acids is not possible.

Circulating lipids in men with type 2 diabetes following 3 days on a carbohydrate-free diet versus 3 days of fasting.

OBJECTIVE: We have been interested in determining the effects of dietary changes on fuel metabolism and regulation in men with type 2 diabetes mellitus (T2DM). In this study, the changes in 24-hr circulating lipid profiles were determined when the major fuel source was endogenous versus exogenous fat. METHODS: Seven males with T2DM were randomized in a crossover design with a 4-week washout period. A standard mixed (control) diet (30%fat:15%protein:55%carbohydrate) was provided initially. Subsequently, a 72-hr (3-day) fast, or a high fat (85%), 15% protein, essentially carbohydrate-free (CHO-free) diet was provided for 72 hr. Triacylglycerol (TAG), non-esterified fatty acids (NEFA), ß-hydroxybutyrate (bHB), and insulin-like growth factor-binding protein-1 (IGFBP-1) profiles were determined during the last 24 hr of intervention, as well as during the control diet. RESULTS: Regardless of the amount of dietary fat (30% vs 85%) and differences in 24-hr profiles, TAG, NEFA, and bHB all returned to the previous basal concentrations within 24 hr. TAGs and NEFAs changed only modestly with fasting; bHB was elevated and increasing. The IGFBP-1 profile was essentially unchanged with either diet but increased with fasting. CONCLUSION: A CHO-free diet resulted in a large increase in TAG and NEFA versus the control diet; however, both were cleared by the following morning. A negative NEFA profile occurred with the control diet. Thus, mechanisms are present to restore lipid concentrations to their original AM concentrations daily. Fasting resulted in stable concentrations, except for a continuing increase in bHB. Glucose and insulin, common fuel regulators, could not explain the results.

The degree of saturation of fatty acids in dietary fats does not affect the metabolic response to ingested carbohydrate.

BACKGROUND: We are interested in the metabolic response to ingested macronutrients, and the interaction between macronutrients in meals. Previously, we and others reported that the postprandial rise in serum glucose following ingestion of 50 g carbohydrate, consumed as potato, was markedly attenuated when butter was ingested with the carbohydrate, whereas the serum insulin response was little affected by the combination. OBJECTIVE: To determine whether a similar response would be observed with three other dietary fats considerably different in fatty acid composition. DESIGN: Nine healthy subjects received lard, twelve received olive oil and eleven received safflower oil as a test meal. The subjects ingested meals of 25 g fat (lard, olive oil or safflower oil), 50 g CHO (potato), 25 g fat with 50 g CHO or water only. Glucose, C peptide, insulin, triacylglycerols and nonesterified fatty acids were determined. RESULTS: Ingestion of lard, olive oil or safflower oil with potato did not affect the quantitative glucose and insulin responses to potato alone. However, the responses were delayed, diminished and prolonged. All three fats when ingested alone modestly increased the insulin concentration when compared to ingestion of water alone. When either lard, olive oil or safflower oil was ingested with the potato, there was an accelerated rise in triacylglycerols. This was most dramatic with safflower oil. CONCLUSIONS: Our data indicate that the glucose and insulin response to butter is unique when compared with the three other fat sources varying in their fatty acid composition.

Stability of body weight in type 2 diabetes.

OBJECTIVE: There is a concern that an "epidemic of obesity" is occurring in Western societies. One consequence of obesity is that type 2 diabetes may develop. Presumably, a great increase in body weight would continue in people with diabetes and may be accelerated due to pharmacological treatment. In this retrospective study, we tested the hypothesis that the weight gain in a diabetic population is greater than that in the general population. RESEARCH DESIGN AND METHODS: Data were obtained from the records of 205 adult men who have attended a diabetes clinic for > or =5 years. Their weight and glycohemoglobin at the last visit were compared with the initial visit data. The subjects were categorized according to treatment modalities. The mean follow-up was 9.4 years (range 5-23). RESULTS: For the group as a whole, the mean increase in body weight was 0.23 +/- 0.2 kg/year. BMI or initial age had little effect on the rate of weight gain. Treatment regimen used did have an effect on weight change. In subjects treated with insulin, with or without oral agents, body weight increased at a rate of 0.44 +/- 0.1 kg/year. In subjects treated with metformin or metformin and a sulfonylurea, there was a mean loss in weight, i.e., -0.24 +/- 0.09 kg/year, and with sulfonylureas alone weight increased by 0.42 +/- 0.2 kg/year. CONCLUSIONS: The men treated with insulin alone or insulin combined with oral agents gained weight at a rate comparable with that reported for the general population, i.e., the weight gain was not extraordinary. Metformin treatment resulted in a modest loss of weight.

