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G F Lewis

Publications and source records attributed to G F Lewis.

At least 19 recordsLinked to original sources
PubMed2004

Prolonged increase of plasma non-esterified fatty acids fully abolishes the stimulatory effect of 24 hours of moderate hyperglycaemia on insulin sensitivity and pancreatic beta-cell function in obese men.

AIMS/HYPOTHESIS: A prolonged increase of plasma NEFA impairs acute glucose-stimulated insulin secretion (GSIS) in vitro and in vivo. Our study therefore examined the combined effect of increased plasma NEFA and glucose on GSIS in humans. METHODS: We examined GSIS on four occasions in eight obese men during a 10 mmol/l hyperglycaemic clamp and after a 24-h infusion of (i) normal saline, (ii) intralipid and heparin to raise plasma NEFA about two-fold above basal, (iii) 20% dextrose to raise plasma glucose to about 7.5 mmol/l and (iv) intralipid and heparin combined with 20% dextrose to raise plasma NEFA and glucose. RESULTS: In study (iii) insulin sensitivity was about 20% greater than in study (i) and the disposition index was about 50% higher. Insulin sensitivity tended to be lower in study (ii) whereas the disposition index was lower than in study (i), confirming previous observations. The combination of increased plasma NEFA and glucose (study iv) reduced insulin sensitivity in comparison with study (i) and completely abolished the increase in insulin sensitivity and disposition index seen in study (iii), but did not reduce the latter to a lower value than that in the saline control study (study i). CONCLUSIONS/INTERPRETATION: We showed that a prolonged increase of plasma NEFA completely abolishes the stimulatory effect of moderate hyperglycaemia on insulin sensitivity and beta-cell function in obese humans. This suggests that previous observations, showing that a prolonged increase of plasma NEFA impairs pancreatic beta-cell function, also apply to the hyperglycaemic state.

Blood Glucose↗
PubMed2003

A molecular Einstein ring: imaging a starburst disk surrounding a quasi-stellar object.

Images of the molecular CO 2-1 line emission and the radio continuum emission from the redshift 4.12 gravitationally lensed quasi-stellar object (QSO) PSS J2322+1944 reveal an Einstein ring with a diameter of 1.5". These observations are modeled as a star-forming disk surrounding the QSO nucleus with a radius of 2 kiloparsecs. The implied massive star formation rate is 900 solar masses per year. At this rate, a substantial fraction of the stars in a large elliptical galaxy could form on a dynamical time scale of 108 years. The observation of active star formation in the host galaxy of a high-redshift QSO supports the hypothesis of coeval formation of supermassive black holes and stars in spheroidal galaxies.

Journal Article↗
PubMed2001

Carotid intima-media thickness in type 2 diabetes is more strongly related to serum apoprotein A-I in females.

BACKGROUND: Dyslipidemia in type 2 diabetes has been shown to be related to the incidence of macrovascular events. Increased carotid intima-media thickness is considered to be a marker of macrovascular disease. MAIN PURPOSE: To investigate a possible relationship between lipoprotein levels and carotid intima-media thickness as a marker of early atherosclerosis in patients with type 2 diabetes. METHODS: Seventy-one consecutively selected eligible patients (31 males, 40 females) with type 2 diabetes were studied. Common carotid intima-media thickness was measured bilaterally by high-resolution ultrasound and the mean value from both sides was used for further analysis. Fasting blood samples were taken from each individual and their serum was analyzed for lipoprotein levels. RESULTS: In the entire group of patients, intima-media thickness was inversely related to apoprotein A-I (r = -0.33, p = 0.008) and HDL cholesterol (r = -0.23, p = 0.059) in univariate correlation analysis, and a positive correlation between intima-media thickness and apoprotein B/apoprotein A-I ratio was found (r = 0.33, p = 0.007). When genders were analyzed separately, intima-media thickness was significantly correlated with apoprotein A-I and apoprotein B/apoprotein A-I ratio in females, while no significant correlation of any lipid variable with intima-media thickness was observed in males. In multiple linear regression analysis, age (p = 0.005), male gender (p = 0.002) and apoprotein A-I (p = 0.035) were the only risk factors in the entire group of diabetic patients, which significantly predicted carotid intima-media thickness in models adjusted for demographic and other known risk factors. As was the case in the univariate analysis, no risk factor significantly predicted carotid intima-media thickness in males while age, apoprotein A-I and B significantly predicted intima-media thickness in females. CONCLUSIONS: In the present study, low serum apoprotein A-I, a major protein component of HDL, was found to be related to increased carotid intima-media thickness. This relationship was stronger in females than in males, which suggests possible gender differences in the relationship between apoprotein A-1 and early atherosclerotic lesions in subjects with type 2 diabetes mellitus.

