Effect of intramuscular fat difference on glucose and insulin reaction in oral glucose tolerance test

We investigated the relationship between insulin reaction and glycemic control in a 75-g oral glucose tolerance test of lipid in the paraspinal muscles using computed tomography (CT). The subjects were 79 males aged from 30 to 60 years old whose body mass index (BMI) was 25 or more. Those who had already been diagnosed as having type-2 diabetes mellitus in a regular health check and whose fasting plasma glucose was 126 mg/dl or more were excluded. Abdominal CT scan at the umbilicus level was conducted, and the visceral fat area (VFA) and subcutaneous fat area (SFA) were obtained. As an index of the relative lipid content within muscle, the mean skeletal muscle attenuation (MA) was determined. The age-adjusted odds ratio caused by the MA size for each variable was calculated. Compared with those with smaller intramuscular fat volume, those with larger volume demonstrated 8.75 times higher BMI, 3.73 times higher VFA and 2.88 times higher HOMA-IR. A significant difference was observed between the groups with high and low lipid content in the muscle in the values of Age, BMI, VFA, Fasting immunoreactive insulin (IRI) and HOMA-IR. It was suggested that MA of the paraspinal muscles reflected fat content, and this regional body composition parameter was closely related to insulin secretion response and glycemic control.     

Vagal stimulation exaggerates the inhibitory ghrelin response to oral fat in humans

Ghrelin, the growth hormone secretagogue receptor ligand, is a key regulator of adiposity and food intake. However, the regulation of ghrelin in response to dietary fat intake remains largely unclear. Furthermore, cephalic elevation of ghrelin may influence fat absorption and postprandial lipaemia. Therefore, the aim of this study was to examine the effect of fat ingestion and vagal stimulation on the regulation of plasma ghrelin.Vagal stimulation was achieved by modified sham feeding (MSF). Eight healthy subjects (four male/four female) consumed a 50 g fat load on two separate occasions. On one occasion, the fat load was preceded by the MSF of a meal for 1 h. Blood, appetite and breath were analysed for 5 h postprandially.A 25% (S.E.M. 3.4) suppression in ghrelin concentration was observed after fat ingestion (P<0.001), without an increase in glucose or insulin. MSF in addition to oral fat enhanced ghrelin suppression further, as well as elevating plasma triacylglycerol (P<0.001) and reducing appetite (P<0.001). The fasting ghrelin concentration was inversely correlated with gastric half-emptying time (P=0.036).We conclude that ghrelin release may be influenced directly by both vagal stimulation and oral fat ingestion.     

Effect of oral fat on plasma levels of neurotensin and neurotensin fragments in humans

The effect of ingestion of fat (Lipomul 1 g/kg) on the circulating levels of neurotensin (NT^1–3) and amino-terminal fragments (NT^1–8, NT^1–11) and carboxy-terminal fragment (NT^8–13) of NT were investigated in six healthy male volunteers. NT and NT fragments were extracted from plasma collected at 0, 15, 30, and 60 min after ingestion of fat, and the plasma levels of NT^1–13 and NT fragments were characterized using high-pressure liquid chromatography and radioimmunoassay techniques. Significant elevations of plasma levels of NT^1–8, NT^1–11, and NT^1–13 were observed at 15, 30, and 60 min after fat ingestion. The maximum elevations were 273% for NT^1–8, 234% for NT^1–11, and 54% for NT^1–13. NT^8–13 levels failed to rise significantly when compared to basal levels. These findings indicate that both the aminoterminal and carboxyterminal fragments of NT are either released along with intact NT or are formed as metabolites from NT^1–13 in response to ingestion of fat in man.Dr. Upp was awarded a fellowship grant from the American Cancer Society Texas Division.Supported by grants from the National Institutes of Health (5R37 DK 15241, PO1 DK 35608, MO1 RR00073) and a grant from the American Cancer Society (PDT-220).     

