What nutritional physiology tells us about diet, sugar and obesity.

In this closing perspective, the author exposes why targeting a single nutrient like sugar is in his opinion unlikely to be efficient in preventing obesity and metabolic diseases. He defends the proposal that the concept of fructose toxicity is based on major misconceptions of nutritional physiology. He specifically proposes that (1) sugar being a non-essential nutrient does not obligatorily imply that it has no beneficial effect; (2) alterations of blood triglyceride concentration and hepatic glucose production within the normal range may merely reflect adaptations to a fructose-rich diet rather than early markers of diseases; (3) overfeeding is a normal physiological response to exposure to an energy-dense, palatable nutrient rather than the consequence of 'leptin resistance'; (4) we may presently overemphasize the role of biological regulations and of gene-related heredity when assessing the effects of fructose in particular, and the determinants of obesity in general.

Sweeteners and health: findings from recent research and their impact on obesity and related metabolic conditions.

Few topics in nutrition engender more controversy than added sugars in general, and fructose-containing sugars in particular. Some investigators have argued that added sugars are associated with increased risk of obesity, cardiovascular disease, diabetes, non-alcoholic fatty liver disease and even sugar 'addiction'. Other investigators have questioned the scientific basis for all of these assertions. This debate has extended far beyond the scientific community into various media outlets including the internet and other non-refereed venues often with heated rhetoric and little science. Against this backdrop, a group of experts and researchers in the metabolism and health effects of added sugars presented a symposium 'Sweeteners and Health: Findings from Recent Research and their Impact on Obesity and Related Metabolic Conditions' at the European Congress on Obesity on 7 May 2015. The papers in this supplement are based on the presentations made at this meeting. The current article is intended to serve as an Introduction to this supplement.

Physiological handling of dietary fructose-containing sugars: implications for health.

Fructose has always been present in our diet, but its consumption has increased markedly over the past 200 years. This is mainly due to consumption of sucrose or high-fructose corn syrup in industrial foods and beverages. Unlike glucose, fructose cannot be directly used as an energy source by all cells of the human body and needs first to be converted into glucose, lactate or fatty acids in the liver, intestine and kidney. Because of this specific two-step metabolism, some energy is consumed in splanchnic organs to convert fructose into other substrates, resulting in a lower net energy efficiency of fructose compared with glucose. A high intake of fructose-containing sugars is associated with body weight gain in large cohort studies, and fructose can certainly contribute to energy imbalance leading to obesity. Whether fructose-containing foods promote obesity more than other energy-dense foods remains controversial, however. A short-term (days-weeks) high-fructose intake is not associated with an increased fasting glycemia nor to an impaired insulin-mediated glucose transport in healthy subjects. It, however, increases hepatic glucose production, basal and postprandial blood triglyceride concentrations and intrahepatic fat content. Whether these metabolic alterations are early markers of metabolic dysfunction or merely adaptations to the specific two-step fructose metabolism remain unknown.

Effects of four-week high-fructose diet on gene expression in skeletal muscle of healthy men.

AIMS: A high-fructose diet (HFrD) may play a role in the obesity and metabolic disorders epidemic. In rodents, HFrD leads to insulin resistance and ectopic lipid deposition. In healthy humans, a four-week HFrD alters lipid homoeostasis, but does not affect insulin sensitivity or intramyocellular lipids (IMCL). The aim of this study was to investigate whether fructose may induce early molecular changes in skeletal muscle prior to the development of whole-body insulin resistance. METHODS: Muscle biopsies were taken from five healthy men who had participated in a previous four-week HFrD study, during which insulin sensitivity (hyperinsulinaemic euglycaemic clamp), and intrahepatocellular lipids and IMCL were assessed before and after HFrD. The mRNA concentrations of 16 genes involved in lipid and carbohydrate metabolism were quantified before and after HFrD by real-time quantitative PCR. RESULTS: HFrD significantly (P<0.05) increased stearoyl-CoA desaturase-1 (SCD-1) (+50%). Glucose transporter-4 (GLUT-4) decreased by 27% and acetyl-CoA carboxylase-2 decreased by 48%. A trend toward decreased peroxisomal proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was observed (-26%, P=0.06). All other genes showed no significant changes. CONCLUSION: HFrD led to alterations of SCD-1, GLUT-4 and PGC-1alpha, which may be early markers of insulin resistance.