Adult↗
PubMed2001

Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans.

AIMS/HYPOTHESIS: We have shown previously that the increase of plasma non-esterified fatty acids for 48 h results in decreased glucose-stimulated insulin secretion in lean and non-diabetic obese subjects. It is currently not known if a prolonged increase in non-esterified fatty acids also impairs the insulin secretory response to non-glucose secretagogues. METHODS: Heparin and intralipid (to increase plasma non-esterified fatty acid concentrations by about two- to fourfold) or normal saline was infused intravenously for 48 h in 14 non-diabetic obese subjects. On the third day in both studies, insulin, C-peptide, proinsulin, and insulin secretion rate were assessed in response to an intravenous arginine infusion at fasting glucose concentration and a second arginine infusion after a 60-min 11 mmol/l hyperglycaemic clamp. RESULTS: There were no significant differences detected in acute (5 min) or total (90 min) arginine-stimulated C-peptide or insulin secretion response in the heparin-intralipid study compared with the control group at fasting glucose or during hyperglycaemia. CONCLUSION/INTERPRETATION: We have shown that a prolonged increase in plasma NEFA does not blunt arginine-stimulated insulin secretion or plasma insulin concentrations in non-diabetic obese subjects. These findings suggest that the previously demonstrated NEFA-induced impairment in insulin secretory response to glucose cannot be generalized for non-glucose secretagogues.

Adult↗
PubMed2001

Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance.

An important complication of insulin-resistant states, such as obesity and type 2 diabetes, is an atherogenic dyslipidemia profile characterized by hypertriglyceridemia, low plasma high-density lipoproteins (HDL) cholesterol and a small, dense low-density lipoprotein (LDL) particle profile. The physiological basis of this metabolic dyslipidemia appears to be hepatic overproduction of apoB-containing very low-density lipoprotein (VLDL) particles. This has focused attention on the mechanisms that regulate VLDL secretion in insulin-resistant states. Recent studies in animal models of insulin resistance, particularly the fructose-fed hamster, have enhanced our understanding of these mechanisms, and certain key factors have recently been identified that play important roles in hepatic insulin resistance and dysregulation of the VLDL secretory process. This review focuses on these recent developments as well as on the hypothesis that an interaction between enhanced flux of free fatty acids from peripheral tissues to liver, chronic up-regulation of de novo lipogenesis by hyperinsulinemia and attenuated insulin signaling in the liver may be critical to the VLDL overproduction state observed in insulin resistance. It should be noted that the focus of this review is on molecular mechanisms of the hypertriglyceridemic state associated with insulin resistance and not that observed in association with insulin deficiency (e.g., in streptozotocin-treated animals), which appears to have a different etiology and is related to a catabolic defect rather than secretory overproduction of triglyceride-rich lipoproteins.

Animals↗
PubMed2001

The effect of systemic versus portal insulin delivery in pancreas transplantation on insulin action and VLDL metabolism.

Combined kidney-pancreas transplantation (KPT) with anastomosis of the pancreatic vein to the systemic circulation (KPT-S) or to the portal circulation (KPT-P) provides a human model in which the chronic effects of portal versus systemic insulin delivery on glucose and VLDL metabolism can be examined. Despite similar plasma glucose and C-peptide levels, KPT-S (n = 9) had an approximate twofold elevation of fasting and intravenous glucose-stimulated plasma insulin levels compared with both KPT-P (n = 7) and healthy control subjects (n = 15). The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation necessary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects. Endogenous glucose production was similar in KPT-S and KPT-P, despite approximately 35% higher hepatic insulin levels in the latter, and was suppressed to a greater extent during a euglycemic-hyperinsulinemic clamp in KPT-S versus KPT-P. Total-body glucose utilization during the euglycemic-hyperinsulinemic clamp was approximately 40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not hepatic insulin resistance in KPT-S versus KPT-P. Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apolipoprotein B (apoB) and lipids versus control subjects. Elevation of VLDL-apoB and VLDL-TG in both transplant groups was entirely explained by an approximately 50% reduction in clearance of VLDL compared with healthy control subjects. In the presence of increased FFA load but in the absence of hepatic overinsulinization and marked hepatic insulin resistance, there was no elevation of VLDL secretion in KPT-S versus KPT-P and control subjects. These findings suggest that chronic systemic hyperinsulinemia and peripheral tissue insulin resistance with the consequent elevation of plasma FFA flux are insufficient per se to cause VLDL overproduction and that additional factors, such as hepatic hyperinsulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL overproduction in the common form of the insulin resistance syndrome.

