Suppression Of Nonesterified Fatty Acids Research Articles

Intrahepatic Lipid Content and Insulin Resistance Are More Strongly Associated with Impaired NEFA Suppression after Oral Glucose Loading Than with Fasting NEFA Levels in Healthy Older Individuals

Introduction. The mechanisms underlying the association between insulin resistance and intrahepatic lipid (IHL) accumulation are not completely understood. We sought to determine whether this association was explained by differences in fasting non-esterified fatty acid (NEFA) levels and/or NEFA suppression after oral glucose loading. Materials and Methods. We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 ± 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin, and NEFA levels measured over two hours. IHL was quantified with magnetic resonance spectroscopy. Insulin sensitivity was measured with the oral glucose insulin sensitivity (OGIS) model, the leptin: adiponectin ratio (LAR), and the homeostasis model assessment (HOMA). Results. Measures of insulin sensitivity were not associated with fasting NEFA levels, but OGIS was strongly associated with NEFA suppression at 30 minutes and strongly inversely associated with IHL. Moreover, LAR was strongly inversely associated with NEFA suppression and strongly associated with IHL. This latter association (beta = 1.11 [1.01, 1.21], P = 0.026) was explained by reduced NEFA suppression (P = 0.24 after adjustment). Conclusions. Impaired postprandial NEFA suppression, but not fasting NEFA, contributes to the strong and well-established association between whole body insulin resistance and liver fat accumulation.

Nonalcoholic Fatty Liver Disease: Its Mechanisms and Complications

Nonalcoholic Fatty Liver Disease: Its Mechanisms and Complications

Effect of Colesevelam Hydrochloride on Glycemia and Insulin Sensitivity in Men With the Metabolic Syndrome

Colesevelam hydrochloride (colesevelam) lowers low-density lipoprotein (LDL) cholesterol and glycated hemoglobin in patients with type 2 diabetes mellitus. The present study examined the effects of colesevelam treatment in nondiabetic men with metabolic syndrome. Twenty men completed the study, which consisted of two 8-week phases of treatment with colesevelam (3.75 g/day) or placebo and a 6-week washout between study phases. Of the 20 men, 17 took statins throughout. The fasting plasma LDL cholesterol, triglyceride, glucose, and glycated hemoglobin levels were measured in the last 2 weeks of each study phase. Nonesterified fatty acids and 3-hydroxybutyrate, insulin, and glucose were measured hourly for 5 hours during fasting and during an extended glucose tolerance test. The colesevelam treatment reduced LDL cholesterol from 96 ± 28 mg/dl to 78 ± 32 mg/dl (p <0.006) and non-high-density lipoprotein cholesterol by 8.2% (p = 0.07). Triglycerides increased by 17% (p <0.02). The fasting plasma glucose was reduced by 5 mg/dl (p <0.03), and glycated hemoglobin remained unchanged by colesevelam. No significant treatment changes were noted for the 2-hour glucose test or insulin sensitivity. The fasting nonesterified fatty acid level was significantly reduced with treatment but the 3-hydroxybutyrate level was unchanged. Insulin-mediated suppression of nonesterified fatty acids during extended glucose tolerance test was significantly less effective during treatment than during placebo. In conclusion, colesevelam significantly reduced the LDL cholesterol levels, even though the baseline LDL cholesterol level was low owing to statin treatment. The fasting and postprandial blood glucose level but not the glycated hemoglobin level was lowered by colesevelam therapy. The effect on fasting glucose was unrelated to the changes in insulin resistance or fatty acid oxidation. Finally, an increase in triglycerides with colesevelam therapy might have been related to a lesser suppression of nonesterified fatty acids levels in the postprandial state.

Insulin Resistance, Defective Insulin-Mediated Fatty Acid Suppression, and Coronary Artery Calcification in Subjects With and Without Type 1 Diabetes

OBJECTIVETo assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls.RESEARCH DESIGN AND METHODSInsulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m2/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female).RESULTSPeripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m2/min insulin infusion = 370 ± 27 vs. 185 ± 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = −0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22–0.93, P = 0.03; OR = 2.4, 95% CI = 1.08–5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters.CONCLUSIONSType 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes.

