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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

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.

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.

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.

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.

We have developed a method using a bolus of [(2)H(5)]glycerol to determine parameters of VLDL-triglyceride (VLDL-TG) turnover and have compared the data to that obtained using simultaneously a bolus of [2-(3)H]glycerol in six young normolipidemic men. No measurable enrichment was found after 12 h for [(2)H(5)]glycerol; therefore, we could only perform a monoexponential analysis of its data. No differences in fractional catabolic rate (FCR) were seen when comparing the multicompartmental modeling of [2-(3)H]glycerol data (modeled over 48 h) either to the monoexponential analyses of the [2-(3)H]glycerol or that of the [(2)H(5)]glycerol data. The two monoexponential approaches were highly correlated (r = 0.96 for FCR), however, FCR was 18% higher with the [(2)H(5)]glycerol than with the [2-(3)H]glycerol data (P < 0.003). In all six subjects, a 10-h infusion of [1-(13)C]acetate was started at the same time as the glycerol boluses were given. In two men we were able reliably to detect VLDL-TG-fatty acid enrichment. The measurement of FCR in these two subjects using the mass isotopomer distribution analysis (MIDA) approach was in good agreement (within 10%) with FCRs determined with the labeled glycerol methods. In conclusion, our results have shown that results obtained with the [(2)H(5)]glycerol bolus were highly correlated with those obtained with the [2-(3)H]glycerol, but the FCRs were slightly higher with the former. We have also demonstrated that FCRs determined from monoexponential modeling were in good agreement with those determined from the multicompartmental modeling of the TG-glycerol data.

Polycystic ovarian syndrome (PCOS) is a common disorder associated with hyperandrogenemia and infertility. Abdominal obesity, insulin resistance, and dyslipoproteinemias are other common metabolic disorders typically found in women with PCOS. The cause-effect relationship between hyperandrogenemia and insulin resistance-dyslipoproteinemia remains unclear. In this study, we have investigated the changes in androgenemia, insulin sensitivity, and plasma lipid-lipoprotein levels after laparoscopic ovarian cautery (LOC) for ovulation induction in eight infertile women with clomiphene citrate-resistant PCOS. After LOC, significant decreases in androstenedione (43%), testosterone (48%), and free testosterone (48%) concentrations were observed (P < 0.05). Glucose utilization during an euglycemic-hyperinsulinemic clamp did not change after LOC. In addition, no significant changes after the surgical procedure were observed for cholesterol, triglycerides, and apolipoprotein concentrations measured in total plasma and in different lipoprotein fractions. In conclusion, within the short duration of observation of this study, our findings demonstrate that insulin resistance and lipoprotein abnormalities associated with PCOS are not secondary to hyperandrogenemia. The clinician, therefore, must be cognizant of the persistence of these metabolic risk factors for cardiovascular disease once successful ovulation and fertility is restored, and institute appropriate monitoring, counseling, and medical intervention as required.

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.

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.

Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether FFAs impair hepatic insulin extraction (E(H)) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml x kg(-1) x min(-1)) plus heparin (0.44 U x kg(-1) x min(-1)) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol x kg(-1) x min(-1) for 150 min (period A, high insulin dose), and then at 2.4 pmol x kg(-1) x min(-1) for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol x kg(-1) x min(-1) for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 +/- 167, 1,491 +/- 240, 1,159 +/- 221 micromol/l (IH) and 221 +/- 44, 329 +/- 72, 176 +/- 44 micromol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 +/- 114, 126 +/- 12, 1,050 +/- 72 pmol/l for IH vs. 1,344 +/- 168, 96 +/- 4.2, 882 +/- 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E(H) were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 +/- 0.6, 12.0 +/- 0.9, 10.2 +/- 0.6 ml x kg(-1) x min(-1)) than with SAL (11.2 +/- 1, 13.6 +/- 0.7, 11.9 +/- 0.9 ml x kg(-1) x min(-1)) in periods A, B, and C. E(H) was also lower (P < 0.05) with IH (25 +/- 4, 40 +/- 5, 32 +/- 5%) than with SAL (30 +/- 2.8, 47 +/- 3, 38 +/- 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity.

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.

We and others have shown that insulin acutely suppresses glucose production in fasting nondiabetic humans and dogs, by both a direct hepatic effect and an indirect (extrahepatic) effect, and in diabetic dogs by an indirect effect alone. In type 2 diabetes, there is resistance to insulin's ability to suppress hepatic glucose production, but it has not previously been determined whether the resistance is primarily at the level of the hepatocyte or the peripheral tissues. To determine whether the diabetic state reduces the direct effect of insulin in humans, we studied nine patients with untreated type 2 diabetes who underwent three studies each, 4-6 weeks apart. 1) Portal study (POR): intravenous tolbutamide was infused for 3 h with calculation of pancreatic insulin secretion from peripheral plasma C-peptide. 2) Peripheral study (PER): equidose insulin was infused by peripheral vein. 3) Half-dose peripheral insulin study (1/2 PER): matched peripheral insulin levels with study 1. In all studies, glucose was clamped at euglycemia, glucose turnover was measured with the constant specific activity method, and 3-[3H]glucose was purified by high-performance liquid chromatography. Peripheral insulin was lower in POR versus PER but slightly higher in POR versus 1/2 PER, although most of the difference could be accounted for by higher proinsulin levels in POR (stimulated by tolbutamide). Calculated portal insulin was approximately 1.3-fold higher in POR versus PER and approximately 2.2-fold higher in POR versus 1/2 PER. In the final 30 min of the clamp, glucose production reached a lower steady-state level in PER than in POR (4.0 +/- 0.4 vs. 5.3 +/- 0.5 pmol(-1) x kg(-1) x min(-1), P < 0.05), despite the higher hepatic insulin level in POR. In contrast with our studies in nondiabetic individuals, glucose production was not more suppressed at steady state in POR versus 1/2 PER (5.3 +/- 0.4 micromol x kg(-1) x min(-1)), despite much higher hepatic insulin levels in POR. In conclusion, this is the first study in patients with type 2 diabetes to characterize insulin resistance to the acute direct suppressive effect of insulin on hepatic glucose production.