Adult↗
PubMed2001

Triglyceride enrichment of HDL does not alter HDL-selective cholesteryl ester clearance in rabbits.

Triglyceride (TG) enrichment of high density lipoprotein (HDL), which occurs in hypertriglyceridemic states, significantly enhances the rate at which HDL apolipoprotein (apo)A-I is cleared from the circulation of healthy humans. In the New Zealand White (NZW) rabbit, a species naturally deficient in hepatic lipase (HL), TG enrichment of HDL requires prior lipolytic modification to enhance apoA-I clearance. However, the effect of TG enrichment of HDL on the subsequent clearance of HDL cholesteryl ester (CE) has not previously been examined in vivo. Therefore, we investigated, in the NZW rabbit, the effect of ex vivo TG enrichment of rabbit HDL (by incubation with human very low density lipoprotein) on the clearance of HDL CE and apoA-I radiolabeled with (3)H-cholesteryl oleyl ether and with (131)I, respectively. In nine experiments, TG enrichment of rabbit HDL resulted in an 87% average increase in HDL TG and a corresponding 31% reduction in HDL CE content. The calculated apoA-I and CE fractional catabolic rates associated with TG-rich versus fasting HDL tracers were not significantly different (apoA-I: 0.119 +/- 0.017 vs. 0.107 +/- 0.024 pools per h, P = 0.68; CE: 0.147 +/- 0.014 vs. 0.114 +/- 0.019 pools per h, P = 0.20). In an animal model deficient in HL, TG enrichment of HDL did not alter the rates of HDL apoA-I or selective CE clearance. Further studies are needed to determine whether, in the presence of HL, TG enrichment of HDL alters selective HDL CE clearance.

Animals↗
PubMed2001

Deterioration in renal function associated with fibrate therapy.

BACKGROUND: Fibric acid derivatives (fibrates) are commonly used for the treatment of hyperlipidemia. A side-effect of these medications that is not well recognized is deterioration in renal function during therapy. This study reviewed a series of patients who showed such a deterioration. METHODS: The design was a retrospective chart review. Data extracted included creatinine, urea, cyclosporine levels, medical history, and medications. Charts were examined for other potential reasons for a change in creatinine. RESULTS: There were a total of 10 patients. All were males between the ages of 37 and 71. All had a history of renal insufficiency. Six had received a renal transplant and, of these, 5 were on cyclosporine. Reasons for underlying renal impairment included diabetes, hypertension, nephrosclerosis, and renal disease of unknown etiology. Most patients had risk factors for or the presence of vascular disease. The mean pre-treatment creatinine was 182 +/- 14 micromol/l (2.1 +/- 0.2 mg/dl) (mean +/- SE), compared to a peak creatinine on the medication of 247 +/- 16 micromol/l (2.8 +/- 0.2 mg/dl) (p < 0.001). The post-medication mean was 183 +/- 13 (2.1 +/- 0.1 mg/dl) (p < 0.001 vs maximum creatinine). Urea values also increased with therapy and decreased following discontinuation of the fibrate. Cyclosporine levels did not change with treatment. All recorded creatine kinase values were within the normal range. CONCLUSIONS: A group of 10 men showed a reversible deterioration in renal function while being treated with a fibrate for hyperlipidemia. The mechanism involved in the deterioration in renal function is not clear. The most plausible mechanism is one based on renal hemodynamics, given the rapid and complete reversibility that was noted and the finding that most patients had risk factors for vascular disease. If patients with pre-existing renal dysfunction are to receive a trial of fibrate therapy, this should be done with caution and

Adult↗
PubMed2000

Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model.