Lipid-dependent control of hepatic glycogen stores in healthy humans

Aims/hypothesis. Non-esterified fatty acids and glycerol could stimulate gluconeogenesis and also contribute to regulating hepatic glycogen stores. We examined their effect on liver glycogen breakdown in humans.¶Methods. After an overnight fast healthy subjects participated in three protocols with lipid/heparin (plasma non-esterified fatty acids: 2.2 ± 0.1 mol/l; plasma glycerol: 0.5 ± 0.03 mol/l; n = 7), glycerol (0.4 ± 0.1 mol/l; 1.5 ± 0.2 mol/l; n = 5) and saline infusion (control; 0.5 ± 0.1 mol/l; 0.2 ± 0.02 mol/l; n = 7). Net rates of glycogen breakdown were calculated from the decrease of liver glycogen within 9 h using ¹³C nuclear magnetic resonance spectroscopy. Endogenous glucose production was measured with infusion of D-[6,6-²H₂]glucose.¶Results. Endogenous glucose production decreased by about 25 % during lipid and saline infusion (p < 0.005) but not during glycerol infusion (p < 0.001 vs lipid, saline). An increase of plasma non-esterified fatty acids or glycerol reduced the net glycogen breakdown by about 84 % to 0.6 ± 0.3 μmol · kg^–1· min^–1 (p < 0.001 vs saline: 3.7 ± 0.5 μmol · kg^–1· min^–1) and by about 46 % to 2.0 ± 0.4 μmol · kg^–1· min^–1 (p < 0.01 vs saline and lipid), respectively. Rates of gluconeogenesis increased to 11.5 ± 0.8 μmol · kg^–1· min^–1 (p < 0.01) and 12.8 ± 1.0 μmol · kg^–1· min^–1 (p < 0.01 vs saline: 8.2 ± 0.7 μmol · l^–1· min^–1), respectively.¶Conclusion/interpretation: An increase of non-esterified fatty acid leads to a pronounced inhibition of net hepatic glycogen breakdown and increases gluconeogenesis whereas glucose production does not differ from the control condition. We suggest that this effect is not due to increased availability of glycerol alone but rather to lipid-dependent control of hepatic glycogen stores. [Diabetologia (2001) 44: 48–54]     

Contribution of net hepatic glycogen synthesis to disposal of an oral glucose load in humans

The contribution of hepatic glycogen synthesis to whole body glucose disposal after an oral glucose load was examined using (13)C nuclear magnetic resonance (NMR) spectroscopy to measure liver glycogen content in healthy, volunteers after an overnight fast. In group 1 (n = 14), hepatic glycogen synthesis was measured using (13)C-NMR spectroscopy for 240 minutes after ingestion of 98 +/- 1 g glucose. Liver volumes were measured using magnetic resonance imaging (MRI). To assess the direct (glucose --> glucose-6-P --> glucose-1-P --> uridine diphosphate (UDP)-glucose --> glycogen) and indirect (3-carbon units --> --> glycogen) pathways of liver glycogen synthesis, group 2 (n = 6) was studied with an identical glucose load enriched with [1-(13)C]glucose along with acetaminophen to noninvasively assess the (13)C enrichment in hepatic UDP-glucose. The fasting hepatic glycogen content was 305 +/- 17 mmol/L liver, and the liver volume was 1.46 +/- 0.07 L. For the initial 180 minutes after ingestion of glucose, hepatic glycogen concentrations increased linearly (r =.94, P =.0006) achieving a maximum concentration of 390 +/- 7 mmol/L liver and then remained constant until the end of the study. The mean maximum rate of net hepatic glycogen synthesis was 0.48 +/- 0.07 mmol/L liver-minute. Total liver glycogen synthesis could account for 16.7 +/- 3.8 g (17% +/- 4%) of the glucose ingested, and of this, 10.5 +/- 2.4 g (63% +/- 7%) was synthesized by the direct pathway. In conclusion, after ingestion of 98 g of glucose: (1) 16.7 +/- 3.8 g (17% +/- 4%) glucose was stored in the liver as glycogen, and (2) 63% +/- 7% (10.5 +/- 2.4 g) of this glycogen was formed via the direct pathway.     