Fish oil after abdominal aorta aneurysm surgery.

OBJECTIVE: Fish oil (FO) may attenuate the inflammatory response after major surgery such as abdominal aortic aneurysm (AAA) surgery. We aimed at evaluating the clinical impact and safety aspects of a FO containing parenteral nutrition (PN) after AAA surgery. METHODS: Intervention consisted in 4 days of either standard (STD: Lipofundin medium-chain triglyceride (MCT): long-chain triglyceride (LCT)50%-MCT50%) or FO containing PN (FO: Lipoplus: LCT40%-MCT50%-FO10%). Energy target were set at 1.3 times the preoperative resting energy expenditure by indirect calorimetry. Blood sampling on days 0, 2, 3 and 4. Glucose turnover by the (2)H(2)-glucose method. Muscle microdialysis. CLINICAL DATA: maximal daily T degrees, intensive care unit (ICU) and hospital stay. RESULTS: Both solutions were clinically well tolerated, without any differences in laboratory safety parameters, inflammatory, metabolic data, or in organ failures. Plasma tocopherol increased similarly; with FO, docosahexaenoic and eicosapentaenoic acid increased significantly by day 4 versus baseline or STD. To increased postoperatively, with a trend to lower values in FO group (P=0.09). After FO, a trend toward shorter ICU stay (1.6+/-0.4 versus 2.3+/-0.4), and hospital stay (9.9+/-2.4 versus 11.3+/-2.7 days: P=0.19) was observed. CONCLUSIONS: Both lipid emulsions were well tolerated. FO-PN enhanced the plasma n-3 polyunsaturated fatty acid content, and was associated with trends to lower body temperature and shorter length of stay.

Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans.

The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.

Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans.

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation of carbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic [6 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle.

Nonbinding inhibitory antiinsulin receptor antibodies. A new type of autoantibodies in human diabetes.

Sera and their IgG from 10/104 diabetic patients (five with insulin-dependent and five with noninsulin-dependent diabetes, NIDDM), contained antibodies that bound 125I-labeled purified human insulin receptors. 9 of these 10 sera failed to inhibit insulin binding (to rat hepatocytes and human placental membranes), did not stimulate glucose oxidation (by isolated rat adipocytes), and did not bind human placental IGF-1 receptors. Only one serum (and its IgG) modestly inhibited insulin binding and stimulated glucose oxidation. We conclude (a) that sera from 9/104 diabetics (five insulin-dependent and four noninsulin-dependent) contained a newly identified species of IgG antiinsulin receptor autoantibodies (AIRA), which bound to the insulin receptor at a locus different from the insulin binding site and did not inhibit insulin binding; and (b) that only 1/104 diabetic sera contained low-titer "conventional" antiinsulin receptor autoantibodies that bound to the insulin receptor at or near the insulin binding site, inhibited insulin binding and caused a clinical condition, which was difficult to distinguish from typical NIDDM.

Carbohydrates and insulin resistance in clinical nutrition: Recommendations from the ESPEN expert group.

