Peripheral metabolism was studied with the forearm technique in six fasting normal subjects before and after oxprenolol administration. With the forearm technique the product of blood flow and arteriovenous differences is a measure of substrate uptake or release, and, therefore, an index of metabolism. Blood flow was measured with venous occlusion plethysmography, and arterial and venous samples obtained through indwelling catheters in the radial artery and deep forearm vein.
Oxprenolol administration influenced both peripheral flow and the basal pattern of substrate exchange. Before oxprenolol blockade a net uptake of glucose, triglycerides, and FFA, and a net release of glycerol were recorded across the forearm. After oxprenolol blockade there was a marked reduction in triglyceride uptake, with augmentation of glucose uptake and inhibition of lipolysis.
When dietary carbohydrate is unavailable, glucose required to support metabolism in vital tissues is generated via gluconeogenesis in the liver. Expression of phosphoenolpyruvate carboxykinase (PEPCK), commonly considered the control point for liver gluconeogenesis, is normally regulated by circulating hormones to match systemic glucose demand. However, this regulation fails in diabetes. Because other molecular and metabolic factors can also influence gluconeogenesis, the explicit role of PEPCK protein content in the control of gluconeogenesis was unclear. In this study, metabolic control of liver gluconeogenesis was quantified in groups of mice with varying PEPCK protein content. Surprisingly, livers with a 90% reduction in PEPCK content showed only a ~40% reduction in gluconeogenic flux, indicating a lower than expected capacity for PEPCK protein content to control gluconeogenesis. However, PEPCK flux correlated tightly with TCA cycle activity, suggesting that under some conditions in mice, PEPCK expression must coordinate with hepatic energy metabolism to control gluconeogenesis.
Previous reports have shown alterations in carbohydrate metabolism in mice infected with Listeria monocytogenes. This study was undertaken to elucidate mechanisms involved in these changes. Female CD-1 mice were injected intraperitoneally with 106L. monocytogenes strain A4413. Animals were fasted 12 hr prior to infection, and pooled tissue from several mice was observed at intervals after infection. Blood glucose, liver glucose, and liver glycogen decreased within 10 hr after infection. Sustained treatment with gluconeogenic precursors, including glucose-6-phosphate, fructose-1, 6-biphosphate, phosphoenolpyruvate, α-glycerophosphate, pyruvate, and amino acids, did not restore and maintain glucose and glycogen at normal levels and did not affect survival. Administration of hydrocortisone induced restoration of liver glycogen early in the infection but did not maintain normal levels as the infection progressed. Activities of succinic dehydrogenase and cytochrome oxidase in liver homogenates from infected mice were elevated as early as 10 hr after infection. Liver function tests using rose bengal sodium-131I showed no significant differences in plasma clearance or liver uptake between normal and infected mice except in terminal infections (60 hr after infection).
Compared with nondiabetic subjects, type 2 diabetic subjects are metabolically inflexible with impaired fasting fat oxidation and impaired carbohydrate oxidation during a hyperinsulinemic clamp. We hypothesized that impaired insulin-stimulated glucose oxidation is a consequence of the lower cellular glucose uptake rate in type 2 diabetes. Therefore, we compared metabolic flexibility to glucose adjusted for glucose disposal rate in nondiabetic versus type 2 diabetic subjects and in the latter group after 1 year of lifestyle intervention (the Look AHEAD [Action For Health in Diabetes] trial).
RESEARCH DESIGN AND METHODS
Macronutrient oxidation rates under fasting and hyperinsulinemic conditions (clamp at 80 mU/m2 per min), body composition (dual-energy X-ray absorptiometry), and relevant hormonal/metabolic blood variables were assessed in 59 type 2 diabetic and 42 nondiabetic individuals matched for obesity, sex, and race. Measures were repeated in diabetic participants after weight loss.
Metabolic flexibility to glucose (change in respiratory quotient [RQ]) was mainly related to insulin-stimulated glucose disposal rate (R2 = 0.46, P < 0.0001) with an additional 3% of variance accounted for by plasma free fatty acid concentration at the end of the clamp (P = 0.03). The impaired metabolic flexibility to glucose observed in type 2 diabetic versus nondiabetic subjects (ΔRQ 0.06 ± 0.01 vs. 0.10 ± 0.01, respectively, P < 0.0001) was no longer observed after adjusting for glucose disposal rate (P = 0.19). Additionally, the increase in metabolic flexibility to glucose after weight loss was accounted for by the concomitant increase in insulin-stimulated glucose disposal rate.