The metabolic response to a high-protein, low-carbohydrate diet in men with type 2 diabetes mellitus.

We recently reported that in subjects with untreated type 2 diabetes mellitus, a 5-week diet of 20:30:50 carbohydrate-protein-fat ratio resulted in a dramatic decrease in 24-hour integrated glucose and total glycohemoglobin compared with a control diet of 55:15:30. Body weight, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and serum ketones were unchanged; insulin and nonesterified fatty acids were decreased. We now present data on other hormones and metabolites considered to be affected by dietary macronutrient changes. The test diet resulted in an elevated fasting plasma total insulin-like growth factor 1, but not growth hormone. Urinary aldosterone was unchanged; free cortisol was increased, although not statistically. Urinary pH and calcium were unchanged. Blood pressure, creatinine clearance, serum vitamin B12, folate, homocysteine, thyroid hormones, and uric acid were unchanged. Serum creatinine was modestly increased. Plasma alpha-amino nitrogen and urea nitrogen were increased. Urea production rate was increased such that a new steady state was present. The calculated urea production rate accounted for 87% of protein ingested on the control diet, but only 67% on the test diet, suggesting net nitrogen retention on the latter. The lack of negative effects, improved glucose control, and a positive nitrogen balance suggest beneficial effects for subjects with type 2 diabetes mellitus at risk for loss of lean body mass.

Effect of a high-protein, low-carbohydrate diet on blood glucose control in people with type 2 diabetes.

There has been interest in the effect of various types and amounts of dietary carbohydrates and proteins on blood glucose. On the basis of our previous data, we designed a high-protein/low-carbohydrate, weight-maintaining, nonketogenic diet. Its effect on glucose control in people with untreated type 2 diabetes was determined. We refer to this as a low-biologically-available-glucose (LoBAG) diet. Eight men were studied using a randomized 5-week crossover design with a 5-week washout period. The carbohydrate:protein:fat ratio of the control diet was 55:15:30. The test diet ratio was 20:30:50. Plasma and urinary beta-hydroxybutyrate were similar on both diets. The mean 24-h integrated serum glucose at the end of the control and LoBAG diets was 198 and 126 mg/dl, respectively. The percentage of glycohemoglobin was 9.8 +/- 0.5 and 7.6 +/- 0.3, respectively. It was still decreasing at the end of the LoBAG diet. Thus, the final calculated glycohemoglobin was estimated to be approximately 6.3-5.4%. Serum insulin was decreased, and plasma glucagon was increased. Serum cholesterol was unchanged. Thus, a LoBAG diet ingested for 5 weeks dramatically reduced the circulating glucose concentration in people with untreated type 2 diabetes. Potentially, this could be a patient-empowering way to ameliorate hyperglycemia without pharmacological intervention. The long-term effects of such a diet remain to be determined.

Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes.

OBJECTIVE: Hyperglycemia improves when patients with type 2 diabetes are placed on a weight-loss diet. Improvement typically occurs soon after diet implementation. This rapid response could result from low fuel supply (calories), lower carbohydrate content of the weight-loss diet, and/or weight loss per se. To differentiate these effects, glucose, insulin, C-peptide and glucagon were determined during the last 24 h of a 3-day period without food (severe calorie restriction) and a calorie-sufficient, carbohydrate-free diet. RESEARCH DESIGN: Seven subjects with untreated type 2 diabetes were studied. A randomized-crossover design with a 4-week washout period between arms was used. METHODS: Results from both the calorie-sufficient, carbohydrate-free diet and the 3-day fast were compared with the initial standard diet consisting of 55% carbohydrate, 15% protein and 30% fat. RESULTS: The overnight fasting glucose concentration decreased from 196 (standard diet) to 160 (carbohydrate-free diet) to 127 mg/dl (fasting). The 24 h glucose and insulin area responses decreased by 35% and 48% on day 3 of the carbohydrate-free diet, and by 49% and 69% after fasting. Overnight basal insulin and glucagon remained unchanged. CONCLUSIONS: Short-term fasting dramatically lowered overnight fasting and 24 h integrated glucose concentrations. Carbohydrate restriction per se could account for 71% of the reduction. Insulin could not entirely explain the glucose responses. In the absence of carbohydrate, the net insulin response was 28% of the standard diet. Glucagon did not contribute to the metabolic adaptations observed.