Growing evidence underscores the important role of glycemic control in health and recovery from illness. Carbohydrate ingestion in the diet or administration in nutritional support is mandatory, but carbohydrate intake can adversely affect major body organs and tissues if resulting plasma glucose becomes too high, too low, or highly variable. Plasma glucose control is especially important for patients with conditions such as diabetes or metabolic stress resulting from critical illness or surgery. These patients are particularly in need of glycemic management to help lessen glycemic variability and its negative health consequences when nutritional support is administered. Here we report on recent findings and emerging trends in the field based on an ESPEN workshop held in Venice, Italy, 8-9 November 2015. Evidence was discussed on pathophysiology, clinical impact, and nutritional recommendations for carbohydrate utilization and management in nutritional support. The main conclusions were: a) excess glucose and fructose availability may exacerbate metabolic complications in skeletal muscle, adipose tissue, and liver and can result in negative clinical impact; b) low-glycemic index and high-fiber diets, including specialty products for nutritional support, may provide metabolic and clinical benefits in individuals with obesity, insulin resistance, and diabetes; c) in acute conditions such as surgery and critical illness, insulin resistance and elevated circulating glucose levels have a negative impact on patient outcomes and should be prevented through nutritional and/or pharmacological intervention. In such acute settings, efforts should be implemented towards defining optimal plasma glucose targets, avoiding excessive plasma glucose variability, and optimizing glucose control relative to nutritional support.

Effects of colostrum feeding and glucocorticoid administration on insulin-dependent glucose metabolism in neonatal calves.

Colostrum feeding and glucocorticoid administration affect glucose metabolism and insulin release in calves. We have tested the hypothesis that dexamethasone as well as colostrum feeding influence insulin-dependent glucose metabolism in neonatal calves using the euglycemic-hyperinsulinemic clamp technique. Newborn calves were fed either colostrum or a milk-based formula (n=14 per group) and in each feeding group, half of the calves were treated with dexamethasone (30 microg/[kg body weight per day]). Preprandial blood samples were taken on days 1, 2, and 4. On day 5, insulin was infused for 3h and plasma glucose concentrations were kept at 5 mmol/L+/-10%. Clamps were combined with [(13)C]-bicarbonate and [6,6-(2)H]-glucose infusions for 5.5h (i.e., from -150 to 180 min, relative to insulin infusion) to determine glucose turnover, glucose appearance rate (Ra), endogenous glucose production (eGP), and gluconeogenesis before and at the end of the clamp. After the clamp liver biopsies were taken to measure mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate carboxylase (PC). Dexamethasone increased plasma glucose, insulin, and glucagon concentrations in the pre-clamp period thus necessitating a reduction in the rate of glucose infusion to maintain euglycemia during the clamp. Glucose turnover and Ra increased during the clamp and were lower at the end of the clamp in dexamethasone-treated calves. Dexamethasone treatment did not affect basal gluconeogenesis or eGP. At the end of the clamp, dexamethasone reduced eGP and PC mRNA levels, whereas mitochondrial PEPCK mRNA levels increased. In conclusion, insulin increased glucose turnover and dexamethasone impaired insulin-dependent glucose metabolism, and this was independent of different feeding.

Protein synthesis in jejunum and liver of neonatal calves fed vitamin A and lactoferrin.

Rates of protein synthesis (PS) and turnover are more rapid during the neonatal period than during any other stage of postnatal life. Vitamin A and lactoferrin (Lf) can stimulate PS in neonates. However, newborn calves are vitamin A deficient and have a low Lf status, but plasma vitamin A and Lf levels increase rapidly after ingestion of colostrum. Neonatal calves (n = 6 per group) were fed colostrum or a milk-based formula without or with vitamin A, Lf, or vitamin A plus Lf to study PS in the jejunum and liver. l-[(13)C]Valine was intravenously administered to determine isotopic enrichment of free (nonprotein-bound) Val (AP(Free)) in the protein precursor pool, atom percentage excess (APE) of protein-bound Val, fractional protein synthesis rate (FSR) in the jejunum and liver, and isotopic enrichment of Val in plasma (APE(Pla)) and in the CO(2) of exhaled air (APE(Ex)). The APE, AP(Free), and FSR in the jejunum and liver did not differ significantly among groups. The APE(Ex) increased, whereas APE(Pla) decreased over time, but there were no group differences. Correlations were calculated between FSR(Jej) and histomorphometrical and histochemical data of the jejunum, and between FSR(Liv) and blood metabolites. There were negative correlations between FSR(Liv) and plasma albumin concentrations and between FSR(Jej) and the ratio of villus height:crypt depth, and there was a positive correlation between FSR(Jej) and small intestinal cell proliferation in crypts. Hence, there were no effects of vitamin A and Lf and no interactions between vitamin A and Lf on intestinal and hepatic PS. However, FSR(Jej) was correlated with histomorphometrical traits of the jejunum and FSR(Liv) was correlated with plasma albumin concentrations.