Effect of adipose tissue on the sexual dimorphism in metabolic flexibility

Metabolic flexibility is the ability to transition between fat oxidation (fasting state) and glucose oxidation (fed state). We hypothesized that adipose tissue inflammation and lipid metabolism contribute to sexual dimorphism in metabolic flexibility. Respiratory quotient (ΔRQ, metabolic flexibility) and nonesterified fatty acids (NEFAs) before and during euglycemic-hyperinsulinemic clamp were measured in healthy young women (n = 22) and men (n = 56). Adiponectin levels were measured in plasma. Abdominal subcutaneous adipose tissue gene expression was measured by quantitative reverse transcriptase polymerase chain reaction. As compared with men, women had higher ΔRQ (0.14 ± 0.04 vs 0.09 ± 0.04, P < .01). Fasting RQ and fat cell size were not different between sexes. As compared with men, women had lower insulin-suppressed NEFAs ( P < .05); greater adiponectin levels; and higher expression of adipogenesis, fatty acid storage, and oxidation genes (PPAR γ2, PCK1, SCD1, and PPAR α; P < .05). There were no sex differences in messenger RNA of macrophage markers or chemokines. Stepwise regression analysis revealed that the only adipose tissue characteristics that influenced metabolic flexibility in women were SCD1 and PCK1 messenger RNA (model R 2 = 0.49, P < .05); in men, these were serum adiponectin and insulin-suppressed NEFAs (model R 2 = 0.34, P < .05). Healthy young women are more metabolically flexible than men, driven by an increase in insulin-stimulated glucose oxidation rather than differences in fasting fat oxidation. Women have greater capacity for insulin suppression of NEFAs despite similar chemokine and macrophage content in adipose tissue. Combined, these results provide evidence for a role of adipose tissue characteristics in the sexual dimorphism of metabolic flexibility.

Relationship of Postprandial Nonesterified Fatty Acids, Adipokines, and Insulin Across Gender in Human Immunodeficiency Virus–Positive Patients Undergoing Highly Active Antiretroviral Therapy

Metabolic derangements are common in human immunodeficiency virus (HIV)-positive subjects undergoing antiretroviral therapy, but little is known about postprandial conditions. We investigated the relationship between leptin, adiponectin, nonesterified fatty acids (NEFA), and insulin in response to a day-long meal pattern and evaluated gender differences in HIV-positive men (n = 12) and women (n = 13) undergoing highly active antiretroviral therapy (HAART). For both men and women, a significant decrease in postprandial NEFA levels was observed following breakfast (0.53 vs. 0.22 mmol/L, P < 0.001, baseline and at 3 hours, respectively), whereas day-long postprandial leptin and adiponectin levels showed small nonsignificant oscillations. In contrast to NEFA and adiponectin, postprandial leptin levels were significantly higher among women compared to men (P < 0.05). Postprandial NEFA levels correlated positively with fasting insulin levels (r(2) = 0.25, P = 0.016), and the postbreakfast decrease in NEFA levels correlated significantly with the postbreakfast increase in insulin levels (r(2) = 0.17, P = 0.038). No significant association between postprandial adipokines and insulin was observed. In HAART-treated, HIV-infected men and women, levels of NEFA, but not adipokines, showed significant postprandial variation. Furthermore, food intake resulted in significant NEFA suppression in proportion to the food-stimulated insulin increase.