Splanchnic galactose extraction is regulated by coingestion of glucose in humans

When compared with galactose alone, coingestion of glucose with galactose decreases plasma galactose. The objective of this study was to determine if this was due to increased peripheral clearance or increased first pass clearance of galactose. Five adult volunteers were studied on 2 occasions during infusion of [6,6-(2)H(2)]glucose and [1-(13)C]galactose and ingestion of galactose alone at 11, 22, and 33 micromol x kg(-1) x min(-1) or galactose plus glucose at 11, 22, and 33 micromol x kg(-1) x min(-1) of each sugar. At 33 micromol x kg(-1) x min(-1) of galactose alone (1) plasma galactose increased to 2.3 +/- 0.3 mmol/L and galactose rates of appearance (Ra) to 18.3 +/- 1.6 micromol x kg(-1) x min(-1); (2) plasma glucose and glucose Ra were unaffected; (3) splanchnic extraction of galactose plateaued at approximately 15 micromol x kg(-1) x min(-1); and (4) galactose became the primary source of glucose Ra (75% +/- 9%). Coingestion of glucose and galactose at 33 micromol x kg(-1) x min(-1) each resulted in (1) decreased plasma galactose (0.3 +/- 0.1 mmol/L) and galactose Ra (6.4 +/- 1.8 micromol x kg(-1) x min(-1)); (2) increased plasma glucose and insulin; (3) doubling of splanchnic extraction of galactose; and (4) decreased contribution of galactose to glucose Ra (11% +/- 4%). We conclude that coingestion of glucose with galactose increases the splanchnic extraction, but decreases the conversion of galactose to glucose.     

Modulation of glucose production by indomethacin and pentoxifylline in healthy humans

Indomethacin, an inhibitor of prostaglandin synthesis that modulates cytokine production, increases hepatic glucose output (HGO) in humans. However, prostaglandins stimulate glucose production in vitro. To investigate the mechanism of HGO stimulation by indomethacin, we compared the effect of pentoxifylline, an inhibitor of cytokine production, versus saline (study 1, N = 6) and of indomethacin versus the combination of indomethacin and pentoxifylline (study 2, N = 5) on basal HGO. HGO was measured by primed, continuous infusion of 3-³H-glucose. In study 1, pentoxifylline infusion resulted in an immediate, transient decrease of HGO of approximately 50% (from 12.9 ± 0.4 to 6.0 ± 1.7 μmol/kg/min after 15 minutes, P < .03 v control). There were no differences in concentrations of glucoregulatory hormones between the two experiments. In study 2, after indomethacin administration, HGO increased transiently by approximately 84% (from 9.7 ± 0.7 at baseline to 16.7 ± 2.4 μmol/kg/min after 135 minutes, P < .05). However, pentoxifylline did not affect the increase in HGO induced by indomethacin. There were no differences in concentrations of glucoregulatory hormones between the two experiments. Therefore, indomethacin stimulates HGO by mechanisms unrelated to glucoregulatory hormones, prostaglandins, or cytokines.     

Liver fat and lipid oxidation in humans

Background: Studies in animals show that changes in hepatic fatty acid oxidation alter liver fat content. Human data regarding whole‐body and hepatic lipid oxidation are controversial and based on studies of only a few subjects. Aims: We examined whether whole‐body and hepatic lipid oxidation are altered in subjects with non‐alcoholic fatty liver disease (NAFLD) compared with controls. Methods: In vivo measurements of rates of substrate oxidation and insulin sensitivity (using the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry and infusion of [3‐³H]glucose) were performed in subjects with NAFLD [mean liver fat 14.0% (interquartile range 7.5–20.5%), n=29] and in control subjects [1.6% (1.0–3.0%), n=29]. Liver fat was measured using proton magnetic resonance spectroscopy. Plasma concentrations of 3‐hydroxybutyrate (3‐OHB) were measured as markers of hepatic lipid oxidation. Results: In the basal state, substrate oxidation rates and serum 3‐OHB concentrations were comparable in subjects with and without NAFLD. Plasma 3‐OHB concentrations were similarly suppressed by insulin in both the groups. During the insulin infusion, whole‐body lipid oxidation was inversely correlated with insulin‐stimulated glucose disposal (r=?0.48, P<0.0001), which was lower in subjects with NAFLD [3.7±0.2 mg/(kg fat‐free mass min)] than in the control subjects [5.0±0.3 mg/(kg fat‐free mass min), P=0.0008]. Conclusions: Hepatic lipid oxidation is unchanged in NAFLD. Whole‐body lipid oxidation is increased because of peripheral insulin resistance. These data imply that alterations in hepatic fatty acid oxidation do not contribute to liver fat content in humans.     