The metabolic response of subjects with type 2 diabetes to a high-protein, weight-maintenance diet.

In a randomized, crossover 5-wk study design, we recently reported that a weight-maintaining diet in which the percentage of total food energy as protein was increased from 15-30% resulted in a decrease in postprandial glucose and glycohemoglobin in people with untreated type 2 diabetes without a significant change in insulin. Protein was substituted for carbohydrate in the diet. The fat content remained unchanged. In this publication, we present data on other hormones and metabolites that were considered to potentially be affected by substitution of protein for carbohydrate in the diet. The mean fasting plasma GH and total IGF-I concentrations were elevated on the 30% protein diet. The urinary free cortisol also was increased. However, the urinary aldosterone was unchanged. Although urinary pH was decreased, calcium excretion was not significantly increased. The plasma postprandial alpha-amino nitrogen concentrations were increased, but the 24-h integrated concentration was unchanged, indicating an accelerated amino acid removal rate. The plasma urea nitrogen was increased as expected. The urea production rate also was increased such that a new steady-state fasting value was present. The calculated urea production rate accounted for 97% of the protein ingested on the 15% protein diet, but only 80% on the 30% protein diet, suggesting net nitrogen retention on the high-protein diet. In conclusion, an increase in dietary protein results in a number of metabolic adaptations in addition to reducing the circulating glucose concentration. Serum TSH, total T(3), free T(4), B(12), folate, homocysteine, uric acid, and creatinine concentrations were unchanged.

The metabolic response to ingested glycine.

BACKGROUND: The metabolic effects of dietary protein are complex. In persons with type 2 diabetes, protein ingestion results in little or no increase in plasma glucose concentrations but a stimulation of insulin and glucagon secretion. Furthermore, when protein is ingested with glucose, a synergistic effect on insulin secretion is observed. The most potent protein is gelatin, which consists of 30% glycine residues. OBJECTIVE: The objective of the present study was to determine whether glycine per se stimulates insulin secretion or reduces the glucose response when ingested with glucose. DESIGN: Nine healthy subjects were tested on 4 separate occasions. Plasma glucose, insulin, glucagon, and glycine concentrations were measured at various times during a 2-h period after the ingestion of 1 mmol glycine/kg lean body mass, 25 g glucose, 1 mmol glycine/kg lean body mass + 25 g glucose, or water only, given in random order. RESULTS: Plasma concentrations of glycine and glucagon were elevated after the ingestion of glycine, as expected. The serum insulin concentration also was slightly elevated after the ingestion of glycine alone. When glycine was ingested with glucose, the plasma glucose area response was attenuated by > 50% compared with the response after the ingestion of glucose alone. The dynamics of the insulin response after the ingestion of glycine plus glucose were modestly different from those after the ingestion of glucose alone, but the area response was not significantly different. CONCLUSION: The data are compatible with the hypothesis that oral glycine stimulates the secretion of a gut hormone that potentiates the effect of insulin on glucose removal from the circulation.

Oral arginine does not stimulate an increase in insulin concentration but delays glucose disposal.

BACKGROUND: Ingested protein increases circulating insulin concentrations. Several years ago it was also determined that an intravenously administered mixture of 10 essential amino acids stimulated insulin secretion. Of these, arginine was the most potent. The effect was synergistic with administered glucose. OBJECTIVE: Because the amounts of amino acid administered intravenously were very large and because ingested arginine is partially metabolized in the intestinal mucosa, we were interested in determining whether orally administered arginine stimulates a rise in circulating insulin concentration and whether arginine affects the glucose-induced rise in insulin concentration. DESIGN: Nine healthy subjects (4 women and 5 men aged 21-52 y) ingested 1 mmol arginine/kg lean body mass, 1 mmol arginine/kg lean body mass + 25 g glucose, 25 g glucose alone, and water only, in random order on separate occasions, at 0800. Blood samples were obtained at baseline and at 10-min intervals over the next 2 h and were assayed for glucose, insulin, glucagon, and amino acid concentrations. The half-time for gastric emptying was determined by scintigraphy. RESULTS: Unlike with intravenous administration, ingested arginine did not stimulate a rise in insulin concentration. The glucagon concentration was increased. Arginine attenuated and prolonged the glucose rise when it was ingested with glucose. Gastric emptying time was similar after ingestion of glucose alone or arginine plus glucose. CONCLUSION: Arginine, in an amount likely to be ingested in a high-protein meal, does not stimulate insulin secretion but attenuates the increase in glucose when given with glucose.