Relation of adipose tissue to metabolic flexibility

Metabolic flexibility is the capacity for skeletal muscle to shift reliance between lipids and glucose during fasting or in response to insulin. We hypothesized that body fat, adipose tissue characteristics, e.g. larger adipocytes, presence of inflammatory gene markers and impaired suppression of non-esterified fatty acids (NEFAs) during insulin infusion might be related to metabolic flexibility. We measured changes in respiratory quotient (ΔRQ) before and during euglycemic-hyperinsulinemic clamp in healthy young males. Body fat by DXA, laboratory measurements, abdominal subcutaneous adipose tissue biopsies and fat cell size (FCS) were obtained after an overnight fast. Gene expression for 17 adipose tissue genes related to lipid synthesis, uptake, oxidation and storage, lipolysis and inflammation were measured. Reduced metabolic flexibility was associated with higher body fat, larger FCS and impaired insulin suppression of NEFAs. Metabolic flexibility was associated with higher serum adiponectin levels. Lower adipose tissue gene expression for inflammation markers was associated with greater NEFA suppression by insulin and metabolic flexibility. Combined, these results indicate that body fat, larger adipocytes, failure of insulin to suppress NEFAs, decreased adiponectin levels and inflammation markers in adipose tissue are associated with decreased insulin-stimulated glucose uptake and oxidation, which is an important component of reduced metabolic flexibility.

Insulin’s actions on plasma free fatty acids are normal in patients with stage 2 to 3 chronic kidney disease

Resistance to insulin’s action to suppress plasma nonesterified fatty acids (NEFA) is implicated in the hypertension and hyperlipidemia characterizing the metabolic syndrome. It is unknown whether insulin resistance to NEFA suppression is linked to hypertension and dyslipidemia in patients with mild chronic kidney disease (CKD). Eight patients with nonnephrotic, nondiabetic stage 2 to 3 CKD (I 125–iothalamate clearances of 56 ± 6 mL/min) and 7 hypertensive (HT) and 8 normotensive (NT) subjects with normal kidney function matched for age, gender, race, and percent body fat were studied. Plasma oleate, linoleate, palmitate, and stearate were measured during a 2–stage euglycemic hyperinsulinemic clamp procedure. Insulin suppressed plasma linoleate and oleate similarly in CKD (81%, 84%) and NT subjects (84%, 85%, respectively; P = NS) but less in HT patients (67%, 70%, P < .05 vs. CKD and NT). Likewise, the sum of NEFA were equally suppressed in the CKD and NT groups ( P = NS) but not in HT subjects ( P < .01 both vs. CKD and NT). Percent body fat correlated highly with NEFA suppression in the CKD and NT groups but not in HT subjects. Impairment of insulin’s antilipolytic actions is not involved in the early pathogenesis of dyslipidemia and hypertension in patients with mild to moderated renal dysfunction.

Second meal effects of dietary calcium and vitamin D

To determine the second meal effects of calcium and vitamin D on postprandial glucose, insulin, non-esterified fatty acids (NEFA) and glycerol. Eight volunteers aged (mean+/-s.e.m.) 55.5+/-1.2 years and body mass index 29.0+/-1.6 kg/m(2), completed a randomized within-subject design that compared a low calcium-low vitamin D breakfast and an isocaloric high calcium-high vitamin D breakfast (HCB). Four hours following each breakfast, a very low calcium standard lunch was ingested. Serial blood collections were made on the hour over a duration of 8 h. Postprandial responses were calculated as the percentage change (Delta) from the fasting value for breakfast meals, and the 4th hour breakfast value for each lunch, respectively. Non-parametric tests of significance were employed. The change in glucose, insulin, serum ionized calcium (iCa(2+)) and intact parathyroid hormone was not different between the two breakfasts, or the two lunches. However, HCB resulted in a lesser suppression of NEFA that significantly carried over to lunch (P=0.036, Wilcoxon test). A similar pattern of change in glycerol did not attain overall statistical significance. DeltaNEFA and Deltaglycerol were related at lunch (Spearman's r=0.52, P=0.04). Relative to breakfast, both lunches resulted in significantly higher glucose and insulin responses (P=0.011, Wilcoxon test). The data are suggestive of second meal effects of calcium and vitamin D. Our observations of higher glucose and insulin after lunch may include the involvement of second meal factors as well.