Prolonged exposure of pancreatic islets to free fatty acids (FFAs) inhibits glucose-stimulated insulin secretion (GSIS) in vitro. However, FFA inhibition of GSIS has not been clearly demonstrated in vivo. We examined the in vivo effect of prolonged elevation of plasma FFAs on GSIS using a two-step hyperglycemic clamp in rats treated with a 48-h intravenous infusion of either 20% Intralipid plus heparin (INT) (5 microl/min plus heparin, 0.1 U/min; n = 8), oleate (OLE) (1.3 microEq/min; n = 6), saline (SAL) (n = 6), or bovine serum albumin (BSA) (vehicle for OLE; n = 5). Because there was no difference in any of the parameters between BSA and SAL rats, these groups were combined as control rats (CONT) (n = 11). At the end of the 48-h OLE/INT/CONT infusions, after an overnight fast, plasma glucose was clamped for 2 h at 13 mmol/l and for another 2 h at 22 mmol/l. Preclamp plasma FFAs were elevated twofold (P < 0.01) versus CONT with both INT and OLE (NS, INT vs. OLE). Preclamp glucose, insulin, and C-peptide levels were higher in INT than in CONT rats (P < 0.05), suggesting insulin resistance, but they were not different in OLE and CONT rats. The insulin and C-peptide responses to the rise in plasma glucose from basal to 13 mmol/l were lower in OLE (336 +/- 72 pmol/l and 1.2 +/- 0.1 nmol/l, P < 0.01 and P < 0.05, respectively) than in CONT (552 +/- 54 and 1.9 +/- 0.1) rats, but they were not different between CONT and INT rats (648 +/- 150 and 2.0 +/- 0.4). The insulin and C-peptide responses to the rise in plasma glucose from 13 to 22 mmol/l were lower in both INT (1,188 +/- 204 pmol/l and 3.0 +/- 0.3 nmol/l, P < 0.01 and P < 0.001) and OLE (432 +/- 60 and 1.7 +/- 0.2, P < 0.001 vs. CONT or INT) rats than in CONT rats (1,662 +/- 174 and 5.0 +/- 0.6). In summary, 1) both INT and OLE decreased GSIS in vivo in rats, and 2) the impairing effect of INT on GSIS was less than that of OLE, which might be due to the different type of fatty acid (mostly polyunsaturated in INT versus monounsaturated as OLE) and/or to differential effects of INT and OLE on insulin sensitivity. In conclusion, prolonged elevation of plasma FFAs can desensitize the insulin secretory response to glucose in vivo, thus inducing a beta-cell defect that is similar to that found in type 2 diabetes.

The magnitude of the counterregulatory response to insulin-induced hypoglycemia is primarily determined by the degree of hypoglycemia. We examined whether the route of acute insulin delivery (portal or peripheral venous) is also important in determining the magnitude of the counterregulatory response to hypoglycemia in nine healthy nondiabetic men. Pancreatic insulin secretion, stimulated by an i.v. tolbutamide infusion (portal insulin study), was matched with an exogenous insulin infusion into the peripheral vein 4-6 weeks later (peripheral insulin study). Each study consisted of a 150-min baseline tracer equilibration period, a 180-min euglycemic hyperinsulinemic (portal or peripheral insulin delivery) period, a 60-min hypoglycemic period in which insulin secretion diminished during tolbutamide or was reduced during exogenous insulin, and a 30-min recovery period. Peripheral venous glucose concentrations were well matched in the portal and peripheral studies during euglycemia and hypoglycemia (glucose nadir, 2.9 +/- 0.1 mmol/L in the portal and 2.7 +/- 0.1 mmol/L in the peripheral; mean +/- SEM; P = NS), and insulin concentrations were about 1.5-fold higher throughout the experiment in the peripheral vs. the portal insulin study due to the first pass extraction of insulin in the portal study. There was a much greater increment (P < 0.0001) in FFA in the portal vs. the peripheral study (area under the curve: portal, 19.5 +/- 3.9 mmol/L x 90 min; peripheral, 3.3 +/- 1.1 mmol/L x 90 min), whereas plasma glucagon and GH were higher in the peripheral study (P = 0.01 for glucagon; P = 0.015 for GH). There was no significant difference between studies in epinephrine and norepinephrine responses to hypoglycemia or stimulation of endogenous glucose production (area under the curve: portal, 636 +/- 103 micromol/kg x 90 min; peripheral, 705 +/- 69 micromol/kg x 90 min; P = NS). In summary, we have shown that the glucagon, GH, and FFA responses to hypoglycemia during insulin dissipation are affected by the route of insulin delivery and are not controlled exclusively by the nadir blood glucose level. The clinical importance of these observations in diabetic subjects as they relate to route of insulin delivery (portal or peripheral) during insulin dissipation remains to be determined.

This study compared retinyl palmitate and apolipoprotein (apo) B-48 as markers of postprandial triglyceride-rich lipoproteins. Nine non-diabetic men received an oral vitamin A-containing fat load. We measured retinyl palmitate, apoB-48, apoB-100, and triglyceride levels in Sf > 400, Sf 60-400 and Sf 20-60 lipoproteins. The peak retinyl palmitate concentration was delayed compared to the peak apoB-48 concentration in each fraction. The discrepancy between retinyl palmitate and apoB-48 was further investigated in another study of 12 men. In that study, a fat load was given and 5 h later, lipolysis was stimulated in vivo with heparin (60 U/kg, i.v.) and the same parameters were followed. Thirty minutes after heparin, triglyceride levels decreased significantly in the three triglyceride-rich lipoprotein fractions (Sf > 400, Sf 60-400 and Sf 20-60). ApoB-48 levels also fell significantly in the three triglyceride-rich lipoprotein fractions. In contrast, retinyl palmitate concentrations did not change significantly in Sf > 400 and Sf 60-400 fractions and increased significantly in the Sf 20-60 fraction. Our results indicate that retinyl palmitate and apolipoprotein B-48 do not mark the same properties of postprandial intestinal lipoproteins. The metabolic pattern of apolipoprotein B-48 parallels that of triglyceride. One possible explanation for these observations is that the apoB-48-containing triglyceride-rich lipoproteins are metabolically heterogeneous and that older particles, those in circulation for a longer period of time, may be cleared more rapidly than newer ones.

We have shown previously that the greater suppression of endogenous glucose production (GP) with equimolar peripheral vs. portal insulin cannot be detected or is minimally reversed when the insulin-induced suppression of either free fatty acids (FFA) or glucagon alone is prevented. The present experiments were designed to minimize the insulin suppression of both glucagon and FFA in an attempt to further examine the mechanism of insulin's peripheral effect on GP. In nine healthy men, we investigated the effect of limiting the insulin suppression of both FFA and glucagon by infusing heparin (250 U/h), Intralipid 10% (25 ml/h), and glucagon (0.65 ng . kg-1 . min-1) during 1) portal (n = 9), 2) equimolar peripheral (n = 9), and 3) half-dose peripheral insulin delivery (n = 4) by use of our previously published tolbutamide infusion method, with calculation and matching of insulin secretion rate. GP decreased by 57.2 +/- 2. 6% with portal, 39.0 +/- 4.1% with equimolar peripheral, and 31.5 +/- 2.7% with half-dose peripheral insulin delivery (P < 0.001 for portal vs. peripheral and P < 0.001 for portal vs. half-dose peripheral). In contrast, in six control subjects in whom glucagon and FFA were not replaced, GP decreased by 62.6 +/- 2.4% with portal (n = 6), 75.7 +/- 3.0% with peripheral (n = 6), and 56.3 +/- 3.0% with half-dose peripheral (n = 4) insulin delivery (P < 0.01 for portal vs. peripheral and P = not significant for portal vs. half-dose peripheral). In summary, the greater suppression of GP with equimolar peripheral vs. portal insulin is eliminated and markedly reversed if the acute insulin-induced suppression of both plasma FFA and glucagon is minimized. This suggests that the insulin-induced suppression of glucagon and FFA has additive or cooperative effects in mediating the acute extrahepatic effect of insulin on GP.