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the mechanisms mediating the overproduction of very low density lipoprotein (VLDL) in the insulin resistant state. Fructose feeding for a 2-week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance was documented using the euglycemic-hyperinsulinemic clamp technique. In vivo Triton WR-1339 studies showed evidence of VLDL-apoB overproduction in the fructose-fed hamster. Fructose feeding induced a significant increase in cellular synthesis and secretion of total triglyceride (TG) as well as VLDL-TG by primary hamster hepatocytes. Increased TG secretion was accompanied by a 4.6-fold increase in VLDL-apoB secretion. Enhanced stability of nascent apoB in fructose-fed hepatocytes was evident in intact cells as well as in a permeabilized cell system. Analysis of newly formed lipoprotein particles in hepatic microsomes revealed significant differences in the pattern and density of lipoproteins, with hepatocytes derived from fructose-fed hamsters having higher levels of luminal lipoproteins at a density of VLDL versus controls. Immunoblot analysis of the intracellular mass of microsomal triglyceride transfer protein, a key enzyme involved in VLDL assembly, showed a striking 2.1-fold elevation in hepatocytes derived from fructose-fed versus control hamsters. Direct incubation of hamster hepatocytes with various concentrations of fructose failed to show any direct stimulation of its intracellular stability or extracellular secretion, further supporting the notion that the apoB overproduction in the fructose-fed hamster may be related to the fructose-induced insulin resistance in this animal model. In summary, hepatic VLDL-apoB overproduction in fructose-fed hamsters appears to result from increased intracellular stability of nascent apoB and an enhanced expression of MTP, which act to facilitate the assembly and secretion of apoB-containing lipoprotein particles.

Animals↗
PubMed2000

Portal venous and enteric exocrine drainage versus systemic venous and bladder exocrine drainage of pancreas grafts: clinical outcome of 40 consecutive transplant recipients.

OBJECTIVE: To test the hypothesis that pancreas transplantation using the more physiologic method of portal venous-enteric (PE) drainage could be performed without compromising patient and graft outcome, compared with the standard method of systemic venous-bladder (SB) drainage. METHODS: Between November 1995 and November 1998, the authors prospectively followed up 20 consecutive patients with SB drainage followed by 20 consecutive patients with PE drainage. All patients underwent simultaneous pancreas-kidney transplantation, and all were immunosuppressed with antilymphocyte serum, cyclosporin, azathioprine, and steroids. RESULTS: The actuarial patient survival rate at 1 year was 95% in the SB group and 100% in the PE group. Death-censored kidney graft survival was 100% in both groups; pancreas graft survival was 95% in the SB group and 100% in the PE group. The mean initial hospital stay was 15 days for both groups. However, during the first 6 months after transplantation, the SB group required more medical day-unit visits, mostly for treatment of metabolic acidosis and dehydration. The incidence of urinary tract infections was similar in both groups. The incidence of cytomegalovirus infections was significantly less in the PE group. The incidence of acute rejection was 37% in the SB group and 15% in the PE group. Mean serum creatinine levels 6 months after transplantation were significantly lower in the PE group than in the SB group. Glycemic control was excellent in both groups, but fasting serum insulin levels were significantly lower in the PE group. CONCLUSIONS: The PE method of pancreas transplantation can be performed with excellent patient and graft outcomes.

Adolescent↗
PubMed2000

Beta-blockade, but not normoglycemia or hyperinsulinemia, markedly diminishes stress-induced hyperglycemia in diabetic dogs.

Stress-induced hyperglycemia can lead to significant deterioration in glycemic control in individuals with diabetes. Previously, we have shown in normal dogs that, after intracerebroventricular (ICV) administration of carbachol (a model of moderate stress), increases in both the metabolic clearance rate (MCR) of glucose and endogenous glucose production (GP) occur. However, in hyperglycemic diabetic dogs subjected to the same stress, the MCR of glucose does not increase and glycemia therefore markedly deteriorates because of stimulation of GP. Our aims were to determine the following: 1) whether insulin-induced acute normalization of glycemia, with or without beta-blockade, would correct glucose clearance and prevent the hyperglycemic effect of stress, and 2) whether hyperinsulinemia per se could correct these abnormalities. Stress was induced by ICV carbachol in 27 experiments in five alloxan-administered diabetic dogs subjected to the following protocols in random order: 1) basal insulin infusion (BI) to restore normoglycemia; 2) basal insulin infusion with beta-blockade (BI+block); 3) normoglycemic-hyperinsulinemic clamp with threefold elevation of insulin above basal (3x BI); and 4) normoglycemic-hyperinsulinemic clamp with fivefold elevation of insulin above basal (5 x BI). The BI+block protocol fully prevented stress-induced hyperglycemia, both by increasing MCR (deltaMCR at peak: 0.72 +/- 0.25 ml x kg(-1) x min(-1) vs. no change in BI, P < 0.05) and by diminishing the stress-induced increment in GP observed in BI (deltaGP at peak: 3.72 +/- 0.09 micromol x kg(-1) x min(-1) for BI+block vs. 14.10 +/- 0.31 micromol x kg(-1) x min(-1) for BI, P < 0.0001). In contrast, 3x BI and 5x BI treatments with normoglycemic-hyperinsulinemic clamps proportionately increased basal MCR at baseline, but paradoxically were not associated with an increase in MCR in response to stress, which induced a twofold increase in GP. Thus, in alloxan-administered diabetic dogs, stress increased GP but not MCR, despite normalization of glycemia with basal or high insulin. In contrast, beta-adrenergic blockade almost completely restored the metabolic response to stress to normal and prevented marked hyperglycemia, both by limiting the rise in GP and by increasing glucose MCR. We conclude that acute normalization of glycemia with basal insulin or hyperinsulinemia does not prevent hyperglycemic effects of stress unless accompanied by beta-blockade, and we speculate that short-term beta-blockade may be a useful treatment modality under some stress conditions in patients with diabetes.