This study suggests that metabolic inflexibility to glucose in type 2 diabetic subjects is mostly related to defective glucose transport.
Fasted dogs prepared with catheters in the femoral artery, portal vein, and hepatic vein and infused intravenously with palmitate-1-14C were used to estimate uptake of free fatty acids in liver and their conversion to major metabolic products secreted into hepatic venous blood. Animals were studied under ordinary conditions and when fat mobilization was increased abruptly by infusing norepinephrine or for a prolonged period by withdrawing insulin from depancreatized dogs. 80% of hepatic blood flow was assumed to be derived from the portal vein.
Hepatic uptake was proportional to net outflow transport of plasma free fatty acids in the three groups and, in each, hepatic extraction fraction was about 25%. Since specific activity of free fatty acids entering and leaving the liver was equal and their composition was closely similar in the three sites sampled, it was concluded that palmitate is a representative tracer for free fatty acids entering the liver and that the liver does not release free fatty acids into the blood.
In norepinephrine-infused dogs, the fraction of free fatty acids secreted in triglycerides (13%) was similar to that of control animals, so that transport of triglycerides was increased. In diabetic dogs no increased transport could be demonstrated since an average of only 2% of free fatty acids was converted to plasma triglyceride fatty acids; the hyperlipemia uniformly observed therefore appeared to result from defective removal of triglycerides from the blood.
A similar fraction of free fatty acids was converted to ketones in normal and norepinephrine-infused dogs. This fraction was somewhat higher in diabetic animals and, in addition, a substantial quantity of ketones was derived from unlabeled precursors. Fractional conversion of free fatty acids to CO2 was similar in normal and norepinephrine-infused dogs, but reduced in the diabetics.
Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.
RESEARCH DESIGN AND METHODS
Forty-one subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m2 per min) combined with 3-[3H] glucose infusion.
Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = −0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]).
Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.
Several fluorine-18 labelled fluoroamino acids have been evaluated as tracers for the quantitative assessment of cerebral protein synthesis in vivo by positron emission tomography (PET). Among these, 2-[18F]fluoro-L-tyrosine (2-[18F]Tyr) has been studied in mice at a low specific activity. Its incorporation into proteins is fast and metabolism via other pathways is limited. The present in vivo study was carried out in normal awake rats using no-carrier-added 2-[18F]Tyr. Under normal physiological conditions, we have studied the incorporation into proteins and the metabolism of the tracer in different brain areas.
No-carrier-added 2-[18F]Tyr was administered to awake rats equipped with chronic arterial and venous catheters. The time course of the plasma activity was studied by arterial blood sampling. The biodistribution of the activity in the main organs was studied at the end of the experiment. The distribution of radioactive species in plasma and brain regions was studied by acidic precipitation of the proteins and HPLC analysis of the supernatant.
The absolute uptake of radioactivity in brain regions was homogenous. In awake rats, no-carrier-added 2-[18F]Tyr exhibits a fast and almost quantitative incorporation into the proteins fractions of cerebellum and cortex. In striatum, this incorporation into proteins and the unchanged fraction of the tracer detected by HPLC could be lower than in other brain regions.
This study confirms the potential of 2-[18F]fluoro-L-tyrosine as a tracer for the assessment of the rate of protein synthesis by positron emission tomography. The observed metabolism suggests a need for a correction for the appearance of metabolites, at least in plasma.
Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr–/– mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link.
Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.
Glucose is an indispensable fuel for all cells and organs, but at the same time leads to problems at high concentrations. As a consequence, blood glucose is controlled in a narrow range to guarantee constant supply and on the other hand avoid damages associated with elevated glucose levels. The liver is the main organ controlling blood glucose by (i) releasing newly synthesized or stored glucose in the blood stream when blood glucose is low (ii) using and storing glucose when blood glucose is elevated. These processes are regulated by hormones, in particular insulin, glucagon and epinephrine. We developed the first detailed kinetic model of this crucial metabolic system integrated with its hormonal control and validated the model based on a multitude of experimental data. Our model enables for the first time to simulate hepatic glucose metabolism in depth. Our results show how due to the hormonal control of key enzymes the liver metabolism can be switched between glucose production and utilization. We provide an essential model to analyze glucose regulation in the normal state and diseases associated with defects in glucose homeostasis like diabetes.