Several lines of evidence have demonstrated that increased plasma cholesterol plays a primary role in the etiology of atherosclerosis and ischemic heart disease (IHD). Our ability to manage IHD adequately based on plasma cholesterol or low density lipoprotein (LDL) cholesterol concentrations is challenged, however, by evidence suggesting that a significant proportion of individuals with IHD or who will eventually develop IHD have desirable cholesterol concentrations. These observations have generated much interest in the scientific community, with the resultant identification of new metabolic risk factors that may help, in the future, to improve our ability to reduce the risk of IHD adequately. This review presents evidence that hypertriglyceridemia, particularly when associated with reduced high density lipoprotein (HDL) cholesterol concentrations and abdominal or visceral obesity, is a highly atherogenic phenotype, one that requires aggressive risk reduction management. Hypertriglyceridemia is frequently associated with elevated plasma apolipoprotein B concentrations, with states of hyperinsulinemia or insulin resistance and with small, dense LDL particles, which may all contribute to increase the risk of IHD further. This evidence suggests that a therapeutic strategy based on the assessment of plasma triglyceride concentrations, along with HDL cholesterol levels and abdominal obesity, may be a cost effective approach to assessing the high atherogenic risk of visceral obesity and insulin resistance. We can no longer afford to focus our attention exclusively on the detection and management of elevated LDL cholesterol concentrations, and need to adopt comprehensive risk reduction strategies in order to lower the incidence of IHD.

Hypertriglyceridemia is commonly associated with triglyceride (TG) enrichment of high density lipoprotein (HDL) and reduction in HDL cholesterol and apolipoprotein A-I levels. We have recently reported that lipolytic modification of TG-rich HDL, which reduces particle size, enhances its clearance from the circulation. In the present study, we examined the role of particle size and lipid composition in determining the metabolic clearance of human HDL, in the absence of substantial in vivo modification of the particle by hepatic lipase. The rabbit, which has a very low hepatic lipase activity, was used for this purpose. Plasma fractions d < 1.21 g/ml were first isolated by ultracentrifugation from fasting humans with normal (NTG, n=6, mean plasma TG concentration=1.26+/-0.21 (SEM) mmol/l) or elevated plasma TG levels (HTG, n=5, TG=4.49+/-0.65 mmol/l). Small and large HDL particles were separated by gel filtration chromatography and were labeled with either 125I or (131)I. Large HDL were cleared more rapidly than small HDL in 10 out of 11 studies (P=0.006). There was, however, no difference in the fractional catabolic rate (FCR) of large HDL isolated from NTG versus from HTG subjects or in the FCR of small HDL from NTG versus HTG individuals. There was also no correlation between the TG content of HDL and its FCR. In summary, large, lipid-rich human high density lipoproteins (HDL) are cleared more rapidly than small human HDL in rabbits. These results, combined with our previous observation, also support the hypothesis that triglyceride enrichment of HDL, in the absence of substantial lipolytic modification, is not sufficient to enhance its clearance from the circulation.

Background: Serum creatinine level has been reported to be related to the incidence of strokes., Objective: To examine the relationship between serum creatinine level and the severity of extracranial carotid artery atherosclerosis., Design and Methods: This is a secondary analysis of data from 88 patients (59 men and 29 women) who had previously had transient ischaemic attacks or minor strokes and had been included in intervention trials of symptomatic carotid disease. Narrowing of internal carotid artery was estimated by angiography. Both internal carotid arteries were measured and the severity was expressed as the sum of percentage stenoses on both sides. The risk profiles of patients with moderate and severe internal carotid artery stenosis were compared., Results: The sex-adjusted mean serum creatinine concentration in those with severe carotid disease was significantly higher than that in those with moderate disease (106.3 +/- 3.3 versus 91.3 +/- 3.7 mumol/l, P = 0.003), but still within the normal range. The risk of having severe disease was compared with risk of having moderate disease for people ranked by their serum creatinine levels. Univariate logistic regression showed that the odds ratio (OR) for having severe involvement of internal carotid artery was greater for patients in mid-tertile of creatinine values than it was for those in the lowest tertile (OR 6.3, 95% confidence interval 2.0-20.4, P = 0.002). The creatinine levels of patients in these two tertiles were within the normal range. The OR was no greater for patients in the highest tertile of creatinine values, which were slightly elevated above the normal range. These OR did not change after adjustment for age, sex, hypertension or systolic blood pressure, diabetes, smoking and lipid levels., Conclusion: Results of this study demonstrate for the first time that serum creatinine level, even within the range of upper normal or mildly elevated levels, is related to the angiographic severity of internal carotid artery disease in patients who have previously had transient ischaemic attacks and that this relationship is independent of classic cardiovascular risk factors.

The aim of the present study was to determine the contributions of particle size versus number to differences in plasma triglyceride-rich lipoprotein concentrations in patients with type 2 diabetes. Fasting plasma was obtained from 174 consecutive eligible men and women with type 2 diabetes (with or without insulin treatment, mean age 57.0 + 6.3 years) who were undergoing coronary angiography. The triglyceride-rich (Sf 12-400) lipoproteins (TRL) were subfractionated into the Sf 12-60 and Sf 60-400 subfractions. Particle numbers, estimated by measuring apolipoprotein B by electroimmunoassay, in each of these lipoprotein fractions were related to enzymatically determined triglyceride levels in the triglyceride-rich lipoproteins. Approximately 87% of the triglyceride-rich lipoprotein particles were in the Sf 12-60 fraction and 13% in the Sf 60-400 fraction. Multiple linear regression indicated that 69% (i.e. r2=0.69) of the variance in the triglyceride levels could by explained by differences in TRL particle number and 17% (i. e. r2=0.17) by the differences in particle triglyceride content. These observations are similar in each gender and in those with or without insulin treatment. In conclusion, in type 2 diabetes, the vast majority of triglyceride-rich lipoproteins are smaller particles which are in the Sf 12-60 fraction. Differences in particle number, rather than triglyceride content, account for approximately 70% of the differences in triglyceride levels observed between individuals. Previous demonstrations, in those without diabetes, of an association between small triglyceride-rich lipoproteins with coronary artery disease suggest the importance of these findings to the increased atherosclerosis in diabetes.