Adrenergic beta-Antagonists↗
PubMed2000

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

Our recent in vivo observations in healthy nonobese humans have demonstrated that prolonged elevation of plasma free fatty acids (FFAs) results in diminished glucose-stimulated insulin secretion (GSIS) when the FFA-mediated decrease in insulin sensitivity is taken into account. In the present study, we investigated whether obese individuals and patients with type 2 diabetes are more sensitive than healthy control subjects to the inhibitory effect of prolonged elevation of plasma FFAs on GSIS. In seven patients with type 2 diabetes and seven healthy nondiabetic obese individuals, we assessed GSIS with a programmed graded intravenous glucose infusion on two occasions, 6-8 weeks apart, with and without a prior 48-h infusion of heparin and Intralipid, which was designed to raise plasma FFA concentration approximately twofold over basal. The nondiabetic obese subjects had a significant 21% decrease in GSIS (P = 0.0008) with the heparin and Intralipid infusion, associated with a decrease in whole body insulin clearance. The impairment in GSIS was evident at low (<11 mmol/l) but not at higher plasma glucose concentrations. In contrast, the patients with type 2 diabetes had a slight increase in GSIS (P = 0.027) and no change in insulin clearance, although there was marked interindividual variability in response. Plasma proinsulin concentrations measured in a subset of subjects were not altered in either group by the infusion of heparin and Intralipid. In summary, 1) obese nondiabetic individuals are susceptible to a desensitization of GSIS with heparin and Intralipid infusion, and 2) patients with type 2 diabetes do not demonstrate such susceptibility when FFAs are elevated approximately twofold above basal with heparin and Intralipid. Our results suggest that FFAs could play an important role in the development of beta-cell failure in obese individuals who are at risk for developing type 2 diabetes. They do not, however, seem to further deteriorate the beta-cell function of patients who already have established type 2 diabetes and may even result in a slight increase in GSIS in this latter group.

Adult↗
PubMed1999

Elevated plasma lipids in patients with binge eating disorders are found only in those who are anorexic.

OBJECTIVE: We have previously shown that patients with restricting type anorexia nervosa (AN-R) have low plasma lipid levels, which increase with refeeding. In this study, we investigated plasma lipid levels in patients with eating disorders, distinguishing between individuals with bulimia nervosa (BN) and anorexia nervosa of the binge eating/purging type (AN-B). METHODS: We examined the fasting lipid levels in individuals with BN (n = 10) and AN-B (n = 9), and compared these findings with a group of age-matched normal weight healthy controls (C) (n = 10). RESULTS: The AN-B group had significantly higher concentrations of total plasma cholesterol, apolipoprotein (apo) B, apoA1, and low-density lipoprotein (LDL)-cholesterol than both control and BN groups (p < .05). The AN-B group also had higher plasma triglycerides and intermediate-density lipoprotein (IDL)-apo B levels (p < .05) than controls. DISCUSSION: In conclusion, the issue of hyperlipidemia in patients with eating disorders is a complex one and this study, taken together with the findings of our previous study, demonstrates the importance of carefully distinguishing between the major types of eating disorders (AN-R, BN, and AN-B) when examining plasma lipid levels.

Adult↗
PubMed1999

HDL metabolism in hypertriglyceridemic states: an overview.