FoxO1 plays an important role in mediating the effect of insulin on hepatic metabolism. Increased FoxO1 activity is associated with reduced ability of insulin to regulate hepatic glucose production. However, the underlying mechanism and physiology remain unknown. We studied the effect of FoxO1 on the ability of insulin to regulate hepatic metabolism in normal vs. insulin-resistant liver under fed and fasting conditions. FoxO1 gain of function, as a result of adenovirus-mediated or transgenic expression, augmented hepatic gluconeogenesis, accompanied by decreased glycogen content and increased fat deposition in liver. Mice with excessive FoxO1 activity exhibited impaired glucose tolerance. Conversely, FoxO1 loss of function, caused by hepatic production of its dominant-negative variant, suppressed hepatic gluconeogenesis, resulting in enhanced glucose disposal and improved insulin sensitivity in db/db mice. FoxO1 expression becomes deregulated, culminating in increased nuclear localization and accounting for its increased transcription activity in livers of both high fat-induced obese mice and diabetic db/db mice. Increased FoxO1 activity resulted in up-regulation of hepatic peroxisome proliferator-activated receptor-γ coactivator-1β, fatty acid synthase, and acetyl CoA carboxylase expression, accounting for increased hepatic fat infiltration. These data indicate that hepatic FoxO1 deregulation impairs the ability of insulin to regulate hepatic metabolism, contributing to the development of hepatic steatosis and abnormal metabolism in diabetes.
Magnetic resonance imaging (MRI), which provides superior soft-tissue imaging and no known harmful effects, has the potential as an alternative modality to guide various medical interventions. This review will focus on MR-guided endovascular interventions and present its current state and future outlook. In the first technical part, enabling technologies such as developments in fast imaging, catheter devices, and visualization techniques are examined. This is followed by a clinical survey that includes proof-of-concept procedures in animals and initial experience in human subjects. In preclinical experiments, MRI has already proven to be valuable. For example, MRI has been used to guide and track targeted cell delivery into or around myocardial infarctions, to guide atrial septal puncture, and to guide the connection of portal and systemic venous circulations. Several investigational MR-guided procedures have already been reported in patients, such as MR-guided cardiac catheterization, invasive imaging of peripheral artery atheromata, selective intraarterial MR angiography, and preliminary angioplasty and stent placement. In addition, MR-assisted transjugular intrahepatic portosystemic shunt procedures in patients have been shown in a novel hybrid double-doughnut x-ray/MRI system. Numerous additional investigational human MR-guided endovascular procedures are now underway in several medical centers around the world. There are also significant hurdles: availability of clinical-grade devices, device-related safety issues, challenges to patient monitoring, and acoustic noise during imaging. The potential of endovascular interventional MRI is great because as a single modality, it combines 3-dimensional anatomic imaging, device localization, hemodynamics, tissue composition, and function.
interventional MRI; endovascular procedures; real-time MRI
Insulin secretory responses to paired intravenous and oral glucose loads were determined in 38 nonobese individuals classified as normal (nondiabetic) subjects, “mild” diabetics (fasting blood glucose below 105 mg per 100 ml), or “moderate” diabetics (fasting glucose below 192 mg per 100 ml). Studies were also performed in 29 obese persons who were similarly grouped. The intravenous load was given to assess the alacrity of hormonal release after glycemic stimulus, and the oral glucose to determine how the speed of initial insulinogenesis modifies the disposition of ingested carbohydrate.
In the nonobese group, normal subjects responded to massive hyperglycemia after rapid injection of glucose with immediate and maximal outpouring of insulin, in contrast to a desultory insulinogenic response in patients with mild diabetes, and no initial response at all in moderate diabetics. During oral glucose tolerance tests, the much faster clearance of blood sugar in nondiabetic subjects was actually associated with lower absolute insulin output than was found in mildly diabetic patients, since the latter exhibited delayed hyperinsulinemia in concert with prolonged hyperglycemia. Moderate diabetics never showed excessive insulin release despite even greater hyperglycemia. An empirical “insulinogenic index,” the ratio relating enhancement of circulating insulin to magnitude of corresponding glycemic stimulus, was used to compare the secretory capacities of respective groups. Despite the higher absolute hormonal output after oral glucose in mild diabetics, the index revealed that insulin release in normal subjects was proportionally more than twice as great. This relatively greater normal secretory response declared itself shortly after the administration of glucose by either route, and was maintained throughout both tests.