Effects of amino acids on glucose disposal.

Free fatty acids are known to inhibit carbohydrate disposal and oxidation. This action may play an important role in the pathophysiology of insulin resistance and non-insulin-dependent diabetes mellitus. To investigate whether amino acids (AAs) have similar actions, we determined the effects of an intravenously infused mixture of 15 AAs on carbohydrate disposal during euglycemic-hyperinsulinemic clamps associated with either basal or high glucagon concentrations in healthy male volunteers. Plasma glucose concentration was clamped at approximately 4.7 mM (coefficient of variation 4.7%). Insulin infusion (7.18 pmol.kg-1.min-1) raised serum insulin concentrations from 36-50 pM to between 300 and 600 pM. AA infusions (0.5 g.kg-1.h-1.4 h) raised plasma alpha-amino N2 concentrations about five- to six-fold. Infusion of AAs, somatostatin (somatotropin release inhibitory factor, SRIF), and high-glucagon replacement (3.0 ng.kg-1.min-1) reduced the rate of exogenous glucose infusion needed to maintain euglycemia from 51.1 +/- 7.2 mumol.kg-1.min-1 (saline + SRIF + high glucagon) to 28.3 +/- 11.1 mumol.kg-1.min-1 and stimulated endogenous glucose production (from 0 to approximately 17 mumol.kg-1.min-1). Thus, glucose disposal (exogenous infusion plus endogenous production of glucose) remained essentially unchanged. During infusion of AAs + SRIF + basal glucagon replacement (0.25 ng.kg-1.min-1), endogenous glucose production remained completely suppressed, and the rates of exogenous glucose infusion did not change (compared with saline + SRIF + basal glucagon replacement). The data showed that 1) hyperaminoacidemia associated with hyperglucagonemia stimulated endogenous glucose production despite hyperinsulinemia, and 2) intravenous infusion of a mixture of 15 AAs had no inhibitory effect on insulin-stimulated total-body glucose disposal.

Effect of hyperinsulinemia on urea pool size and substrate oxidation rates.

Recently, indirect calorimetry has frequently been used together with hyperinsulinemic clamps. With few exceptions, however, no attention was paid in these studies to the possible effects of hyperinsulinemia on urea nitrogen (N) pool size and the consequences of such changes on the calculated rates of protein, lipid, and carbohydrate (CHO) oxidation. We have determined the effects of euglycemic-hyperinsulinemic clamps on urea N pool size, urinary N excretion, and rates of protein, lipid, and CHO oxidation (measured by indirect calorimetry) in six normal men. Insulin infusion (1 mU.kg-1.min-1) increased peripheral venous insulin concentration from 7 +/- 1.2 (mean +/- SE) to 51 +/- 4 microU/ml. Glucose concentration was clamped at 84 +/- 1.1 mg/dl. Between 0 (preclamp) and 360 min (end of clamp), blood urea N concentration decreased from 17.2 +/- 1.1 to 11 +/- 0.8 mg/dl (P less than .001), and the urea N pool decreased from 604 +/- 41 to 388 +/- 30 mmol (P less than .001). The urea N production rate decreased from 461 +/- 91 (preclamp) to 91 +/- 63 mumol/min during the last 4 h of the clamp (P less than .05). Urinary N excretion remained unchanged (705 +/- 113 vs. 905 +/- 125 mumol/min, NS). Correction of urinary N excretion for insulin-induced reductions in the urea N pool resulted in the following changes in substrate oxidation rates (calculated for the last 4 h of the clamp).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-induced sympathetic activation and vasodilation in skeletal muscle. Effects of insulin resistance in lean subjects.

