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.

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.

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.

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.

Body Mass Index: Obesity, BMI, and Health: A Critical Review.

The body mass index (BMI) is the metric currently in use for defining anthropometric height/weight characteristics in adults and for classifying (categorizing) them into groups. The common interpretation is that it represents an index of an individual's fatness. It also is widely used as a risk factor for the development of or the prevalence of several health issues. In addition, it is widely used in determining public health policies.The BMI has been useful in population-based studies by virtue of its wide acceptance in defining specific categories of body mass as a health issue. However, it is increasingly clear that BMI is a rather poor indicator of percent of body fat. Importantly, the BMI also does not capture information on the mass of fat in different body sites. The latter is related not only to untoward health issues but to social issues as well. Lastly, current evidence indicates there is a wide range of BMIs over which mortality risk is modest, and this is age related. All of these issues are discussed in this brief review.

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.

Effect of a LoBAG30 diet on protein metabolism in men with type 2 diabetes. A Randomized Controlled Trial.

BACKGROUND: We previously reported that a weight-maintenance diet with a carbohydrate:protein:fat ratio of 30:30:40%, ingested for 5 weeks, improved blood glucose control in subjects with untreated type 2 diabetes. In this study we also determined that insulin and insulin-like growth factor-I (IGF-I) were increased. In this report we provide further information. Specifically, 24-hour total and individual amino acids, glucagon and cortisol data are provided. In addition, we determined whether these multiple effectors resulted in a positive nitrogen balance and an increase in fat-free mass. Insulin and IGF-I should stimulate protein accumulation. An increase in amino acids, particularly branched chain amino acids, should facilitate this, whereas glucagon and cortisol could have adverse effects in this regard. METHODS: Eight men with untreated type 2 diabetes were studied. A randomized crossover design was used. Data were obtained before and after 5 weeks on a control diet (55% carbohydrate:15% protein:30% fat) and on a 30% carbohydrate:30% protein:40% fat diet. Nitrogen balance and body composition were determined at the beginning and end of each dietary intervention. RESULTS: As expected, the mean 24-hour total amino acid area response was higher after ingesting the 30:30:40 diet. However, the increase was only statistically significant for the branched chain amino acids, and phenylalanine and tyrosine. The 24-hour cortisol profile was unchanged. Glucagon was increased. Nitrogen balance was positive. Body weight was stable. Body composition and computed tomography data indicate no change in the fat-free mass. CONCLUSION: This high protein, low carbohydrate diet induced a metabolic milieu which strongly favors a positive protein balance, and a positive balance was present. However, an increase in lean (protein) mass was not documented. Whether such a diet in people with type 2 diabetes is useful in preventing or delaying the loss of total lean body mass and/or sarcopenia associated with aging remains to be determined.

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.

Further decrease in glycated hemoglobin following ingestion of a LoBAG30 diet for 10 weeks compared to 5 weeks in people with untreated type 2 diabetes.

BACKGROUND: We previously determined that a weight-maintenance, non-ketogenic diet containing 30% carbohydrate (CHO), 30% protein, 40% fat, (30:30:40) (LoBAG30) decreased glycated hemoglobin (%tGHb) from 10.8 to 9.1% over a 5 week period in subjects with untreated type 2 diabetes. Both the fasting glucose and postprandial glucose area were decreased. Our objective in the present 10-week study was to determine: 1) whether the above results could be maintained, or even improved (suggesting a metabolic adaptation) and 2) whether the subjects would accept the diet for this longer time period. In addition, protein balance, and a number of other blood and urine constituents were quantified at 5 and at 10 weeks on the LoBAG30 diet to address metabolic adaptation. METHODS: Eight men with untreated type 2 diabetes were studied over a 10-week period. Blood was drawn and urine was collected over a 24 hour period at the beginning of the study with subjects ingesting a standard diet of 55% CHO, 15% protein, 30% fat, and at the end of 5 and 10 weeks following ingestion of a LoBAG30 diet. RESULTS: Body weight was stable. Fasting glucose decreased by 19% at week 5 and 28% at week 10; 24-h total glucose area decreased by 27% at week 5 and 35% at week 10 compared to baseline. Insulin did not change. Mean %tGHb decreased by 13% at week 5, 25% at week 10, and was still decreasing linearly, indicating that a metabolic adaptation occurred. Serum NEFA, AAN, uric acid, urea, albumin, prealbumin, TSH, Total T3, free T4, B12, folate, homocysteine, creatinine, growth hormone and renin did not differ between weeks 5 and 10. IGF-1 increased modestly. Urinary glucose decreased; urinary pH and calcium were similar. CONCLUSIONS: A LoBAG30 diet resulted in continued improvement in glycemic control. This improvement occurred without significant weight loss, with unchanged insulin and glucagon profiles, and without deterioration in serum lipids, blood pressure or kidney function. Extending the duration of time on a LoBAG30 diet from 5 to 10 weeks had little or no further effect on the hormones and metabolites measured, i.e. a metabolic equilibrium was established.