A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans

High fructose consumption is suspected to be causally linked to the epidemics of obesity and metabolic disorders. In rodents, fructose leads to insulin resistance and ectopic lipid deposition. In humans, the effects of fructose on insulin sensitivity remain debated, whereas its effect on ectopic lipids has never been investigated. We assessed the effect of moderate fructose supplementation on insulin sensitivity (IS) and ectopic lipids in healthy male volunteers (n = 7). IS, intrahepatocellular lipids (IHCL), and intramyocellular lipids (IMCL) were measured before and after 1 and 4 wk of a high-fructose diet containing 1.5 g fructose . kg body wt(-1) . d(-1). Adipose tissue IS was evaluated from nonesterified fatty acid suppression, hepatic IS from suppression of hepatic glucose output (6,6-2H2-glucose), and muscle IS from the whole-body glucose disposal rate during a 2-step hyperinsulinemic euglycemic clamp. IHCL and IMCL were measured by 1H magnetic resonance spectroscopy. Fructose caused significant (P < 0.05) increases in fasting plasma concentrations of triacylglycerol (36%), VLDL-triacylglycerol (72%), lactate (49%), glucose (5.5%), and leptin (48%) without any significant changes in body weight, IHCL, IMCL, or IS. IHCL were negatively correlated with triacylglycerol after 4 wk of the high-fructose diet (r = -0.78, P < 0.05). Moderate fructose supplementation over 4 wk increases plasma triacylglycerol and glucose concentrations without causing ectopic lipid deposition or insulin resistance in healthy humans.

Insulin sensitivity, fat distribution, and adipocytokine response to different diets in lean and obese cats before and after weight loss

Obesity is a major health problem in cats and a risk factor for diabetes. It has been postulated that cats are always gluconeogenic and that the rise in obesity might be related to high dietary carbohydrates. We examined the effect of a high-carbohydrate/low-protein (HC) and a high-protein/low-carbohydrate (HP) diet on glucose and fat metabolism during euglycemic hyperinsulinemic clamp, adipocytokines, and fat distribution in 12 lean and 16 obese cats before and after weight loss. Feeding diet HP led to greater heat production in lean but not in obese cats. Regardless of diet, obese cats had markedly decreased glucose effectiveness and insulin resistance, but greater suppression of nonesterified fatty acids during the euglycemic hyperinsulinemic clamp was seen in obese cats on diet HC compared with lean cats on either diet or obese cats on diet HP. In contrast to humans, obese cats had abdominal fat equally distributed subcutaneously and intra-abdominally. Weight loss normalized insulin sensitivity; however, increased nonesterified fatty acid suppression was maintained and fat loss was less in cats on diet HC. Adiponectin was negatively and leptin positively correlated with fat mass. Lean cats and cats during weight loss, but not obese cats, adapted to the varying dietary carbohydrate/protein content with changes in substrate oxidation. We conclude that diet HP is beneficial through maintenance of normal insulin sensitivity of fat metabolism in obese cats, facilitating the loss of fat during weight loss, and increasing heat production in lean cats. These data also show that insulin sensitivity of glucose and fat metabolism can be differentially regulated in cats.

Fatty acid turnover, substrate oxidation, and heat production in lean and obese cats during the euglycemic hyperinsulinemic clamp

Simultaneous application of the euglycemic hyperinsulinemic clamp (EHC) and indirect calorimetry was used to examine heat production, fat, and glucose metabolism in lean and obese adult neutered male and female cats. The results show that in lean insulin-sensitive cats glucose oxidation predominated during fasting, whereas lipid oxidation became more prominent in obese cats. Insulin infusion during the EHC in lean cats and obese male cats led to a large increase in glucose oxidation, glycogenesis, and lipogenesis. It also led to an increase in glucose oxidation and glycogenesis in obese female cats but it was significantly less compared to lean cats and obese males. This indicates that obese females show greater metabolic inflexibility. In obese cats of either gender, insulin caused greater suppression of non-esterified fatty acids compared to lean cats suggesting that obese cats show greater fatty acid clearance than lean cats. The heat production per metabolic size was lower in obese cats than lean cats. This would perpetuate obesity unless food intake is decreased. The higher glucose oxidation rate in obese neutered male cats suggests that they are able to replete their glycogen and lipid stores at a faster rate than females in response to insulin and it implies that they gain weight more rapidly. Further studies are needed to investigate if the different response to insulin of male cats is involved in their higher risk to develop diabetes.