In the 29 obese individuals, differences among groups were essentially the same as in persons of normal weight. Obese nondiabetics did show much larger absolute insulinogenic responses during both tests than did nonobese controls. Since corresponding glucose tolerance curves were also higher, the mean insulinogenic indexes for obese subjects were not statistically greater. Moreover, when comparable glucose curves of obese and nonobese controls
To delineate the potential role of disordered glucose and glucose-precursor kinetics in the abnormal carbohydrate metabolism of chronic renal failure, alanine and glucose production and utilization and gluconeogenesis from alanine were studied in patients with chronic compensated renal insufficiency and in normal volunteers. With simultaneous primed injection-continuous infusions of radiolabeled alanine and glucose, rates of metabolite turnover and precursor-product interrelationships were calculated from the plateau portion of the appropriate specific activity curves. All subjects were studied in the postabsorption state. In 13 patients with chronic renal failure (creatinine = 10.7±1.2 mg/100 ml; mean±SEM), glucose turnover was found to be 1,035±99.3 μmol/min. This rate was increased 56% (P = 0.003) over that observed in control subjects (664±33.5 μmol/min). Alanine turnover was 474±96.0 μmol/min in azotemic patients. This rate was 191% greater (P = 0.007) than the rate determined in control subjects (163±19.4 μmol/min). Gluconeogenesis from alanine and the percent of glucose production contributed by gluconeogenesis from alanine were increased in patients with chronic renal failure (192% and 169%, respectively) as compared to controls (P < 0.05 for each). Alanine utilization for gluconeogenesis was increased from 40.2±3.86 μmol/min in control subjects to 143±39.0 μmol/min in azotemic patients (P < 0.05). The percent of alanine utilization accounted for by gluconeogenesis was not altered in chronic renal insufficiency. In nondiabetic azotemic subjects, mean fasting glucose and immunoreactive insulin levels were increased 24.3% (P = 0.005) and 130% (P = 0.046), respectively.
These results in patients with chronic renal failure demonstrate (a) increased glucose production and utilization, (b) increased gluconeogenesis from alanine, (c) increased alanine production and utilization, and (d) a relative impairment to glucose disposal. We conclude that chronic azotemia is characterized by increased rates of glucose and glucose precursor flux and by a relative impairment to glucose disposal. These findings may suggest an underlying hepatic and peripheral insensitivity to the metabolic action of insulin in patients with chronic renal insufficiency.
We report a case of a 45-year-old male patient diagnosed with liver cirrhosis by hepatitis C and alcohol, with a Child-Pugh score C and a model for end-stage liver disease (MELD) score of 27, and submitted to liver transplantation. The subject underwent insertion of the pulmonary artery catheter (PAC) in the right internal jugular vein, with technical difficulty concerning catheter advance. There was sudden hypotension, increase in central venous pressure (CVP), and decrease in SvO2 15 minutes after the PAC had been inserted, followed by cardiorespiratory arrest in pulseless electrical activity (PEA), which was promptly assisted with resuscitation. Pericardiocentesis was performed without success, so the individual was subjected to a subxiphoid pericardial window, which led to output of large amounts of blood as well as PEA reversal to sinus rhythm. Sternotomy was performed; rupture of the apex of the right ventricle (RV) was detected, and suture of the site was accomplished. After hemodynamic stabilization, the patient was transferred to the ICU, where he developed septic shock and, despite adequate therapy, died on the eighteenth day after ICU admission.
Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and lipid metabolism, whereas the status of protein metabolism is not well studied. Here, we performed comparative polysome and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic reticulum (ER)–associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We discovered that ER from livers of obese mice exhibits a general reduction in protein synthesis, and comprehensive analysis of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial components, and bile acid metabolism in the obese translatome. Nutrient availability also plays an important but distinct role in remodeling the hepatic ER translatome in lean and obese mice. Fasting in obese mice partially reversed the overall translatomic differences between lean and obese nonfasted controls, whereas fasting of the lean mice mimicked many of the translatomic changes induced by the development of obesity. The strongest examples of such regulations were the reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver translatome by obesity and nutrient availability, and it identifies a novel role for bile acid metabolism in the pathogenesis of metabolic abnormalities associated with obesity.