An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes.

BACKGROUND: In single-meal studies, dietary protein does not result in an increase in glucose concentrations in persons with or without type 2 diabetes, even though the resulting amino acids can be used for gluconeogenesis. OBJECTIVE: The metabolic effects of a high-protein diet were compared with those of the prototypical healthy (control) diet, which is currently recommended by several scientific organizations. DESIGN: The metabolic effects of both diets, consumed for 5 wk each (separated by a 2-5-wk washout period), were studied in 12 subjects with untreated type 2 diabetes. The ratio of protein to carbohydrate to fat was 30:40:30 in the high-protein diet and 15:55:30 in the control diet. The subjects remained weight-stable during the study. RESULTS: With the fasting glucose concentration used as a baseline from which to determine the area under the curve, the high-protein diet resulted in a 40% decrease in the mean 24-h integrated glucose area response. Glycated hemoglobin decreased 0.8% and 0.3% after 5 wk of the high-protein and control diets, respectively; the difference was significant (P < 0.05). The rate of change over time was also significantly greater after the high-protein diet than after the control diet (P < 0.001). Fasting triacylglycerol was significantly lower after the high-protein diet than after the control diet. Insulin, C-peptide, and free fatty acid concentrations were not significantly different after the 2 diets. CONCLUSION: A high-protein diet lowers blood glucose postprandially in persons with type 2 diabetes and improves overall glucose control. However, longer-term studies are necessary to determine the total magnitude of response, possible adverse effects, and the long-term acceptability of the diet.

The metabolic response to ingestion of proline with and without glucose.

Ingested protein results in an increase in circulating insulin and glucagon concentrations and no change, or a slight decrease, in circulating glucose. In subjects with type 2 diabetes, when protein is ingested with glucose, insulin is further increased and the glucose rise is less than when glucose is ingested alone. Presumably these effects are due to the amino acids present in the proteins. The effects of individual amino acids, ingested in physiologic amounts, with or without glucose, have not been determined. Therefore, we have begun a systematic study of the response to ingested amino acids. Eight young, non-obese, subjects (4 men, 4 women) ingested 1 mmol proline/kg lean body mass, 25 g glucose, 25 g glucose + 1 mmol proline/kg lean body mass or water only on 4 separate occasions at 8 am. Blood was obtained before and after ingestion of the test meal over the following 150 minutes. Proline ingestion resulted in a 13-fold increase in the plasma proline concentration. This was decreased by 50% when glucose was ingested with proline. Proline alone had little effect on glucose, insulin, or glucagon concentrations. However, ingestion of proline with glucose resulted in a 23% attenuation of the glucose area response and no change in insulin response compared with the response to that of glucose alone. A glucose-stimulated decrease in glucagon was further facilitated by proline. Ingested proline is readily absorbed. It reduces the glucose-induced increase in glucose concentration in the presence of an unchanged insulin and a decreased glucagon response.

A fasting-induced decrease in plasma glucose concentration does not affect the insulin response to ingested protein in people with type 2 diabetes.

We previously have reported that protein, on a weight basis, is just as potent as glucose in increasing the insulin concentration in people with type 2 diabetes. In people without diabetes, protein is only approximately 30% as potent as glucose in this regard. In the present study, we tested the hypothesis that the increased insulin responsiveness to protein in people with type 2 diabetes is due to the elevated plasma glucose concentration in these individuals. Seven male subjects with untreated type 2 diabetes were given 50 g protein in the form of very lean beef at 8 AM after an overnight fast. On another occasion, the same individuals were fasted for an additional 24 hours to lower their plasma glucose concentration to near the normal reference range. They were then given 50 g protein. The 8 AM glucose concentration was lower after 24 hours of additional fasting, as expected. After ingestion of the protein meal, there was an unexpected, modest increase in glucose concentration after an additional 24 hours of fasting that was not observed with only an overnight fast. Despite the approximately 15% lower plasma glucose concentration at the time of the protein meal, the insulin responses were nearly identical. Thus, the greater insulin response to ingested protein is not likely to be due merely to a higher initial glucose concentration.