Insulin-induced stimulation of blood flow and sympathetic nerve activity in skeletal muscle tissue is impaired in obesity, but the underlying mechanism is unknown. To determine whether insulin resistance alters sympathetic and vasodilatory responses to euglycemic hyperinsulinemia, in eight healthy subjects we measured calf blood flow and muscle sympathetic nerve activity (MSNA) (n = 5) during insulin/glucose infusion (euglycemic hyperinsulinemic [6 pmol.kg-1.min-1] clamp) performed alone and performed during concomitant fat emulsion infusion, a maneuver designed to induce insulin resistance. The major new finding is that fat emulsion infusion, which attenuated insulin-induced stimulation of carbohydrate oxidation by 39 +/- 7% (P < 0.01), did not have any detectable effect on insulin-induced vasodilatory and sympathetic responses: at the end of the 2-h clamp, blood flow and MSNA had increased by 35 +/- 6% (P < 0.01) and 152 +/- 58% (P < 0.01), respectively, during insulin infusion alone and by 35 +/- 7% (P < 0.01) and 244 +/- 90% (P < 0.01), respectively, during insulin infusion superimposed on free fatty acid infusion. These observations in lean healthy subjects indicate that induction of resistance to the stimulatory effects of insulin on carbohydrate metabolism does not attenuate muscle blood flow and MSNA responses evoked by acute euglycemic hyperinsulinemia. These findings provide further evidence that hyperinsulinemia per se is the primary stimulus that triggers stimulation of muscle blood flow and MSNA during insulin/glucose infusion in humans and suggest that the impaired insulin-induced vasodilation in obese subjects is not related primarily to impaired stimulation of muscle carbohydrate metabolism.

Insulin sensitivity and exogenous insulin clearance in Graves' disease. Measurement by the glucose clamp technique and continuous indirect calorimetry.

Insulin sensitivity was measured in a group of seven thyrotoxic patients and in a group of seven normal subjects by means of the glucose clamp technique. Infusion of insulin at a rate of 0.80 +/- 0.05 mU/kg X min in the hyperthyroid patients and of 0.55 +/- 0.04 mU/kg X min in the control group was performed to obtain a steady-state plasma insulin concentration of approximately 50 microU/ml. Substrate oxidation rates were measured in the postabsorptive state and during the 2 h of the clamp by means of continuous indirect calorimetry. In the postabsorptive state, hyperthyroid patients presented a preferential oxidation of lipids. During the period 60-120 min of the clamp, mean plasma glucose (92 +/- 2 versus 93 +/- 2 mg/dl), insulin (50 +/- 5 versus 58 +/- 3 microU/ml), and total glucose metabolism (5.8 +/- 0.7 versus 6.1 +/- 0.3 mg/kg X min) were similar in the hyperthyroid patients and the control subjects. The rate of glucose oxidation was higher in hyperthyroid patients than in control subjects (4.3 +/- 0.5 versus 2.2 +/- 0.2 mg/kg X min, P less than 0.001), while that of lipid oxidation was similar in both groups (0.6 +/- 0.2 versus control 0.7 +/- 0.1 mg/kg X min). The calculated metabolic clearance rate of insulin was markedly higher in the hyperthyroid patients (1144 +/- 132 ml/min) than in the normal subjects (812 +/- 56 ml/min, P less than 0.025). It is concluded that insulin sensitivity is not altered in the thyrotoxic state. The major route of insulin-stimulated glucose disposal in the hyperthyroid patients appears to be glucose oxidation.

Antibodies to insulin-like growth factor I receptors in diabetes and other disorders.