In hypertriglyceridemic states, triglyceride enrichment of high-density lipoprotein (HDL) may play an important role in decreasing the HDL cholesterol and apolipoprotein (apo) A-1 plasma concentration. We have shown previously that HDL particles are transformed into small HDLs when lipolysis is stimulated in vivo or in vitro, and this process is more marked if the HDL is triglyceride-rich. The present study was conducted to determine whether the susceptibility of HDL to transformation can be altered by triglyceride-lowering therapy in humans. Seventeen moderately hypertriglyceridemic individuals (nine with type II diabetes mellitus and eight moderately hypertriglyceridemic nondiabetic subjects) were studied before and after 3 months of triglyceride-lowering therapy with gemfibrozil. Since no significant differences in postprandial and postheparin HDL metabolism were detected between type II diabetic and nondiabetic subjects, results are reported for the two groups combined (N = 17). Fasting HDL was triglyceride-rich with a preponderance of HDL3, and became more enriched with triglycerides postprandially. Heparin administration resulted in a rapid decrease in plasma and HDL triglycerides and an increase in plasma and HDL free fatty acids (FFAs). Postheparin, there was a reduction in HDL size and an increase in the proportion of small (HDL3c) HDL particles (HDL3c constituted 7.1% +/- 1.8% of total HDL preheparin and 26.6% +/- 3.8% postheparin, P < .001). Triglyceride-lowering treatment resulted in a decrease in fasting triglycerides (-54%, P < .001) and HDL triglyceride content (-36%, P = .002), an increase in fasting HDL cholesterol (19%, P = .004), and proportionately fewer (13.2% +/- 2.1%, P < .001) HDL3c particles formed postheparin. Postheparin HDL size correlated inversely with the fasting triglyceride level (r = -.55, P < .001) and HDL triglyceride concentration (r = -.34, P = .02). These results show that the postprandial increase in triglyceride levels in hypertriglyceridemic subjects is associated with increased production of small HDL particles when lipolysis is stimulated, and that lipid-lowering therapy can contribute to favorably reduce this postprandial production of small HDL particles. Further studies are needed to clarify how these abnormalities ultimately lead to a decrease of plasma HDL cholesterol and apo A-1 in hypertriglyceridemic states.

We have investigated hepatic de novo lipogenesis and the ratio of apoB-48/apoB-100 during chronic carbohydrate supplementation with or without administration of exogenous insulin in rats. Two groups received chronic (2 weeks) carbohydrate supplementation either as 10% glucose or 10% fructose (wt/v) in their drinking water. Two other groups received exogenous insulin chronically, in addition to the monosaccharides above. The insulin was given for 2 weeks as daily human ultralente insulin injections in increasing doses up to 6 units per day. A fifth group of rats (normal control) received only chow and water. The fractional synthetic rate (FSR), the fraction of very low density lipoprotein triglyceride (VLDL-TG) palmitate that was newly made during an 8-h infusion with sodium [1-13C]acetate, was evaluated. The glucose and fructose groups had a 4-fold (0.60%/h) and 7.5-fold (1.13%/h) increase in FSR from baseline, respectively, compared to chow-fed controls (0.15%/h). Chronic exogenous insulin administration resulted in a 11.5 (1.73%/h) and 11.0 (1.65%/h)-fold increase over baseline in the synthesis of newly made VLDL-TG palmitate in the glucose and fructose groups, respectively. The ratio of apoB-48/apoB-100, i.e. apoB-48 enrichment, in VLDL was positively correlated with insulin levels (r = 0.41, P < 0.01) and with FSR (r = 0.39, P < 0.01). The present study shows that carbohydrate supplementation significantly increases the FSR of newly made VLDL-TG palmitate and that this increase is further augmented by chronic hyperinsulinemia.

Triglyceride (TG) enrichment of high density lipoproteins (HDL) in hypertriglyceridemic states renders the particles vulnerable to lipolysis, which reduces their size. In the present study we modified the size and composition of HDL in vivo in hypertriglyceridemic humans by administering a bolus of intravenous heparin, and tested the subsequent clearance of the isolated HDL particles in rabbits and rats. HDL was isolated by ultracentrifugation from 21 moderately hypertriglyceridemic humans, 5 h after ingestion of a high fat meal and then 15 min after an intravenous heparin bolus (60 U/kg). Postprandial large TG-rich preheparin HDL and small, TG-poor postheparin HDL were labeled with either 125I or 131I. The clearance of apoA-I associated with each HDL tracer was determined by injecting the tracers 1) simultaneously (n = 13) and 2) sequentially (n = 8) into male New Zealand White rabbits, an hepatic lipase-deficient animal, and 3) by injecting the tracers simultaneously into male Sprague-Dawley rats (n = 8), an animal that has hepatic lipase. Die-away curves of each radiolabeled tracer were analyzed using a two-pool model that assumes the existence of an intravascular pool in dynamic equilibrium with an extravascular pool. In the rabbit studies, the fractional catabolic rate (FCR) of small, postheparin TG-poor HDL was greater than the FCR of the larger TG-rich HDL (11% greater in the simultaneous study, P < 0.001, and 45% greater in the sequential study, P < 0.001). Opposite results were observed in rats as large TG-rich preheparin particles showed a greater FCR (1.8-fold) than smaller TG-poor postheparin HDL (P < 0.05). These data suggest that although size and composition of HDL can influence its catabolism, the effect is not always in the same direction and depends on other factors present in vivo.