Reduced plasma high-density lipoprotein (HDL) cholesterol levels have been recognized as a highly significant independent risk factor for atherosclerotic cardiovascular disease. HDL levels are also inversely related to plasma triglyceride levels and there is a dynamic interaction between HDL and triglyceride (TG) rich lipoproteins in vivo. The mechanisms underlying the lowering of HDL in hypertriglyceridemic states have not been fully elucidated, but there is evidence to suggest that triglyceride enrichment of HDL, a common metabolic consequence of hypertriglyceridemia, may play an important role in this process. There is accumulating evidence to suggest that the primary mechanisms leading to reduced plasma HDL cholesterol levels and HDL particle number in hypertriglyceridemic states may be due to any one or a combination of the following possibilities: (1) small HDL particles, which are the product of the intravascular lipolysis of triglyceride-enriched HDL, may be cleared more rapidly from the circulation, (2) triglyceride-enriched HDL may be intrinsically more unstable in the circulation, with apo A-I loosely bound, (3) the lipolytic process itself of triglyceride-enriched HDL may lower HDL particle number by causing apo A-I to be shed from the HDL particles and cleared from the circulation, (4) a dysfunctional lipoprotein lipase or reduced LPL activity may contribute to the lowering of HDL levels by reducing the availability of surface constituents of triglyceride-rich lipoproteins that are necessary for the formation of nascent HDL particles. This review summarizes the evidence that triglyceride-enrichment of HDL is an important factor determining the rate at which HDL is catabolized, a mechanism which could explain, at least in part, the reduced plasma HDL cholesterol levels and particle number frequently observed in hypertriglyceridemic states.

Cholesterol, HDL↗
PubMed1999

Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation.

The in vivo effect of elevated free fatty acids (FFA) on beta-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects of an approximately twofold elevation of plasma FFA vs. control on glucose-stimulated insulin secretion (GSIS). GSIS was studied in response to a graded intravenous glucose infusion (peak plasma glucose, approximately 10 mmol/l, n = 8) and a two-step hyperglycemic clamp (10 and 20 mmol/l, n = 8). In the acute studies, GSIS was significantly higher, insulin sensitivity index (SI) was lower, and disposition index (DI = insulin sensitivity x insulin secretion) was unchanged with elevated FFA vs. control [2-step clamp: DI = 8.9 +/- 1.4 x 10(-3) l2. kg-1. min-2 in control vs. 10.0 +/- 1.9 x 10(-3) l2. kg-1. min-2 with high FFA, P = nonsignificant (NS)]. In the chronic studies, there was no difference in absolute GSIS between control and high FFA studies, but there was a reduction in SI and a loss of the expected compensatory increase in insulin secretion as assessed by the DI (2-step clamp: DI = 10.0 +/- 1.2 x 10(-3) l2. kg-1. min-2 in control vs. 6.1 +/- 0.7 x 10(-3) l2. kg-1. min-2 with high FFA, P = 0.01). In summary, 1) acute and chronic FFA elevation induces insulin resistance; 2) with acute FFA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and 3) chronic FFA elevation disables this beta-cell compensation.

Adult↗
PubMed1999

Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men.

Triglyceride (TG) enrichment of HDL resulting from cholesteryl ester transfer protein-mediated exchange with TG-rich lipoproteins may enhance the lipolytic transformation and subsequent metabolic clearance of HDL particles in hypertriglyceridemic states. The present study investigates the effect of TG enrichment of HDL on the clearance of HDL-associated apo A-I in humans. HDL was isolated from plasma of six normolipidemic men (mean age: 29.7 +/- 2.7 years) in the fasting state and after a five-hour intravenous infusion with a synthetic TG emulsion, Intralipid. Intralipid infusion resulted in a 2.1-fold increase in the TG content of HDL. Each tracer was then whole-labeled with 125I or 131I and injected intravenously into the subject. Apo A-I in TG-enriched HDL was cleared 26% more rapidly than apo A-I in fasting HDL. A strong correlation between the Intralipid-induced increase in the TG content of HDL and the increase in HDL apo A-I fractional catabolic rate reinforced the importance of TG enrichment of HDL in enhancing its metabolic clearance. HDL was separated further into lipoproteins containing apo A-II (LpAI:AII) and those without apo A-II (LpAI). Results revealed that the enhanced clearance of apo A-I from TG-enriched HDL could be largely attributed to differences in the clearance of LpAI but not LpAI:AII. This is, to our knowledge, the first direct demonstration in humans that TG enrichment of HDL enhances the clearance of HDL apo A-I from the circulation. This phenomenon could provide an important mechanism explaining how HDL apo A-I and HDL cholesterol are lowered in hypertriglyceridemic states.

Adult↗