Hypoxia causes glucose intolerance in humans

Hypoxic respiratory diseases are frequently accompanied by glucose intolerance. We examined whether hypoxia is a cause of glucose intolerance in healthy subjects. In a double-blind within-subject crossover design, hypoxic versus normoxic conditions were induced in 14 healthy men for 30 minutes by decreasing oxygen saturation to 75% (versus 96% in control subjects) under the conditions of a euglycemic clamp. The rate of dextrose infusion needed to maintain stable blood glucose levels was monitored. Neurohormonal stress response was evaluated by measuring catecholamine and cortisol concentrations as well as cardiovascular parameters, and symptoms of anxiety. To differentiate between the effects of stress hormonal response, and hypoxia itself, on glucose intolerance, we performed hypoglycemic clamps as a nonspecific control. We found a significant decrease in dextrose infusion rate over a period of 150 minutes after the start of hypoxia (p < 0.01). Hypoxia also increased plasma epinephrine concentration (p < 0.01), heart rate (p < 0.01), and symptoms of anxiety (p < 0.05), whereas the other parameters remained unaffected. Glucose intolerance was closely comparable between hypoxic and hypoglycemic conditions (p < 0.9) despite clear differences in stress hormonal responses. Hypoxia acutely causes glucose intolerance. One of the factors mediating this effect could be an elevated release of epinephrine.     

Impaired proinsulin secretion before and during oral glucose stimulation in HIV-infected patients who display fat redistribution

The beta-cell function of HIV-infected patients on highly active antiretroviral therapy who display lipodystrophy may be impaired. An early defect in beta-cell function may be characterized by an increase in secretion of 32-33 split proinsulin (SP) and intact proinsulin (IP). To address this issue, the secretion patterns of SP and IP of 16 HIV-infected men with lipodystrophy (LIPO) and 15 HIV-infected men without lipodystrophy (NONLIPO) were studied during an oral glucose tolerance test (OGTT). All patients received highly active antiretroviral therapy. Insulin secretion rates were determined by deconvolution of plasma C-peptide concentrations. More LIPO than NONLIPO patients displayed diabetes mellitus and impaired glucose tolerance than normal glucose tolerance (LIPO 2/8/6 vs NONLIPO 1/2/12, P = .05). LIPO patients had increased fasting levels of SP and IP, ratio of SP/IP, and area under the curve of SP and IP during the early phase (0, 10, and 20 minutes) and during the late phase (45, 75, and 105 minutes) of the OGTT compared with NONLIPO patients (Ps < .05). LIPO patients exhibited significantly increased fasting SP/IP ratio, fasting SP/insulin ratio, and total proinsulin to C-peptide ratio during the OGTT. LIPO patients displayed increased incremental secretion of IP during the first 10 minutes of the OGTT (P < .05), although the incremental insulin secretion during this period did not differ between LIPO and NONLIPO patients. These data suggest that HIV-infected patients with lipodystrophy display major perturbations of proinsulin secretion in the fasting state and during an OGTT, which is compatible with the notion of a beta-cell dysfunction of such patients.     

Bioavailability of oral melatonin in humans

We administered crystalline melatonin (80 mg) in gelatin capsules to 5 young male volunteers and measured serum and urinary melatonin levels at intervals. Changes in serum melatonin levels were best described by a biexponential equation with an absorption constant (ka) of 1.72 h-1 (half-life = 0.40 h) and an elimination constant (ke1) of 0.87 h-1 (half-life = 0.80 h). Peak serum melatonin levels, ranging from 350 to 10,000 times those occurring physiologically at nighttime, were observed 60-150 min after its administration, remaining stable for approximately 1.5 h. The fraction of ingested melatonin that was absorbed, estimated from the area under the curve describing serum melatonin concentrations as a function of time after melatonin administration (the concentration-time curve), varied by 25-fold among subjects. 3 additional volunteers received three melatonin-containing capsules (80 mg each) at 60-min intervals. This regimen extended the duration of elevated serum melatonin levels to 4-6 h. Melatonin excretion closely paralleled serum melatonin levels until 9 h after the hormone's administration, after which urinary levels tended to be higher than those predicted from serum levels. However, the area under the concentration-time curve for serum melatonin correlated well (r = 0.96) with the cumulative melatonin excretion during the initial 15 h after melatonin's administration, indicating that either approach can be used to estimate the absorption of orally administered melatonin.     