We have shown previously in humans that insulin partly suppresses hepatic glucose production (HGP) by an extrahepatic (indirect) mechanism. In the present study, we investigated the role of free fatty acids (FFAs) in mediating the extrahepatic effects of insulin in humans and determined the extent to which insulin can regulate HGP by a non-FFA-mediated effect. Sixteen healthy men received an intravenous tolbutamide infusion for 3 h, and pancreatic insulin secretion was calculated by deconvolution of peripheral C-peptide levels. On a subsequent occasion, equimolar exogenous insulin was infused by peripheral vein. In both studies, glucose was clamped at euglycemia. We have previously validated this method and shown no independent insulin-like activity of tolbutamide. During the clamp, 9 of the 16 subjects received a low dose of heparin and Intralipid to prevent the insulin-induced suppression of FFAs, while 7 subjects received a high dose of heparin and Intralipid to raise FFAs approximately 2.5-fold. In both the high- and low-dose groups, peripheral insulin was higher and calculated portal insulin lower with peripheral versus portal insulin delivery. In the low-dose group, HGP decreased by 68.3 +/- 2.1% with portal insulin delivery and 64.7 +/- 3.7% with peripheral insulin delivery (NS). In the high-dose group, HGP decreased by 58.0 +/- 4.5% with portal insulin and 48.3 +/- 5.0% with peripheral insulin (P < 0.05). Four individuals who participated in the high-dose group underwent an additional peripheral insulin study in which the same dose of exogenous insulin was infused as in the high-dose group but in the absence of heparin and Intralipid. During this latter study, FFA levels declined by approximately 90% during hyperinsulinemia, and HGP was suppressed by 71.8 +/- 5.6%, which was a much greater suppression (P < 0.01) than when FFA levels were raised in these subjects during the equivalent rate insulin infusion. In summary, the previously observed greater suppression of HGP with equimolar peripheral versus portal insulin is eliminated or reversed, depending on plasma FFA levels, if FFAs are prevented from decreasing, suggesting an important role of FFAs in mediating the extrahepatic effects of insulin on HGP. However, the effect of FFA clamping is relatively small with a significant degree of suppression of HGP (by approximately 50%), which remains even when FFAs are elevated above basal levels, suggesting that in the physiological range FFAs only partially influence the suppression of HGP in humans. This suggests that other mechanisms, most likely hepatic, dominate the acute insulin-induced suppression of glucose production.

The topic covered in this review is the regulation of hepatic VLDL production by fatty acids, with emphasis on the role of plasma free fatty acids. Hepatic VLDL production is primarily substrate driven, the most important regulatory substrate being fatty acids. Fatty acids may be derived from at least four sources: (1) de-novo lipogenesis, (2) cytoplasmic triglyceride stores, (3) fatty acids derived from lipoproteins taken up directly by the liver, or (4) exogenous fatty acids (plasma free fatty acids). Although the total flux of fatty acids reaching hepatocytes plays an important regulatory role in VLDL synthesis, it is the nutritional and hormonal state of the organism that ultimately determines the rate of VLDL secretion. Nutritional and hormonal factors will determine whether intracellular fatty acids are channelled into oxidative, storage or secretory pathways. Conditions associated with both elevated free fatty acid flux to the liver and elevated de-novo lipogenesis, such as occurs in hyperinsulinemic insulin-resistant states, have hepatocytes primed to channel fatty acids into secretory pathways, with consequent high rates of VLDL secretion. Insulin-resistant states are associated not only with the release of larger quantities of free fatty acids from the increased mass of circulating lipoproteins, particularly in the postprandial state, but also with reduced free fatty acid uptake and esterification by peripheral tissues. Thus a vicious cycle is set up in insulin-resistant states involving free fatty acids and hypertriglyceridemia.

The present study examines the role of glucagon in modulating the hepatic and extrahepatic effects of insulin on hepatic glucose production (HGP). We infused glucagon at a constant rate (0.65 ng x kg(-1) x min(-1)) during equimolar portal and peripheral insulin delivery in seven healthy males by our previously published tolbutamide infusion method. In contrast to our previous study, in which glucagon fell by approximately 30% during hyperinsulinemia and suppression of HGP was significantly greater with equimolar peripheral than with portal insulin delivery, HGP was actually suppressed to a lesser extent with peripheral insulin delivery (69 +/- 10%) than when insulin was delivered portally (76 +/- 5%, P < 0.05). To further examine whether glucagon was enhancing the effect of portal insulin, in four additional individuals HGP was suppressed to a greater extent during a tolbutamide infusion when glucagon was administered continuously throughout the basal and hyperinsulinemic periods than when glucagon was infused during the basal period only; HGP suppressed by 63 +/- 3 vs. 52 +/- 3%, respectively, P = 0.02). Tolbutamide had no effect on HGP when infused into three C-peptide-negative individuals with type I diabetes during a low-dose insulin and glucagon infusion. These data suggest that glucagon levels are an important determinant of the balance between insulin's direct and indirect effects on HGP, with glucagon likely potentiating the direct hepatic effect of insulin.

A detailed analysis of postprandial changes in the size, density, composition, and relative proportion of the major high-density lipoprotein (HDL) subfractions, HDL2 and HDL3, was performed in seven normolipidemic patients with insulin-dependent diabetes mellitus (IDDM) in moderate glycemic control and seven age-, sex-, and weight-matched healthy nondiabetic controls. IDDM subjects received an overnight insulin infusion to maintain euglycemia, with an incremental increase in the insulin infusion rate at the time of the test meal (containing 60 g fat/m2). Samples for detailed analysis of HDL by gradient density ultracentrifugation and nondenaturing gradient gel electrophoresis (GGE) were collected at 0, 4, Br, and 12 hours after the test meal. The composition of HDL, HDL2, and HDL3 was significantly altered in the postprandial state in IDDM subjects and controls with an increase in triglyceride content at 4 to 8 hours and a reciprocal decrease in cholesteryl ester, reflecting exchange of lipid constituents of HDL with triglyceride (TG)-rich lipoproteins. In addition, the phospholipid content of the particles increased at 8 hours after the meal. Peak density of HDL2 and HDL3 decreased slightly at 4 to 8 hours, reaching significance only in controls at 8 hours (P < .05), whereas the mean radius size of these subfractions did not change significantly. In controls and IDDM subjects, the ratio of HDL3 to HDL2 at 8 to 12 hours increased significantly (P < .005). Significant differences in the composition, size, density, or subfraction distribution of HDL between subjects with IDDM and controls were not observed following ingestion of the lipid-rich meal. We conclude from these data that in patients with IDDM in moderate glycemic control, there do not appear to be any significant gross abnormalities in postprandial HDL metabolism with respect to the size, density, or compositional changes of HDL particles.