A newly developed immunoprecipitation assay, with 125I-labeled highly purified human placental insulin-like growth factor I (IGF-I) receptor, was used to search for IGF-I-receptor antibodies in human sera. Eleven of 141 patient sera tested (7.8%) immunoprecipitated labeled IGF-I receptor. Immunoprecipitation was comparable with sera and IgG prepared from these sera. Seven of the 11 sera (3 of 31 with rheumatic disorders, 3 of 48 with non-insulin-dependent diabetes, and 1 of 52 with insulin-dependent diabetes) failed to inhibit IGF-I binding to human placental membranes and thus contained non-binding-inhibitory IGF-I-receptor antibodies. Their pathophysiological function remained uncertain. The remaining 4 sera (2 of 3 with type B severe insulin resistance, 1 of 7 with polycystic ovary syndrome (PCO), and 1 of 31 with rheumatic disorders) inhibited IGF-I binding. Plasma IGF-I concentrations were elevated (663 and 802 ng/ml, respectively) in 2 patients (1 with PCO and another with systemic lupus erythematosus) with binding-inhibitory IGF-I-receptor antibodies, suggesting IGF-I resistance that was probably mediated by the IGF-I-receptor antibodies. In conclusion, we identified two species of human IGF-I-receptor antibodies. Sera from 7 of 141 patients tested contained IgG autoantibodies that bound to the IGF-I receptor at a locus different from the IGF-I binding site and did not inhibit IGF-I binding. Sera from 4 of 141 patients contained antibodies that bound to the IGF-I receptor at or near the IGF-I binding site, inhibited IGF-I binding, and probably caused IGF-I resistance.

Abnormal regulation of hepatic glucose output in maturity-onset diabetes of the young caused by a specific mutation of the glucokinase gene.

A subtype of maturity-onset diabetes of the young (MODY) is caused by mutations of the glucokinase gene, an enzyme expressed in pancreatic beta-cells and the liver. To assess the consequences of a functional alteration of glucokinase at the level of the liver, endogenous (hepatic) glucose production and glucose cycling (an indirect assessment of hepatic glucokinase activity) were measured with 2-2H glucose and 6,6-2H glucose in patients who developed MODY because of the V203A mutation of glucokinase, and in control subjects at similar levels of glycemia. Measurements were performed in the postabsorptive state and after ingestion of 13C-labeled glucose. In the postabsorptive state, MODY patients had normal glucose production (10.9 +/- 1.3 vs. 11.3 +/- 0.6 micromol x kg(-1) x min(-1)) but decreased glucose cycling (0.6 +/- 0.3 vs. 1.5 +/- 0.3 micromol x kg(-1) x min(-1); P < 0.05) when compared with control subjects. However, at plasma glucose and insulin levels similar to those observed in MODY patients, control subjects' glucose production was markedly lower (3.2 +/- 1.5 micromol x kg(-1) x min(-1). After glucose ingestion, endogenous glucose production was reduced by only 29% in MODY patients compared with 80% in control subjects at a similar level of hyperglycemia (P < 0.05). This suggests that the V203A mutation of glucokinase results in decreased activity of glucokinase in liver cells. Thus endogenous glucose production is inadequately inhibited by hyperglycemia in MODY patients, possibly as a result of impaired hepatic glucokinase activity. These alterations contribute to the pathogenesis of hyperglycemia.

Glucose utilization and production in patients with maturity-onset diabetes of the young caused by a mutation of the hepatocyte nuclear factor-1alpha gene.

Mutations of the hepatocyte nuclear factor (HNF)-1alpha gene cause impaired insulin secretion and hyperglycemia in patients with maturity-onset diabetes of the young (MODY)3. Whether these mutations also affect glucose metabolism in tissues other than the beta-cell has not yet been documented. We therefore assessed, in five MODY3 patients and a dozen healthy control subjects, insulin secretion, oxidative and nonoxidative glucose disposal, and glucose production during a two-step hyperglycemic clamp and a euglycemic hyperinsulinemic (0.4 mU x kg(-1) x min(-1)) clamp. Compared with healthy control subjects, MODY3 patients had higher fasting plasma glucose (+100%) but similar rates of fasting glucose production and oxidation. Both the early and late phases of insulin secretion were virtually abolished during the hyperglycemic clamp, and glucose production was suppressed by only 43% in MODY3 patients vs. 100% in healthy control subjects. The rate of glucose infusion required to produce a 5 mmol/l increase above basal glycemia was reduced by 30%, net nonoxidative glucose disposal (which is equal to net glycogen deposition) was inhibited by 39%, and net carbohydrate oxidation during hyperglycemia was 25% lower in MODY3 patients compared with control subjects. Insulin-stimulated glucose utilization and oxidation measured during the hyperinsulinemic clamp (at approximately 200 pmol/l insulin) were identical in MODY3 patients and in healthy control subjects, indicating that peripheral insulin sensitivity was not altered. Suppression of endogenous glucose production was, however, mildly impaired. It is concluded that MODY3 patients have severely depressed glucose-induced insulin secretion. The development of hyperglycemia in these patients appears to be caused by a decreased stimulation of glucose utilization, oxidation, and nonoxidative glucose disposal as well as by a blunted suppression of endogenous glucose output. These phenomena are essentially secondary to insulinopenia, whereas insulin sensitivity remains intact.