The effect on glucagon, glucagon-like peptide-1, total and acyl-ghrelin of dietary fats ingested with and without potato.

INTRODUCTION: We are interested in the metabolic response to ingested macronutrients and the interaction between macronutrients in meals. Recently, we have determined the insulin and glucose response to ingestion of lard, olive oil, or safflower oil, fat sources varying in fatty acid composition and carbohydrate (CHO), in the form of potato. OBJECTIVE: Our aim was to determine the effect of these dietary fats ingested alone or with potato on glucagon, glucagon-like peptide-1 (GLP-1) (7-37 and 7-36 amide), and total and acyl-ghrelin concentrations. METHODS: Healthy subjects ingested 25 g fat (lard, olive oil, or safflower oil), 50 g CHO (potato), 25 g fat with 50 g CHO, or water only. Glucagon, GLP-1 (7-37 and 7-36 amide), and total and acyl-ghrelin responses were determined over 4 h. RESULTS: All fats when ingested alone increased glucagon. Glucagon increases were dramatically attenuated when fats were ingested with the potato. GLP-1 increased after all meals, but was greatest when fats were ingested alone. The fat-stimulated increase was completely negated when fats were ingested with potato. Both acyl and total ghrelin decreased when only fats were ingested, as expected. When potato was ingested with any of the fats, the fat-induced decrease in acyl-ghrelin response also was essentially negated. Paradoxically, ghrelin increased when potato alone was ingested. CONCLUSIONS: The current data indicate that the glucagon, GLP-1 and ghrelin responses to ingested fats, varying in fatty acid composition, are significantly affected by co-ingestion of CHO. Overall, the interaction between ingested foods in general is likely to be complex.

Lysine ingestion markedly attenuates the glucose response to ingested glucose without a change in insulin response.

BACKGROUND: Ingested proteins are known to stimulate a rise in insulin and glucagon concentrations. In our effort to explain this effect, we have begun to measure the effect of individual amino acids. OBJECTIVES: The objectives were to determine the effect of lysine ingestion on insulin and glucagon concentrations and whether the effect is moderated by glucose ingestion. DESIGN: Thirteen healthy subjects were studied on 4 occasions. Water, 25 g glucose, 1 mmol lysine/kg lean body mass, or lysine plus glucose was given on separate occasions at 0800 after a 12-h fast. Serum lysine, glucose, insulin, and glucagon were measured during a 2.5-h period. The amount of lysine provided was equivalent to that present in a 672-g (24-oz) steak. RESULTS: Lysine ingestion resulted in an approximately 3-fold increase in lysine concentration and in a small decrease in glucose concentration. When lysine was ingested with glucose, the 2.5-h glucose area response decreased by 44% (P < 0.02). Lysine alone increased the insulin area response modestly; the insulin increase when lysine was ingested with glucose was similar to that when only glucose was ingested. Lysine stimulated an increase in glucagon (P < 0.02), whereas glucose decreased glucagon. CONCLUSIONS: Lysine ingestion results in a small decrease in serum glucose and an increase in glucagon and insulin concentrations. Lysine ingested with glucose dramatically attenuated the glucose-stimulated glucose response, but there was no change in insulin response. Whether similar effects will be observed with more physiologic doses of lysine remains to be determined.

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.

Leucine, when ingested with glucose, synergistically stimulates insulin secretion and lowers blood glucose.