The present study examines the effect of the route of insulin delivery on glucose turnover in humans. By using a new noninvasive in vivo method, the acute effect of insulin secreted by the pancreas can be compared with that of insulin delivered by a peripheral vein. Three euglycemic-hyperinsulinemic studies were performed in lean healthy men. In the first study (n = 10), constant portal hyperinsulinemia was produced using a programmed intravenous tolbutamide infusion algorithm, and the insulin secretion rate was mathematically derived by deconvolution from peripheral plasma C-peptide levels. In the second study (n = 10), exogenous insulin was infused by peripheral vein at the same rate as that determined in the first study. In the third study (n = 7), the peripheral insulin levels in the first study were matched by infusing exogenous insulin into a peripheral vein at half that rate. Peripheral insulin levels were higher (P < 0.001) with the full-rate peripheral insulin infusion (266.3 +/- 28.1 pmol/l) than with the portal delivery of insulin (171.1 +/- 30.4 pmol/l) or the half-rate peripheral insulin infusion (158.6 +/- 7.4 pmol/l) (portal versus half-rate peripheral insulin infusion, NS). Calculated hepatic insulin levels were higher (P < 0.001) in the portal insulin study (443.1 +/- 52.6 pmol/l) than in the full-rate peripheral insulin study (303.6 +/- 30.9 pmol/l) or in the half-rate peripheral insulin study (204.5 +/- 9.8 pmol/l). Hepatic glucose production (HGP) was suppressed to a greater extent with the full-rate peripheral insulin infusion (69.3 +/- 7.8%, P < 0.001 vs. portal or half-rate peripheral insulin) than portal (50.3 +/- 9.8%) or half-rate peripheral insulin infusion (36.8 +/- 3.8%). In the portal insulin study, however, suppression was greater than in the half-rate peripheral insulin study (P < 0.01), in spite of equal peripheral insulin levels. The assumption that tolbutamide, when used in this fashion, has no independent effect on glucose turnover, glucagon, or gluconeogenic precursor and energy substrates for gluconeogenesis was validated in five C-peptide-negative patients with IDDM. We conclude that in nondiabetic humans, 1) peripheral effects of insulin are important in suppressing HGP, as evidenced by the greater suppression of HGP with equivalent rate peripheral versus portal insulin delivery, and 2) because HGP was suppressed to a greater extent with portal verus peripheral insulin delivery at half the rate when peripheral insulin levels were matched, insulin-induced suppression of HGP is also partly mediated by a direct hepatic effect.

Patients with diabetes mellitus have a two- to fourfold increase in clinical manifestations of atherosclerotic cardiovascular disease (ASCVD). Traditional risk factors such as age, hypertension, left ventricular hypertrophy, hyperlipidemia and smoking are still operative in diabetes but do not account for the total increase in ASCVD risk associated with diabetes. The most common lipid abnormalities in noninsulin-dependent diabetes mellitus and poorly controlled insulin-dependent diabetes mellitus are hypertriglyceridemia and low high density lipoprotein cholesterol. Evidence is presented to support the hypothesis that these lipid abnormalities are atherogenic in diabetes. Treatment of diabetic dyslipidemia with conservative measures (diet, weight loss, aerobic exercise, improved glycemic control) and pharmacological management have been shown to be highly effective in normalizing the lipid abnormalities. However, few trials of lipid lowering therapy have included patients with known diabetes mellitus and, to date, there have been no well-controlled prospective trials of lipid lowering therapy in diabetes. There is therefore no definitive proof regarding the benefit of lipid lowering therapy in diabetes mellitus. There are also no data regarding the cost effectiveness of lipid lowering therapy in reducing ASCVD complications in diabetes. There are data, however, showing that complications of ASCVD in patients with diabetes account for a large percentage of total health care expenditures. The overwhelming evidence that patients with diabetes have a high rate of ASCVD, that traditional risk factors for ASCVD are operative in diabetes and that the dyslipidemia of diabetes is highly prevalent and proatherogenic, predicts that the treatment of ASVD risk factors, including dyslipidemia, will be associated with a substantial reduction in ASCVD complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in VLDL triglyceride and VLDL apo B production were determined semiquantitatively in healthy young men by examining the effect of altering plasma insulin and/or FFA levels on the change in the slopes of the specific activity of VLDL [3H]triglyceride glycerol or the 131I-VLDL apo B versus time curves. In one study (n = 8) insulin was infused for 5 h using the euglycemic hyperinsulinemic clamp technique. Plasma FFA levels declined by approximately 80% (0.52 +/- 0.01 to 0.11 +/- 0.02 mmol/liter), VLDL triglyceride production decreased by 66.7 +/- 4.2% (P = 0.0001) and VLDL apo B production decreased by 51.7 +/- 10.6% (P = 0.003). In a second study (n = 8) heparin and Intralipid (Baxter Corp., Toronto, Canada) were infused with insulin to prevent the insulin-mediated fall in plasma FFA levels. Plasma FFA increased approximately twofold (0.43 +/- 0.05 to 0.82 + 0.13 mmol/liter), VLDL triglyceride production decreased to a lesser extent than with insulin alone (P = 0.006) (-31.8 +/- 9.5%, decrease from baseline P = 0.03) and VLDL apo B production did not decrease significantly (-6.3 +/- 13.6%, P = NS). In a third study (n = 8) when heparin and Intralipid were infused without insulin, FFA levels rose approximately twofold (0.53 +/- 0.04 to 0.85 +/- 0.1 mmol/liter), VLDL triglyceride production increased by 180.1 +/- 45.7% (P = 0.008) and VLDL apo B production increased by 94.2 +/- 28.7% (P = 0.05). We confirm our previous observation that acute hyperinsulinemia suppresses VLDL triglyceride and VLDL apo B production in healthy humans. In addition, we have demonstrated that elevation of plasma FFA levels acutely stimulates VLDL production in vivo in healthy young males. Elevating plasma FFA during hyperinsulinemia attenuates but does not completely abolish the suppressive effect of insulin on VLDL production, at least with respect to VLDL triglycerides. Therefore, in normal individuals the acute inhibition of VLDL production by insulin in vivo is only partly due to the suppression of plasma FFA, and may also be due to an FFA-independent process.