Effects of intravenous infusion of amino acids,fat, or glucose on unstimulated pancreatic secretion in healthy humans

The effects of intravenous infusion of amino acids, fat, or glucose on unstimulated pancreatic secretion were studied in 31 healthy male volunteers. Each subject was studied twice on two separate days. On both days pancreatic outputs were measured during a 4-hr basal period that was followed by a 4-hr test period. During the test period either one of the digestive end products (100 ml/hr 10% amino acids in 13 subjects; 100 ml/hr 10% fat in 8 subjects; 150 ml/hr 10% glucose in 10 subjects) or saline was intravenously infused. The infusion of the digestive end products or saline on the two separate days was done in a randomized order. Six of the 10 subjects that had already been studied for glucose received a higher glucose dose (100 ml 20% glucose as a bolus followed by 300 ml/hr 10% glucose) in a third additional experiment. Intravenous infusion of amino acids significantly stimulated pancreatic outputs of trypsin and chymotrypsin, but left the outputs of amylase, lipase, bicarbonate, and volume unaffected. The low-glucose dose, as well as the fat infusion did not alter any of the pancreatic outputs. To analyze the relationships between different enzymes during the infusion of digestive end products, regression lines were calculated from the scatter of all individual pairs of enzyme measurements. Significantly different regression functions were found for each condition (NaCl control, amino acids, fat, glucose) when trypsin and chymotrypsin were plotted versus lipase and amylase: amino acids shifted the function to a trypsin- and chymotrypsin-dominant pattern of secretion, glucose to an amylase-dominant pattern, and fat to a lipasedominant pattern. These results demonstrate that although intravenous infusion of digestive end products had only minor effects on the overall amount of pancreatic secretion, circulating end products of digestion can alter the proportion of various digestive enzymes in a selective and short-term manner.This study was presented in part at the 84th Annual Meeting of the American Gastroenterological Association in Washington, D.C., May 1983. An abstract of this part was published in Gastroenterology 84:1260, 1983.     

Acid-independent release of secretin and cholecystokinin by intraduodenal infusion of fat in humans

In order to clarify a possible role of fat content in the release of secretin and cholecystokinin by liquid nutritional supplements in humans, duodenal pH and plasma concentrations of secretin and cholecystokinin were studied during the intraduodenal infusion of Ensure, Vivonex, 10% Intralipid, and sodium oleate. Significant release of secretin was observed with Intralipid and sodium oleate, while significant release of cholecystokinin was observed with all four testing solutions. Duodenal pH was rarely below 4.5 during the infusion of Ensure, Intralipid, and sodium oleate. Duodenal pH was high, greater than 6.0, when plasma secretin and cholecystokinin levels were elevated during the administration of Ensure, Intralipid, and sodium oleate. We conclude that both secretin and cholecystokinin are released in response to fat solutions in the duodenum and that low duodenal pH was not responsible for either secretin or cholecystokinin release during intraduodenal infusions of Ensure, Intralipid, or sodium oleate.     

Assay of glucose transport in human fat cells obtained by needle biopsy

Summary A method was developed for repeated measurements of glucose transport in human fat cells obtained by needle biopsy aspiration. Assay conditions, reproducibility and normal values of the measurements are described. Transport rates were measured in the absence and presence (25, 50, 100, 200, 800 pmol/l; 8, 80 nmol/l) of insulin using U-(¹⁴C)-D-glucose as the tracer. The extracellular glucose concentration was 1.5 mol/l. The reproducibility of glucose transport measurements was assessed by taking two needle biopsies from opposite sides of the same subject (n =11). The mean coefficient of variation for maximal glucose transport was 11±6%. In 14 subjects, a needle biopsy sample was aspirated immediately prior to surgical removal of fat. The maximal insulin-stimulated glucose transport rates averaged 143±15 and 443±15 fl/cell · s, and the ED 50: s 218±124 and 160±28 pmol/l (NS) in fat cells prepared from needle biopsy and surgically removed adipose tissue respectively. The mean coefficient of variation for maximal glucose transport in needle vs. surgical samples was 11±2%. In 6 subjects, a surgical biopsy was taken twice, with a 1-week interval. The coefficient of variation averaged 9±2%. We conclude that measurement of glucose transport rates can be done with similar accuracy using fat cells isolated from needle biopsy aspirates and surgically removed adipose tissue. Use of needle biopsy samples permits, however, study of glucose transport in repeat samples of human fat cells, and may therefore be a useful tool for any perturbation studies.     

Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans

BACKGROUND & AIMS: No blood marker assessing the functional absorptive bowel length has been identified. Plasma citrulline, a nonprotein amino acid produced by intestinal mucosa, is one candidate. We tested this hypothesis in adult patients with the short-bowel syndrome, whose condition can lead to intestinal failure. METHODS: In 57 patients, after a minimal follow-up of 2 years subsequent to final digestive circuit modification, postabsorptive citrulline concentration was measured and parenteral nutrition dependence was used to define permanent (n = 37) and transient (n = 20) intestinal failure. Absorptive function, studied over a 3-day period, was evaluated by net digestive absorption for protein and fat (n = 51). Relations between quantitative values were assessed by linear regression analysis and cutoff citrulline threshold, for a diagnosis of intestinal failure by linear discriminant analysis. Cox model was used to compare citrulline threshold and anatomic variables of the short bowel as indicators of transient as opposed to permanent intestinal failure. RESULTS: In patients with short-bowel syndrome, citrulline levels were lower than in controls (n = 51): 20 +/- 13 vs. 40 +/- 10 micromol/L (mean +/- SD), respectively (P < 0.001). After multivariate analysis, citrullinemia was correlated to small bowel length (P < 0.0001, r = 0.86) and to net digestive absorption of fat, but to neither body mass index nor creatinine clearance. A 20-micromol/L threshold citrullinemia, (1) classified short bowel patients with permanent intestinal failure with high sensitivity (92%), specificity (90%), positive predictive value (95%), and negative value (86%); and (2) was a more reliable indicator (odds ratio, 20.0; 95% confidence interval, 1.9-206.1) than anatomic variables (odds ratio, 2.9; 95% confidence interval, 0. 5-15.8) to separate transient as opposed to permanent intestinal failure. Conclusions: In patients with short-bowel syndrome, postabsorptive plasma citrulline concentration is a marker of functional absorptive bowel length and, past the 2-year adaptive period, a powerful independent indicator allowing distinction of transient from permanent intestinal failure.     

The response of serum sialic acid and other acute phase reactants to an oral fat load in healthy humans

Background: Elevated serum total sialic acid (TSA) has been shown to be associated with increased cardiovascular mortality. It has been postulated that atherogenesis is a postprandial phenomenon. We tested the hypothesis that serum TSA and other acute phase proteins, namely C-reactive protein (CRP) and fibrinogen, may be related to the postprandial state. Methods: Ten healthy male subjects, aged 24–48 years, were fed 62.5 g of total fat (saturates 12 g, monounsaturates 35.3 g and polyunsaturates 12.5 g) in the form of strawberry flavoured Calogen. Venous blood was sampled hourly for 5 h. Concentrations of serum triglyceride, TSA and acute phase proteins were measured. Results: Serum triglyceride concentration increased postprandially, peaking at 240 min. Serum CRP and plasma fibrinogen did not significantly increase after the oral fat load. However, serum TSA did increase from baseline (0.599±0.051 g/l) in response to the oral fat load, peaking at 120 min post-oral fat load (0.633±0.066 g/l, P<0.02). There was a significant correlation between serum TSA and plasma fibrinogen at baseline (ρ=0.62, P=0.05) but not for serum CRP (ρ=−0.22) or triglyceride (ρ=0.21). Conclusions: We conclude that serum TSA increases postprandially and this finding gives further insight as to why the former is considered to be a cardiovascular risk factor.     