In normal men, free fatty acids reduce peripheral but not splanchnic glucose uptake.

Raising plasma free fatty acid (FFA) levels reduces muscle glucose uptake, but the effect of FFAs on splanchnic glucose uptake, total glucose output, and glucose cycling may also be critical to producing lipid-induced glucose intolerance. In eight normal volunteers, we measured glucose turnover and cycling rates ([2H7]glucose infusion) during a moderately hyperglycemic (7.7 mmol/l) hyperinsulinemic clamp, before and after ingestion of a labeled (dideuterated) oral glucose load (700 mg/kg). Each test was performed twice, with either a lipid or a saline infusion; four subjects also had a third test with a glycerol infusion. As shown by similar rates of exogenous glucose appearance, the lipid infusion did not reduce first-pass splanchnic glucose uptake (saline 1.48+/-0.18, lipid 1.69+/-0.17, and glycerol 1.88+/-0.17 mmol/kg per 180 min; NS), but it reduced peripheral glucose uptake by 40% (P < 0.01 vs. both saline and glycerol infusions). Before oral ingestion of glucose, total glucose output was similarly increased by the lipid and glycerol infusions. Total glucose output was significantly increased by FFAs after oral ingestion of glucose (saline 3.68+/-1.15, glycerol 3.68+/-1.70, and lipid 7.92+/-0.88 micromol x kg(-1) x min(-1); P < 0.01 vs. saline and P < 0.05 vs. glycerol). The glucose cycling rate was approximately 2.7 micromol x kg(-1) x min(-1) with the three infusions and tended to decrease all along the lipid infusion, which argues against a stimulation of glucose-6-phosphatase by FFAs. It is concluded that in situations of moderate hyperinsulinemia-hyperglycemia, FFAs reduce peripheral but not splanchnic glucose uptake. Total glucose output is increased by FFAs, by a mechanism that does not seem to involve stimulation of glucose-6-phosphatase.

Effects of breakfast cereals containing various amounts of beta-glucan fibers on plasma glucose and insulin responses in NIDDM subjects.

OBJECTIVE: To determine whether increasing doses (amounts) of beta-glucan present in an extruded breakfast cereal affect the glycemic and insulinemic responses in eight NIDDM subjects, compared with the same responses after a continental breakfast (bread, milk, cheese, ham). RESEARCH DESIGN AND METHODS: Breakfast cereals were produced using various proportions of oat bran enriched in fiber, which contain an unusually high amount of a viscous polysaccharide, called beta-glucan, and oat bran. The carbohydrate load was 35 g. RESULTS: The maximum increases observed in plasma glucose after the breakfast cereal were 67% (P < 0.05), 42% (P < 0.001), and 38% (P < 0.001) with 4.0, 6.0, and 8.4 g beta-glucan, respectively, compared with the continental breakfast. There was a linear inverse relationship between dose of beta-glucan and plasma glucose peak or area under the glucose curve (R2 = 0.94, P < 0.05). Postprandial insulin increase was only 59-67% (P < 0.01) as high as the continental breakfast after all three levels of beta-glucan. CONCLUSIONS: The 50% decrease in glycemic response that was observed after the ingestion of 35 g carbohydrate is estimated to occur with approximately 5 g beta-glucan. This dose of beta-glucan can easily be attained without the loss of taste by incorporating oat bran concentrate in products.