Acute changes in very low-density lipoprotein (VLDL) triglyceride (TG) and VLDL apolipoprotein (apo) B production were examined in 11 healthy young males in response to insulin delivered either by the peripheral venous route or secreted directly by the pancreas. Steady rates of pancreatic insulin secretion were achieved for 5 h by a programmed intravenous tolbutamide infusion, while euglycemia was maintained with a dextrose infusion. Insulin secretory rate was calculated from peripheral C-peptide levels by deconvolution, and, in a subsequent study, exogenous insulin was infused peripherally to match this pancreatic insulin secretory rate in each subject. Changes in VLDL TG and VLDL apo B production were determined semiquantitatively on each occasion by examining the change in slope of the specific activity (SA) of 3H-labeled triglyceride glycerol ([3H]TGG) and 131I-VLDL apo B vs. time curves, respectively, occurring with acute hyperinsulinemia. Plasma-free fatty acids (FFA), TG, apo B, and VLDL TG/VLDL apo B ratio decreased to a similar extent in both studies after the onset of hyperinsulinemia. VLDL TG production decreased significantly in both the tolbutamide (-47.1 +/- 7.3%, P < 0.002) and the exogenous insulin infusion study (-52.8 +/- 12.4%, P < 0.005). VLDL apo B production also decreased significantly in both studies (-58.9 +/- 7.5%, P = 0.0007 and -52.1 +/- 6.8%, P < 0.006, respectively), and there were no significant differences between studies. Tolbutamide was shown to have no independent effect on VLDL TG or VLDL apo B production in four insulin-deficient diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a new noninvasive method for comparing insulin secreted acutely by the pancreas vs. a matched peripheral venous insulin infusion in humans. An intravenous tolbutamide infusion algorithm was developed that produced sustained steady rates of portal insulin secretion over 5 h in 11 healthy young men. Plasma glucose levels were maintained in the euglycemic range by adjusting the rate of an iv dextrose (20%) infusion. The pancreatic insulin secretory rate was calculated from peripheral C-peptide levels by deconvolution using standard parameters for a two-compartment mathematical model for C-peptide distribution and metabolism. On a subsequent occasion in the same subject, exogenous insulin was infused peripherally at a rate that matched the earlier tolbutamide-induced pancreatic insulin secretory rate, and euglycemia was maintained with a variable 20% dextrose infusion. The assumption that tolbutamide, when used in this fashion, has no independent insulin-like or insulin-potentiating effect at either low or high levels of peripheral insulinemia, does not affect insulin clearance, and does not suppress peripheral glucagon levels was validated in four patients with insulin-dependent diabetes mellitus. Mean peripheral immunoreactive insulin was significantly higher in the insulin infusion study than in the tolbutamide study (286 +/- 31 vs. 156 +/- 21 pmol/L; P = 0.0001). The dextrose infusion rates required to maintain euglycemia were also higher in the insulin infusion study (0.44 +/- 0.03 vs. 0.32 +/- 0.03 mmol/kg.min; P = 0.003). The MCR of insulin was greater in the tolbutamide infusion vs. the exogenous insulin infusion study (32.6 +/- 2.9 vs. 19.8 +/- 2.2 mL/kg.min; P = 0.0003), probably due to the hepatic first pass effect on insulin clearance when insulin is delivered by the portal route. This noninvasive method can be used in future studies to examine the relative importance of direct hepatic vs. peripheral effects of insulin in controlling hepatic glucose and lipid production.

Objective: To examine the effect of prior meal ingestion on the glucose, insulin, and C-peptide response to a 50-g glucose challenge test in the third trimester of pregnancy., Research Design and Methods: Ten pregnant women with gestational diabetes mellitus and 12 nondiabetic pregnant control subjects matched for age and weight underwent a 50-g glucose challenge test on three occasions within a 2-wk period, in random order. On one occasion the test was administered in the fasting state (fasting glucose challenge test), on a second occasion the test was administered 1 h after ingestion of a standard mixed meal (1-h postprandial study), and on a third occasion the test was administered 2 h after ingestion of a standard mixed meal (2-h postprandial study)., Results: In the control subjects, the plasma glucose level 1 h after ingestion of 50 g of glucose was higher in the fasting study (7.8 +/- 0.4 mM, 7 of 12 subjects with glucose > or = 7.8 mM) than in the 1-h postprandial study (6.7 +/- 0.3 mM, 3 of 12 subjects with glucose > or = 7.8 mM) and the 2-h postprandial study of (6.3 +/- 0.4 mM, 3 of 12 with glucose > or = 7.8 mM) (P < 0.01). In the postprandial studies of control subjects, insulin and C-peptide levels were higher at the time of ingestion of the 50 g of glucose, but the early (1 h) insulin secretory response was less than in the fasting study. In the diabetic patients, glucose levels 1 h after 50-g glucose ingestion were similar in the fasting study (10.5 +/- 0.4 mM, no subjects with glucose value < 7.8 mM) and the 1-h postprandial study (11.0 +/- 0.6 mM, 1 subject with glucose < 7.8 mM), but was lower in the 2-h postprandial study (9.3 +/- 0.3 mM, 1 subject with glucose < 7.8 mM) (P < 0.03). In contrast to the control subjects, the insulin secretory response to 50 g of oral glucose was greater in the two postprandial studies than in the fasting study., Conclusions: We have reached the following conclusions. 1) In nondiabetic gravidas, plasma glucose concentrations 1 h after ingestion of a 50-g oral glucose load are higher if administered in the fasting state compared with the postprandial state. 2) During normal pregnancy the Staub-Traugott Effect, i.e., improved glucose disposal after successive glucose load administrations, occurs and appears to be caused by mechanisms other than enhanced insulin secretion with successive glucose loads. 3) The effect of the prandial state on plasma glucose response to the 50-g glucose challenge test used to screen for gestational diabetes mellitus may be of sufficient magnitude to significantly alter the operating characteristics, i.e., sensitivity and specificity, of this test.

The effects of short-term hyperinsulinemia on the production of both VLDL triglyceride and VLDL apoB were determined semiquantitatively before and during a 6-h euglycemic hyperinsulinemic clamp (40 mU.m-2 x min-1) in 17 women (8 chronically hyperinsulinemic obese, BMI = 35.7 kg/m2; 9 normal weight, BMI = 22.5 kg/m2). During acute hyperinsulinemia, plasma FFA decreased by approximately 95% within 1 h in both groups. VLDL triglyceride production decreased 66% in the control subjects (P = 0.0003) and 67% in obese subjects (P = 0.0003). ApoB production decreased 53% in control subjects (P = 0.03) but only 8% in obese (NS). Plasma triglycerides decreased by 40% from baseline in control subjects (P < 0.0001) but only by 10% in obese subjects (P = NS). Despite the similar decrease in triglyceride and apoB production in control subjects, VLDL particle size (triglyceride-to-apoB ratio) decreased with hyperinsulinemia (P = 0.003). In obese subjects, despite a decrease in triglyceride production similar to that in control subjects but no change in apoB production, VLDL size did not change appreciably. Acute hyperinsulinemia in humans: 1) suppresses plasma FFA equally in control and obese subjects at this high dose of insulin; 2) inhibits VLDL triglyceride production equally in control and obese subjects, perhaps secondary to the decrease in FFA; 3) inhibits VLDL apoB production in control but less so in obese subjects, suggesting that obese subjects may be resistant to this effect of insulin; 4) decreases plasma triglyceride and VLDL particle size in control subjects, reflecting either stimulation of LPL activity or a greater relative decrease in triglyceride to apoB production; and 5) does not decrease plasma triglyceride or VLDL size in obese subjects to the same extent as it does in control subjects. Thus, the insulin resistance of obesity affects some but not all aspects of VLDL metabolism.