Our laboratory is interested in the metabolic effects of ingested proteins. As part of this research, we currently are investigating the metabolic effects of ingested individual amino acids. The objective of the current study was to determine whether leucine stimulates insulin and/or glucagon secretion and whether, when it is ingested with glucose, it modifies the glucose, insulin, or glucagon response. Thirteen healthy subjects (6 men and 7 women) were studied on 4 different occasions. Subjects were admitted to the special diagnostic and treatment unit after a 12-hour fast. They received test meals at 8:00 am. On the first occasion, they received water only. Thereafter, they received 25 g glucose or 1 mmol/kg lean body mass leucine or 1 mmol/kg lean body mass leucine plus 25 g glucose in random order. Serum leucine, glucose, insulin, glucagon, and alpha-amino nitrogen concentrations were measured at various times during a 2.5-hour period after ingestion of the test meal. The amount of leucine provided was equivalent to that present in a high-protein meal, that is, that approximately present in a 350-g steak. After leucine ingestion, the leucine concentration increased 7-fold; and the alpha-amino nitrogen concentration increased by 16%. Ingested leucine did not affect the serum glucose concentration. When leucine was ingested with glucose, it reduced the 2.5-hour glucose area response by 50%. Leucine, when ingested alone, increased the serum insulin area response modestly. However, it increased the insulin area response to glucose by an additional 66%; that is, it almost doubled the response. Ingested leucine stimulated an increase in glucagon. Ingested glucose decreased it. When ingested together, the net effect was essentially no change in glucagon area. In summary, leucine at a dose equivalent to that present in a high-protein meal, had little effect on serum glucose or insulin concentrations but did increase the glucagon concentration. When leucine was ingested with glucose, it attenuated the serum glucose response and strongly stimulated additional insulin secretion. Leucine also attenuated the decrease in glucagon expected when glucose alone is ingested. The data suggest that a rise in glucose concentration is necessary for leucine to stimulate significant insulin secretion. This in turn reduces the glucose response to ingested glucose.

Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant?

We have been interested in the metabolic effects of ingested fuels, both in normal subjects and in people with type 2 diabetes. Recently, we have become interested in the regulation of glucose production and the regulation of gluconeogenesis in particular. We are not aware of a recent comprehensive review of these topics. Therefore, we have reviewed the currently available literature. The pertinent papers obtained from a Medline search of the words gluconeogenesis, glycogenolysis, hepatic glucose output, as well as papers from our personal files, form the basis of this review. In order to analyse the data, it also was necessary to review the relevant methodology used in determining gluconeogenesis. Pathway diagrams have been included with this review in order to illustrate and highlight key aspects of the methodologies. Current data support the hypothesis that the rate of glucose appearance changes but the rate of gluconeogenesis remains remarkably stable in widely varying metabolic conditions in people without diabetes. In people with diabetes, whether gluconeogenesis remains unchanged is at present uncertain. Available data are very limited. The mechanism by which gluconeogenesis remains relatively constant, even in the setting of excess substrates, is not known. One interesting speculation is that gluconeogenic substrates substitute for each other depending on availability. Thus, the overall rate is either unaffected or only modestly changed. This requires further confirmation.

Protein in optimal health: heart disease and type 2 diabetes.

Diets with increased protein and reduced carbohydrates have been shown to improve body composition, lipid and lipoprotein profiles, and glycemic regulations associated with treatment of obesity and weight loss. Derived from these outcomes, high-protein, low-carbohydrate diets are also being examined for treatment of heart disease, metabolic syndrome, and type 2 diabetes. High-protein, low-carbohydrate diets have been found to have positive effects on reducing risk factors for heart disease, including reducing serum triacylglycerol, increasing HDL cholesterol, increasing LDL particle size, and reducing blood pressure. These diets appear particularly attractive for use with individuals exhibiting the atherogenic dyslipidemia of metabolic syndrome. High-protein, low-carbohydrate diets have also been investigated for treatment of type 2 diabetes with positive effects on glycemic regulation, including reducing fasting blood glucose, postprandial glucose and insulin responses, and the percentage of glycated hemoglobin. Specific effects of increasing protein compared with reducing carbohydrates have not been extensively investigated. Additional research is needed to determine specific levels of protein, carbohydrate, and fat for optimum health of individuals who differ in age, physical activity, and metabolic phenotypes.