Stability over time of glycohemoglobin, glucose, and red blood cell survival in hematologically stable people without diabetes.

We previously have shown that an affinity, high-performance liquid chromatography (HPLC) method is a highly reproducible and sensitive method for determining percent total glycohemoglobin (tGHb) in people with diabetes. In this study we extended the use of this method to a determination of the correlation of percent tGHb with the fasting plasma glucose concentration in people without known diabetes. We also determined the correlation of the tGHb with the reticulocyte count, as an index of red blood cell (RBC) survival, and with a carbon monoxide (CO) method for determining RBC survival. In addition, the stability of the tGHb, glucose, RBC mass, hemoglobin, and reticulocyte counts over a 1-year period was evaluated. Total glycohemoglobin, overnight fasting plasma glucose concentration, hemoglobin, RBC and reticulocyte count, and the calculated percentage of RBC count represented by reticulocytes were determined monthly for at least 12 months (range, 12 to 26 months) in 48 adults (mean age, 51 years; range, 31 to 82 years). In 37 of the subjects, RBC survival using a CO method also was determined. There was a highly significant linear correlation between the fasting glucose concentration and the tGHb. There was only a weak correlation between the percent reticulocytes or with the RBC survival determined by the CO method. The tGHb, plasma glucose, RBC count, hemoglobin, and percent reticulocytes were very stable over a 12-month or greater period. We conclude that there is a good correlation between the tGHb and plasma glucose concentration in a population without known diabetes. Variations in RBC survival as indicated by a reticulocyte count within the reference range is not likely to have a clinically significant effect on interpretation of tGHb data in the context of an integrated glucose concentration. Nevertheless, this remains to be proven using RBC survival methods that are more precise than those currently available.

Interaction of ingested leucine with glycine on insulin and glucose concentrations.

The majority of individual amino acids increase insulin and attenuate the plasma glucose response when ingested with glucose. Objective. To determine whether ingestion of two amino acids simultaneously, with glucose, would result in an additive effect. Leucine (Leu) and glycine (Gly) were chosen because they were two of the most potent glucose-lowering amino acids when given individually. Materials and Methods. Nine subjects received test items on four separate days. The first was a water control, then 25 g glucose, or Leu + Gly (1 mmol/kg fat-free mass each) ±25 g glucose, in random order. Glucose, insulin, and glucagon were measured frequently for 2.5 hours. Net areas were calculated. Results. The glucose area response decreased by 66%. The insulin area response increased by 24% after ingestion of Leu + Gly + glucose compared to ingestion of glucose alone. The decrease in glucose response was not additive; the increase in insulin response was far less than additive when compared to previously published individual amino acid results. The glucagon concentration remained unchanged. Conclusion. There is an interaction between Leu and Gly that results in a markedly attenuated glucose response. This occurred with a very modest increase in insulin response. Changes in glucagon response could not explain the results. The mechanism is unknown.

Ingestion of leucine + phenylalanine with glucose produces an additive effect on serum insulin but less than additive effect on plasma glucose.

Most individual amino acids stimulate insulin secretion and attenuate the plasma glucose response when ingested with glucose. We determined whether ingestion of two amino acids simultaneously with glucose would result in an additive effect on the glucose area response compared with ingestion of amino acids individually. Leucine and phenylalanine were chosen because they were two of the most potent glucose-lowering amino acids when given individually. Eight healthy subjects were studied on four separate days. Test meals were given at 0800. The first meal was a water control. Subjects then received 25 g glucose or leucine + phenylalanine (1 mmol/kg fat free body mass each) ±25 g glucose in random order. Glucose, insulin and glucagon were measured frequently for 2.5 hours thereafter. Net areas under the curves were calculated using the mean fasting value as baseline. The insulin response to leucine + phenylalanine was additive. In contrast, the decrease in glucose response to leucine + phenylalanine + glucose was less than additive compared to the individual amino acids ingested with glucose. Interestingly, the insulin response to the combination was largely due to the leucine component, whereas the glucose response was largely due to the phenylalanine component. Glucose was unchanged when leucine or phenylalanine, alone or in combination, was ingested without glucose. This trial is registered with ClinicalTrials.gov NCT01471509.