Impaired non-esterified fatty acid suppression to intravenous glucose during late pregnancy persists postpartum in gestational diabetes: a dominant role for decreased insulin secretion rather than insulin resistance

Non-esterified fatty acids are implicated in the pathogenesis of gestational (GDM) and type 2 diabetes. We examined the relationship between NEFA dynamics, insulin resistance and beta cell dysfunction in women with GDM in late pregnancy and postpartum. A total of 19 Caucasian women with GDM and 19 healthy pregnant women matched for BMI and age underwent an IVGTT in the third trimester and 4 months postpartum, deriving values for insulin sensitivity (SI), insulin secretion (AIRg) and disposition index (DI). NEFA levels were measured serially. In pregnancy, the GDM women had similar SI but reduced AIRg and DI compared with control subjects. The GDM group demonstrated significantly slower NEFA suppression, which was attributable to the GDM women who required insulin during pregnancy (n=7) and who had markedly reduced AIRg and K(NEFA) (NEFA disappearance constant) compared with their matched controls. In contrast, GDM subjects not requiring insulin (n=12) had similar NEFA suppression curves and AIRg to control subjects. Postpartum, GDM subjects demonstrated reduced SI and DI. The impaired suppression of NEFA persisted postpartum, but again only in the subgroup of GDM subjects who had required insulin during pregnancy. Furthermore, K(NEFA) correlated with AIRg and DI in both states, but not with SI. Impaired NEFA suppression occurs in GDM subjects both in late pregnancy and postpartum in response to IVGTT-induced endogenous insulin secretion. The impaired NEFA suppression is present in GDM women with the most severe beta cell dysfunction (who had required insulin during pregnancy) and is related to their insulin secretory dysfunction rather than their reduced SI.

Nonesterified Fatty Acids as Mediators of Glucose Intolerance in Indian Asian Populations

In India, diabetes is endemic, linked to urbanization (1), and its dispersed migrant populations show a particular vulnerability (2,3). For example, in Britain, diabetes is more frequent among Indian migrants than in the general population (4,5), but reported rates appear to equal those in India (6), although diverse dietary and cultural habits across India are also likely to have an impact (7). Rates of glucose intolerance seem to be similar between particular Indian communities living in East Africa, and British population studies provide increasing support for a causal role of nonesterified fatty acids (NEFAs) in the etiology of type 2 diabetes (8,9). Here, using a standardized comparison of culturally specific Gujarati communities between India and Britain, we hypothesized that factors associated with disordered NEFA suppression following glucose challenge would confer greater glucose intolerance in these populations. We compared a Gujarati community who had migrated to Sandwell (West Midlands, Britain) from rural villages around Navsari (Gujarat) with age-, sex-, and caste-matched contemporaries still living in those villages in India (as described elsewhere [10]). Randomly sampled participants from electoral rolls were invited to clinic sessions (beginning 8:30–10:00 a.m.). Participants without known diabetes had glucose tolerance testing (GTT) using …

Electrical muscle stimulation acutely mimics exercise in neurologically intact individuals but has limited clinical benefits in patients with type 2 diabetes

Electrical muscle stimulation mimics exercise in individuals with neurological injury or disease and improves measures of fitness and glucose metabolism. Physical activity improves features of the metabolic syndrome in patients with type 2 diabetes but many patients find it difficult to exercise. To determine whether use of an electrical muscle stimulator mimics exercise in neurologically intact individuals and has metabolic benefits in patients with type 2 diabetes. Acute changes in pulse, blood pressure and energy expenditure were measured in 33 healthy volunteers using the muscle stimulator. Acute changes in glucose uptake were measured in five subjects with type 2 diabetes. Body composition, features of the metabolic syndrome and measures of insulin sensitivity were measured before and after 12 weeks daily use of the stimulator in four subjects with type 2 diabetes. The muscle stimulator acutely increased pulse, blood pressure, energy expenditure and glucose uptake. Daily use over 12 weeks improved insulin stimulated nonesterified fatty acid suppression but did not result in changes in body composition or clinical parameters. Although the muscle stimulator acutely mimics exercise, limitations in the size of the stimulating current mean that the magnitude of these changes is too small to produce clinical benefit.