Chronic diseases including obesity and associated metabolic abnormalities have become the greatest threat to human health worldwide. How metabolic organs and organelles adapt to nutritional fluctuations, or fail to do so, remains incompletely understood. To explore these issues, we developed a new platform to explore translational responses in the liver, a critical organ for metabolic homeostasis. In this translatomic platform, we integrated polysome profiling and global analysis of polysome-associated mRNAs to systematically quantify protein synthesis on each transcript in obesity and during fasting. Our analysis demonstrated for the first time that protein synthesis is progressively suppressed in the obese liver and that the overall translatome profile of obese liver markedly resembles that of fasting lean mice, particularly in mitochondrial function and bile metabolism. We also examined the physiological impact of some of these alterations and concluded that aberrant bile acid metabolism in the obese liver represents a novel mechanism contributing to hyperglycemia and continuous weight gain. Together, our work reveals abnormal translational regulation as a novel aspect of obesity that could impact future directions in metabolic disease treatment, and we believe translatome profiling represents a new approach to unravel complex mechanisms regulating cellular function and disease pathology.
To evaluate the technical success, clinical outcome and safety of percutaneously placed totally implantable venous power ports (TIVPPs) approved for high-pressure injections, and to analyse their value for arterial phase CT scans.
Retrospectively, we identified 204 patients who underwent TIVPP implantation in the forearm (n=152) or chest (n=52) between November 2009 and May 2011. Implantation via an upper arm (forearm port, FP) or subclavian vein (chest port, CP) was performed under sonographic and fluoroscopic guidance. Complications were evaluated following the standards of the Society of Interventional Radiology. Power injections via TIVPPs were analysed, focusing on adequate functioning and catheter's tip location after injection. Feasibility of automatic bolus triggering, peak injection pressure and arterial phase aortic enhancement were evaluated and compared with 50 patients who had had power injections via classic peripheral cannulas.
Technical success was 100%. Procedure-related complications were not observed. Catheter-related thrombosis was diagnosed in 15 of 152 FPs (9.9%, 0.02/100 catheter days) and in 1 of 52 CPs (1.9%, 0.002/100 catheter days) (p<0.05). Infectious complications were diagnosed in 9 of 152 FPs (5.9%, 0.014/100 catheter days) and in 2 of 52 CPs (3.8%, 0.003/100 catheter days) (p>0.05). Arterial bolus triggering succeeded in all attempts; the mean injection pressure was 213.8 psi. Aortic enhancement did not significantly differ between injections via cannulas and TIVPPs (p>0.05).
TIVPPs can be implanted with high technical success rates, and are associated with low rates of complications if implanted with sonographic and fluoroscopic guidance. Power injections via TIVPPs are safe and result in satisfying arterial contrast. Conventional ports should be replaced by TIVPPs.
[1-14C]glucose oxidation to CO2 and conversion into glyceride by adipose tissue from nonobese and obese subjects has been studied in vitro in the presence of varying medium glucose and insulin concentrations as functions of adipose cell size, the composition of the diet, and antecedent weight gain or loss.
Increasing medium glucose concentrations enhance the incorporation of glucose carbons by human adipose tissue into CO2 and glyceride-glycerol. Insulin further stimulates the conversion of glucose carbons into CO2, but not into glyceride-glycerol. Incorporation of [1-14C]glucose into glyceride-fatty acids by these tissues could not be demonstrated under any of the conditions tested.
Both adipose cell size and dietary composition influence the in vitro metabolism of glucose in, and the response to insulin by, human adipose tissue. During periods of ingestion of weight-maintenance isocaloric diets of similar carbohydrate, fat, and protein composition, increasing adipose cell size is associated with (a) unchanging rates of glucose oxidation and increasing rates of glucose carbon incorporation into glyceride-glycerol in the absence of insulin, but (b) decreasing stimulation of glucose oxidation by insulin. On the other hand, when cell size is kept constant, increasing dietary carbohydrate intake is associated with an increased basal rate of glucose metabolism and response to insulin by both small and large adipose cells. Thus, the rate of glucose oxidation and the magnitude of the insulin response of large adipose cells from individuals ingesting a high carbohydrate diet may be similar to or greater than that in smaller cells from individuals ingesting an isocaloric lower carbohydrate diet.
The alterations in basal glucose metabolism and insulin response observed in adipose tissue from patients with spontaneous obesity are reproduced by weight gain induced experimentally in nonobese volunteers; these metabolic changes are reversible with weight loss. The relationships among adipose cell size, dietary composition, and the metabolism of adipose tissue are similar in spontaneous and in experimental obesity.