The effects of body fat distribution on glucose tolerance in overweight subjects: glucose intolerance and insulin resistance induced by intra-abdominal fat accumulation]

To evaluate the pathophysiological significance of intra-abdominal fat accumulation in Japanese subjects with mild to moderate overweight, 107 subjects (56 men and 51 women, aged 16-68 years) with body mass index (BMI, kg/m2) of 17-39 (mean +/- SD, 25 +/- 4.3) were evaluated. Subjects with disorders which affect glucose metabolism, such as thyroid, adrenal, liver, and kidney diseases, were excluded. A 75 g oral glucose tolerance test (OGTT) was performed in all subjects, and venous samples were obtained before 15, 30, 60, 90 and 120 min after the glucose load for plasma glucose (PG), immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR) measurements. In 72 of the subjects, plasma free fatty acid (FFA) level at fasting was also determined. The degree of visceral fat accumulation was evaluated using a CT-scan by the method reported by Fujioka et al. (Metabolism, 36: 54-59, 1987), and intra-abdominal fat area/subcutaneous fat area (V/S ratio) was obtained. V/S ratio and BMI correlated positively in subjects with BMI less than 25 (17 men and 16 women, aged 28-62 years) but they did not correlate at all with each other in those with BMI greater than or equal to 25 (39 men and 35 women, aged 16-68 years). Based on this finding, the possible adverse effects of increased intra-abdominal fat on glucose metabolism were investigated in the subjects with BMI greater than or equal to 25. For this purpose, the correlation of V/S ratio with fasting PG (FPG), fasting IRI (FIRI), fasting CPR (FCPR), FPG/FIRI, FFA, or PG area (sigma PG) and sigma PG/sigma IRI at OGTT was analyzed. V/S ratio positively correlated with FPG, sigma PG, FPG/FIRI and sigma PG/sigma IRI but not with FFA. The correlation between V/S ratio and FIRI or FCPR was significant in the subjects with V/S ratio greater than or equal to 0.8 in men and greater than or equal to 0.4 in women. In sharp contrast to V/S ratio, BMI did not correlate at all with any of these metabolic indices. We conclude that in Japanese subjects with mild overweight to moderate obesity, intra-abdominal fat accumulation, but not the increase in the degree of obesity, accompanies worsening of glucose tolerance. Because PG elevation relative to IRI secretion is progressively greater with increasing V/S ratio, it is suggested that the deleterious effects of intra-abdominal fat accumulation can be attributed to increased insulin resistance.     

Energy stores and metabolites in chronic reversibly and irreversibly dysfunctional myocardium in humans

OBJECTIVES: Our goal was to study metabolic energy stores and lactate content in chronic reversibly and irreversibly dysfunctional myocardium. BACKGROUND: It is unknown whether metabolism is deranged in chronic reversibly and irreversibly dysfunctional myocardium in humans. Semiquantitative histological examinations have shown altered mitochondrial morphology and glycogen accumulation in dysfunctional regions. METHODS: We studied 25 patients with a mean ejection fraction of 38 +/- 9% scheduled for coronary artery bypass surgery. Regional perfusion and metabolism were assessed by positron emission tomography, and regional function was assessed by echocardiography. Perioperative myocardial biopsies were obtained from a control region and from a dysfunctional region. We analyzed biopsies for contents of noncollagen protein (NCP), ATP, ADP, AMP, glycogen and lactate. Six months after surgery we assessed wall motion by echocardiography to group patients in those with (n = 11) and without (n = 14) functional improvement. RESULTS: Reversibly dysfunctional myocardium had reduced perfusion (0.59 +/- 0.16 vs. 0.69 +/- 0.20 ml/g/min, p < 0.05), similar glucose-tracer uptake (92 +/- 12 and 95 +/- 14%), ATP/ADP ratio (2.4 +/- 1.1 and 2.4 +/- 0.7), glycogen content (631 +/- 174 and 632 +/- 148 nmol/microg NCP) and lactate levels (59 +/- 27 and 52 +/- 29 nmol/microg NCP) compared with control regions. Irreversibly dysfunctional regions (n = 14) had severely reduced perfusion (0.48 +/- 0.15 vs. 0.72 +/- 0.12 ml/g/min, p < 0.001) and glucose-tracer uptake (52 +/- 16 vs. 94 +/- 15%, p < 0.001), reduced ATP/ADP ratio (1.5 +/- 0.9 vs. 2.3 +/- 0.9, p < 0.05), similar glycogen content (579 +/- 265 vs. 593 +/- 127 nmol/microg NCP) and increased lactate levels (114 +/- 52 vs. 89 +/- 24 nmol/microg NCP, p < 0.01) compared with control regions. CONCLUSIONS: Contents of metabolic energy stores and lactate in chronic reversibly dysfunctional myocardium were preserved. In contrast, energy stores were depleted in myocardium without functional recovery after revascularization.