Adipose tissue metabolites and insulin resistance in nondiabetic Asian Indian men.

Obesity-related insulin resistance is associated with changes in adipose tissue release of leptin, adiponectin, and nonesterified fatty acids (NEFAs). We have previously described that persons originating from the Indian subcontinent (Asian Indians) manifest excessive insulin resistance even in the absence of obesity. Therefore, in this study, we tested the hypothesis that nondiabetic, insulin-resistant Asian Indians differ from less insulin-resistant Caucasians of similar age and body composition in adipose tissue production of leptin and adiponectin, and in suppression of plasma NEFA concentrations during hyperinsulinemia. Seventy-nine Asian Indian men were compared with 61 Caucasian men. Higher plasma NEFAs and leptin in Asian Indians (P < 0.0001 and P = 0.003 for NEFAs and leptin, respectively) and lower plasma concentrations of adiponectin (P = 0.009) were not explained by body fat content and distribution. Oral glucose tolerance test studies revealed that Caucasian men had greater suppression of plasma NEFAs than Asian Indian men. We conclude that plasma concentrations of the adipose tissue metabolites leptin and NEFAs are higher and that of adiponectin is lower in insulin-resistant Asian Indians compared with more insulin-sensitive Caucasians. These differences may contribute to the excessive prevalence of type 2 diabetes and cardiovascular disease in nonobese Asian Indians.

Effects of obesity on lipid profiles in neutered male and female cats.

To examine whether obese cats, compared with lean cats, have alterations in lipoprotein metabolism that might lead to a decrease in glucose metabolism and insulin secretion. 10 lean and 10 obese adults cats (5 neutered males and 5 neutered females each). Intravenous glucose tolerance tests with measurements of serum glucose, insulin, and nonesterified fatty acid (NEFA) concentrations were performed. Lipoprotein fractions were examined in serum by isopycnic density gradient ultracentrifugation. Obese cats had insulin resistance. Plasma triglyceride and cholesterol concentrations were significantly increased in obese cats, compared with lean cats. Very low density lipoprotein (VLDL) concentrations were increased in obese cats, compared with lean cats; however, the composition of various fractions remained unchanged between obese and lean cats, indicating greater synthesis and catabolism of VLDL in obese cats. Serum high density lipoprotein (HDL) cholesterol concentrations were increased in obese cats, compared with lean cats. Serum NEFA concentrations were only significantly different between obese and lean cats when separated by sex; obese male cats had higher baseline serum NEFA concentrations and greater NEFA suppression in response to insulin, compared with lean male cats. Lipid metabolism changes in obese cats, compared with lean cats. The increase in VLDL turnover in obese cats might contribute to insulin resistance of glucose metabolism, whereas the increase in serum HDL cholesterol concentration might reflect a protective effect against atherosclerosis in obese cats.

Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study

Objective: To investigate an optimized glucose-insulin-potassium (GIK) solution regimen as an alternate myocardial protective strategy in off-pump coronary artery bypass graft (OP-CAB) surgery and as a supplement to conventional coronary artery bypass graft (CABG) surgery using cardiopulmonary bypass (CPB). Design: Prospective, randomized, placebo-controlled. Setting: Single institution, cardiothoracic specialty hospital. Participants: Forty-four patients scheduled for elective multivessel coronary artery surgery using either conventional CPB (n = 22) or OP-CAB techniques (n = 22). Interventions: Preischemic, ischemic, and postischemic administration of GIK solution was carried out, optimally dosed to ensure nonesterified fatty acid (NEFA) suppression, and supplemented with magnesium, a glycolytic enzymatic cofactor. Measurements and Main Results: GIK solution therapy reduced plasma NEFA levels (p < 0.001) in OP-CAB surgery and CPB groups but failed to affect the incidence of non–Q wave perioperative myocardial infarction, incidence of postoperative atrial fibrillation, incidence of postoperative infection, reduction in creatinine clearance, or duration of postoperative intensive care unit or hospital length of stay. After adjusting for GIK solution therapy, OP-CAB surgery resulted in significantly less ischemic injury (troponin I >15 μg/L, 19.0% v 91.3%; p = 0.0001) and reduced postoperative infections (14.3% v 43.5%; p = 0.049). Conclusion: GIK solution therapy achieved NEFA suppression and an insignificant trend toward reduced biochemical parameters of ischemic injury in OP-CAB surgery and CPB groups, but no major clinical benefit (perioperative myocardial infarction, intensive care unit length of stay, or hospital length of stay) was shown after elective CABG surgery in low-risk patients. Compared with CPB, OP-CAB surgery significantly reduced ischemic injury and postoperative infections. Copyright 2002, Elsevier Science (USA). All rights reserved.

Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).

Diabetes resulting from heterozygosity for an inactivating mutation of the homeodomain transcription factor insulin promoter factor 1 (IPF-1) is due to a genetic defect of beta-cell function referred to as maturity-onset diabetes of the young 4. IPF-1 is required for the development of the pancreas and mediates glucose-responsive stimulation of insulin gene transcription. To quantitate islet cell responses in a family harboring a Pro63fsdelC mutation in IPF-1, we performed a five-step (1-h intervals) hyperglycemic clamp on seven heterozygous members (NM) and eight normal genotype members (NN). During the last 30 min of the fifth glucose step, glucagon-like peptide 1 (GLP-1) was also infused (1.5 pmol x kg(-1) x min(-1)). Fasting plasma glucose levels were greater in the NM group than in the NN group (9.2 vs. 5.9 mmol/l, respectively; P < 0.05). Fasting insulin levels were similar in both groups (72 vs. 105 pmol/l for NN vs. NM, respectively). First-phase insulin and C-peptide responses were absent in individuals in the NM group, who had markedly attenuated insulin responses to glucose alone compared with the NN group. At a glucose level of 16.8 mmol/l above fasting level, GLP-1 augmented insulin secretion equivalently (fold increase) in both groups, but the insulin and C-peptide responses to GLP-1 were sevenfold less in the NM subjects than in the NN subjects. In both groups, glucagon levels fell during each glycemic plateau, and a further reduction occurred during the GLP-1 infusion. Sigmoidal dose-response curves of glucose clearance versus insulin levels during the hyperglycemic clamp in the two small groups showed both a left shift and a lower maximal response in the NM group compared with the NN group, which is consistent with an increased insulin sensitivity in the NM subjects. A sharp decline occurred in the dose-response curve for suppression of nonesterified fatty acids versus insulin levels in the NM group. We conclude that the Pro63fsdelC IPF-1 mutation is associated with a severe impairment of beta-cell sensitivity to glucose and an apparent increase in peripheral tissue sensitivity to insulin and is a genetically determined cause of beta-cell dysfunction.

A common apolipoprotein B signal peptide polymorphism modifies the relation between plasma non-esterified fatty acids and triglyceride concentration in men

Insulin and non-esterified fatty acids (NEFA) are important regulators of triglyceride metabolism. The relations between these compounds and the effect of a common 3 amino acid deletion in the apolipoprotein B (ApoB) signal peptide (SP) following an oral glucose challenge have been investigated. The frequency of the shorter SP-24 allele was 32% (95% C.I. 29.5–36.5) in 725 subjects undergoing an oral glucose tolerance test (OGTT). Fasting plasma triglyceride concentration was positively correlated with fasting plasma insulin concentration and negatively with the degree of plasma NEFA suppression following the glucose challenge. Linear regression analysis showed the relation between triglyceride concentration and NEFA suppression, but not the relation between triglyceride concentration and fasting insulin, to be altered by the SP polymorphism in men but not in women. The strength of the association was dependent on the number of SP-24 alleles, with SP-24 homozygotes showing the greatest dependence (men P=0.031, women P=0.914). It was proposed that the complex regulation of very low density lipoprotein (VLDL) output by NEFA and by insulin may explain, at least in part, the conflicting reports concerning the presence of the ApoB SP polymorphism, fasting serum lipids and ischaemic heart disease (IHD).