This investigation was undertaken in order to (a) characterize the postprandial inflow of individual bile acids to the liver and (b) determine if peripheral venous bile acid levels always adequately reflect the portal venous concentration, or if saturation of hepatic bile acid uptake can occur under physiological conditions. In five patients with uncomplicated cholesterol gallstone disease, the umbilical cord was cannulated during cholecystectomy, and a catheter was left in the left portal branch for 5 to 7 d. The serum concentrations of cholic acid, chenodeoxycholic acid, and deoxycholic acid in portal venous and systemic circulation were then determined at intervals of 15 to 30 min before and after a standardized meal. A highly accurate and specific gas chromatographic/mass spectrometric technique was used.
The sum of the fasting concentrations of the three bile acids averaged 14.04±4.13 μmol/liter in portal venous serum, and 2.44±0.31 μmol/liter in peripheral venous serum. The estimated hepatic fractional uptake of cholic acid was ∼90%, and those of chenodeoxycholic acid and deoxycholic acid were 70-80%. This resulted in an enrichment of systemic bile acids in the dihydroxy bile acid species. In response to a standardized meal, portal venous bile acid concentrations increased two- to sixfold, with a peak seen 15-60 min after the meal. The maximum postprandial portal venous bile acid concentration averaged 43.04±6.12 μmol/liter, and the corresponding concentration in peripheral serum was 5.22±0.74 μmol/liter. The estimated fractional uptakes of the individual bile acids were not affected by the increased inflow to the liver. The peripheral venous concentrations of individual as well as total bile acids were well correlated with those in portal venous serum.
The results (a) give a quantitation of postprandial bile acid inflow to the liver and (b) indicate that the hepatic uptake system for bile acids in healthy man cannot be saturated during maximal inflow of endogenous bile acids. Measurement of peripheral serum bile acids can thus give important information on the status of the enterohepatic circulation.
The present study compared the metabolic responses between a single low-carbohydrate (LC) and low-fat (LF) meal followed by an aerobic exercise bout in females. Subjects included 8 active, premenopausal females. Subjects completed a LC and LF testing session. Respiratory gas exchange (RER) measurements were taken for 20 min fasted, for 55 min postprandial (PP), and during 30 min of exercise. Blood was collected for assessment of glucose (G), insulin (IN), triglycerides (TG), and free fatty acids (FFA) during the final 10 min of each time period. The LF meal provided 396 kcal (78% carbohydrate, 7% fat, and 15% protein). The LC meal provided 392 kcal (15% carbohydrate, 68% fat, and 18% protein). No significant differences existed between test meals for fasting blood measurements. PP IN (μU·mL-1) levels were significantly lower following LC compared to LF [10.7 (6.1) vs. 26.0 (21.0)]. Postexercise (PE) FFA (mEq·L-1) levels were significantly greater following LC [1.1 (0.3) vs. 0.5 (0.3)]. PE TG (mg·dL-1) levels were significantly greater following LC [152.0 (53.1) vs. 114.4 (40.9)]. RER was significantly lower at all time points following LC compared to LF. In moderately active adult females, ingestion of a single LC meal resulted in greater lipid oxidation at rest and during exercise as compared to a single LF meal. Although macronutrient distribution appears to have dictated substrate utilization in the present study, more research is needed regarding the long-term effects of macronutrient redistribution with and without exercise on substrate utilization.
The relative carbohydrate content of a single meal has a significant impact on postprandial metabolism and substrate utilization in healthy, active females.
A single bout of aerobic exercise performed within an hour of meal ingestion has the potential to modify the postprandial response.
Interventions aimed at improving body composition and preventing chronic disease should focus on dietary macronutrient redistribution and postprandial metabolism in concert with exercise training.
Macronutrient distribution; exercise; low-carbohydrate
Clinical experience with the continuous glucose monitoring systems (CGMS) is limited in Korea. The objective of this study is to evaluate the accuracy of the CGMS and the correlation between interstitial fluid and venous plasma glucose level in Korean healthy male subjects.
Thirty-two subjects were served with glucose solution contained same amount of test food's carbohydrate and test foods after separate overnight fasts. CGMS was performed over 3 days during hopitalization for each subjects. Venous plasma glucose measurements were carried out during 4 hours (0, 0.25, 0.5, 0.75, 1, 2, 4 hours) just before and after glucose solution and test food load. The performance of the CGMS was evaluated by comparing its readings to those obtained at the same time by the hexokinase method using the auto biochemistry machine (Hitachi 7600-110). Also, correlations between glucose recorded with CGMS and venous plasma glucose value were examined.
CGMS slightly underestimated the glucose value as compared with the venous plasma glucose level (16.3 ± 22.2 mg/dL). Correlation between CGMS and venous plasma glucose values throughout sensor lifetime is 0.73 (regression analysis: slope = 1.08, intercept = 8.38 mg/dL). Sensor sensitivity can deteriorate over time, with correlations between venous blood glucose and CGMS values dropping from 0.77 during 1st day to 0.65 during 2nd and 3rd day.
The accuracy of data provided by CGMS may be less than expected. CGMS sensor sensitivity is decreased with the passage of time. But, from this study, CGMS can be used for glucose variability tendency monitoring conveniently to the Korean.
Continuous glucose monitoring system; Extracellular fluid; Plasma
Glucose is an important substrate for myocardial metabolism. This study was designed to determine the effect of circulating metabolic substrates on myocardial glucose extraction and to determine the metabolic fate of glucose in normal human myocardium. Coronary sinus and arterial catheters were placed in 23 healthy male volunteers. [6-14C]Glucose was infused as a tracer in 10 subjects. [6-14C]Glucose and [U-13C]lactate were simultaneously infused in the other 13 subjects. Simultaneous blood samples were obtained for chemical analyses of glucose, lactate, and free fatty acids and for the the isotopic analyses of glucose and lactate. Glucose oxidation was assessed by measuring myocardial 14CO2 production. The amount of glucose extracted and oxidized by the myocardium was inversely correlated with the arterial level of free fatty acids (r = -0.71; P less than 0.0001). 20% (range, 0-63%) of the glucose extraction underwent immediate oxidation. Chemical lactate analysis showed a net extraction of 26.0 +/- 16.4%. However, isotopic analysis demonstrated that lactate was being released by the myocardium. In the 13 subjects receiving the dual-carbon-labeled isotopes, the lactate released was 0.09 +/- 0.04 mumol/ml and 49.5 +/- 29.5% of this lactate was from exogenous glucose. This study demonstrates that the circulating level of free fatty acids plays a major role in determining the amount of glucose extracted and oxidized by the normal human myocardium. Only 20.1 +/- 19.4% of the glucose extracted underwent oxidation, and 13.0 +/- 9.0% of the glucose extracted was metabolized to lactate and released by the myocardium. Thus, 60-70% of the glucose extracted by the normal myocardium is probably stored as glycogen in the fasting, resting state.
During very low carbohydrate intake, the regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. Ketone bodies flow from the liver to extra-hepatic tissues (e.g., brain) for use as a fuel; this spares glucose metabolism via a mechanism similar to the sparing of glucose by oxidation of fatty acids as an alternative fuel. In comparison with glucose, the ketone bodies are actually a very good respiratory fuel. Indeed, there is no clear requirement for dietary carbohydrates for human adults. Interestingly, the effects of ketone body metabolism suggest that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. Also, the recent landmark study showed that a very-low-carbohydrate diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men. Contrary to popular belief, insulin is not needed for glucose uptake and utilization in man. Finally, both muscle fat and carbohydrate burn in an amino acid flame.
low-carbohydrate diets; ketogenic diets; ketogenesis; ketosis; diabetic ketoacidosis; ketone bodies; gluconeogenesis; insulin; glucagon; carbohydrate recommendations; glucose utilization; glucose transporters; fatty acids
Urocortins are the endogenous ligands for the corticotropin-releasing factor receptor type 2 (CRFR2), which is implicated in regulating energy balance and/or glucose metabolism. We determined the effects of chronic CRFR2 activation on metabolism in vivo, by generating and phenotyping transgenic mice overproducing the specific CRFR2 ligand urocortin 3.
Body composition, glucose metabolism, insulin sensitivity, energy efficiency and expression of key metabolic genes were assessed in adult male urocortin 3 transgenic mice (Ucn3+) under control conditions and following an obesogenic high-fat diet (HFD) challenge.
Ucn3+ mice had increased skeletal muscle mass with myocyte hypertrophy. Accelerated peripheral glucose disposal, increased respiratory exchange ratio and hypoglycaemia on fasting demonstrated increased carbohydrate metabolism. Insulin tolerance and indices of insulin-stimulated signalling were unchanged, indicating these effects were not mediated by increased insulin sensitivity. Expression of the transgene in Crfr2 (also known as Crhr2)-null mice negated key aspects of the Ucn3+ phenotype. Ucn3+ mice were protected from the HFD-induced hyperglycaemia and increased adiposity seen in control mice despite consuming more energy. Expression of uncoupling proteins 2 and 3 was higher in Ucn3+ muscle, suggesting increased catabolic processes. IGF-1 abundance was upregulated in Ucn3+ muscle, providing a potential paracrine mechanism in which urocortin 3 acts upon CRFR2 to link the altered metabolism and muscular hypertrophy observed.
Urocortin 3 acting on CRFR2 in skeletal muscle of Ucn3+ mice results in a novel metabolically favourable phenotype, with lean body composition and protection against diet-induced obesity and hyperglycaemia. Urocortins and CRFR2 may be of interest as potential therapeutic targets for obesity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2205-6) contains supplementary material, which is available to authorised users.
CRFR2; Energy balance; Glucose uptake; IGF-1; Obesity; Skeletal muscle; Transgenic mice; Urocortin 3
In obese adult diabetics, the concentration of insulin in venous plasma was unrelated to the degree of hyperglycemia after an overnight fast. However, in these subjects, insulin rose and fell in proportion to the magnitude of change in plasma glucose induced by small intravenous infusions of glucose. The minimal dose of glucose to cause a significant rise in insulin above the fasting level was similar in normal subjects, obese nondiabetic subjects, and in obese, hyperglycemic adult diabetics. This dose lay between infusion of 60 and 100 mg of glucose per min for 30 min. These results suggested that the secretion of insulin was under regulation by changes in blood glucose but was not stimulated in proportion to the stable raised blood glucose concentration of the hyperglycemic diabetic. Artificial hyperglycemia was induced in fasting normal subjects by constant intravenous infusion of glucose at rates of 100-250 mg of glucose per min for periods up to 8 hr. Plasma glucose rose during the 1st hr of infusion and then remained constantly elevated for up to 8 hr. The concentration of plasma insulin paralleled that of plasma glucose. During the period of constant hyperglycemia and elevated insulin, superimposition of a brief additional glucose load resulted in a prompt rise in glucose and insulin, both returning to the previous elevated levels.
Thus in normals as well as obese diabetics, stable hyperglycemia does not produce a pancreatic response sufficient to return the blood glucose to an arbitrary normal fasting concentration, yet the beta cells remain readily responsive to a change in plasma glucose. These data suggest that the beta cells do not operate as a control system with an absolute reference point when presented with systemic hyperglycemia. The behavior of the beta cells during hyperglycemia in the fasting obese adult diabetic suggests that the regulation of the basal insulin secretion may not be determined by factors directly related to the prevailing concentration of glucose. It is postulated that the beta cells adapt to hyperglycemia perhaps through the operation of controls directed toward a normal delivery of free fatty acids or some other cellular metabolic substrate during fasting.
Polyphenols, including flavonoids, phenolic acids, proanthocyanidins and resveratrol, are a large and heterogeneous group of phytochemicals in plant-based foods, such as tea, coffee, wine, cocoa, cereal grains, soy, fruits and berries. Growing evidence indicates that various dietary polyphenols may influence carbohydrate metabolism at many levels. In animal models and a limited number of human studies carried out so far, polyphenols and foods or beverages rich in polyphenols have attenuated postprandial glycemic responses and fasting hyperglycemia, and improved acute insulin secretion and insulin sensitivity. The possible mechanisms include inhibition of carbohydrate digestion and glucose absorption in the intestine, stimulation of insulin secretion from the pancreatic β–cells, modulation of glucose release from the liver, activation of insulin receptors and glucose uptake in the insulin-sensitive tissues, and modulation of intracellular signalling pathways and gene expression. The positive effects of polyphenols on glucose homeostasis observed in a large number of in vitro and animal models are supported by epidemiological evidence on polyphenol-rich diets. To confirm the implications of polyphenol consumption for prevention of insulin resistance, metabolic syndrome and eventually type 2 diabetes, human trials with well-defined diets, controlled study designs and clinically relevant end-points together with holistic approaches e.g., systems biology profiling technologies are needed.
diet; phytochemical; polyphenols; phenolic compounds; glucose metabolism; insulin sensitivity; glycemic response