The present study reports on the interaction between basal triglyceride and high density lipoprotein (HDL) cholesterol in determining the magnitude of postprandial triglyceridemia. The vitamin A fat-loading test was used to label intestinally derived triglyceride-rich particles after a high fat meal in 18 subjects with low HDL cholesterol and 6 control subjects who had normal fasting triglyceride and HDL cholesterol levels. The patients with low HDL cholesterol were divided into 2 groups on the basis of their basal triglyceride concentrations; 11 had normal triglyceride levels, and 7 had elevated serum triglycerides (HTG). In the HTG-low HDL group, the incremental area under the triglyceride curve was significantly greater (P less than 0.0003) than that in the other 2 groups, between whom no significant differences in triglyceride response were observed. Retinyl palmitate levels measured in whole plasma, an Sf greater than 1000 chylomicron fraction, and an Sf less than 1000 nonchylomicron fraction were also significantly greater in low HDL subjects with HTG, while the concentrations in low HDL subjects with normal triglyceride levels and control subjects were similar. Although basal HDL cholesterol levels in all study subjects were negatively correlated with the area under the incremental triglyceride curve (r = -0.42; P less than 0.05), this correlation was weak, in contrast to the correlation between fasting triglyceride levels and incremental triglyceride area (r = 0.56; P less than 0.005). Furthermore, basal HDL cholesterol levels did not correlate with the area under the chylomicron or nonchylomicron curves, whereas basal triglyceride levels were significantly correlated (P = 0.0001) with both of these variables. The HDL particles of both low HDL groups had a significantly higher proportion of triglyceride compared to the HDL particles in the control subjects. In conclusion, 1) fasting triglyceride levels are a more powerful indicator of the postprandial lipid response than basal HDL cholesterol in subjects with low HDL cholesterol levels; 2) patients with low HDL cholesterol levels do not preferentially accumulate chylomicron remnants after a meal unless they have coexisting hypertriglyceridemia; and 3) abnormalities in the levels of triglyceride-rich particles post-prandially are unlikely to be responsible for the increased incidence of atherosclerosis in low HDL patients who are normotriglyceridemic.

Fourteen poorly controlled insulin-dependent diabetes mellitus (IDDM) patients (HbA1c 11 +/- 0.5%) with a mean +/- SE duration of disease of 15 +/- 2 yr were studied to evaluate the hypoglycemic threshold for cognitive dysfunction under insulin-induced hypoglycemia. The P300 event-related potential, a measure of cognitive function, and reaction time (RT) in response to visual stimuli under euglycemic conditions and at plasma glucose concentrations of 3.5 and 2.5 mM (63 and 45 mg/dl, respectively) during a constant insulin infusion were recorded. Baseline P300 latency was similar to that of a nondiabetic control group, but baseline RT was greater in the IDDM group. There was no increase in P300 latency or RT under euglycemic clamp conditions or at a plasma glucose level of 3.5 mM (63 mg/dl). However, when plasma glucose was lowered to 2.5 mM (45 mg/dl), there was an increase in P300 latency and a prolongation of RT. As plasma glucose returned to baseline, P300 latency and RT remained prolonged. After administration of intravenous glucose and a meal, P300 latency and RT returned to baseline. P140, an event-related potential reflecting sensory processes, was not altered. Because P300 latency changes paralleled RT changes, hypoglycemia appears to slow decision-making processes in IDDM. This study revealed that 1) baseline P300 latency is not elevated in poorly controlled IDDM patients, suggesting no cumulative cognitive dysfunction.

Subnormal free T4 index (FT4I) values (less than 80) with inappropriately normal serum TSH concentrations that could not be attributed to illness or drugs were found in 2.5% of ambulating elderly clinic patients. Six such individuals (three men and three women, aged 68.8 +/- 4.8 yr) were selected for their persistent thyroid test abnormalities and were sex and age matched to six subjects (67.7 +/- 4.9 yr) with normal FT4I (greater than 90) and TSH levels. The former also had low serum total T4 (TT4) and rT3 (TrT3) concentrations, but total T3 (TT3) and basal TSH values were normal and did not differ between the groups. Responses of ACTH, LH, FSH, TSH, and PRL to stimulation with CRH, GnRH, and TRH showed no differences between the two groups, indicating that the normal TSH concentration, inappropriate for the low FT4I level, is not due to generalized hypothalamic or pituitary dysfunction. Administration of 3 g iopanoic acid (IOP) daily for 3 days produced significant increases in the TT4 and TrT3 concentrations to the same degree in both groups. Also, in both groups the IOP-induced suppression of T4 to T3 conversion in the pituitary gland provoked similar increases in basal TSH (280 +/- 47% and 288 +/- 33%) and TSH secretion in response to TRH (173 +/- 7% and 156 +/- 13%). These results indicate that the low FT4I is not the consequence of reduced pituitary TSH reserve. In addition, evidence for normal thyroid gland reserve and the secretion of TSH of normal biological activity was obtained by comparing the acute iodothyronine responses to TRH-induced TSH release in both groups. It is concluded that the normal serum TSH concentration, inappropriate for the low FT4I value in some elderly subjects, is due to an apparent resetting of the thyroid hormone feedback regulation threshold of TSH secretion. It may, in turn, be the result of enhanced pituitary conversion of T4 to T3 or increased T4 uptake by the thyrotrophs.

Unlabelled: The effect of deteriorating glycaemic control on the lipoprotein responses to the ingestion of a high fat meal was investigated in seven normolipidaemic Type 1 (insulin-dependent) diabetic patients and the results were compared with corresponding responses in seven normolipidaemic control subjects. In addition, the importance of insulin in regulating the postprandial lipoprotein responses was examined by comparing the results obtained from the diabetic patients maintained on a basal infusion of insulin throughout the study with those obtained when a step-up, step-down insulin infusion was administered following the meal. Vitamin A was added to the test meal in all subjects to trace the metabolism of the chylomicron (Sf greater than 1000) and non-chylomicron (Sf less than 1000) fractions in the postprandial period. No differences in fasting and postprandial triglyceride levels nor in the concentration of the chylomicron and non-chylomicron fractions were observed between diabetic and control subjects. In the diabetic patients short-term (two-week) deterioration in glycaemic control did not have any adverse influence on the basal and postprandial lipid responses. However, while the amount of insulin administered after the meal in the diabetic patients did not have any effect on the postprandial triglyceride or chylomicron responses, the concentration of non-esterified fatty acids was significantly higher (p less than 0.0005) when only a basal infusion of insulin was administered., In Conclusion: 1) Short-term deterioration in glycaemic control does not adversely affect lipoprotein concentrations in Type 1 diabetes. 2) Non-esterified fatty acids appear to be a more sensitive index of insulinization post-prandially than triglycerides.

Postprandial lipoprotein metabolism may be important in atherogenesis and has not been studied in detail in noninsulin-dependent diabetes mellitus (NIDDM). We used the vitamin A fat-loading test to label triglyceride-rich lipoprotein particles of intestinal origin after ingestion of a high fat mixed meal containing 60 g fat/m2 and 60,000 U vitamin A/m2 in 12 untreated NIDDM subjects with normotriglyceridemia (NTG; triglycerides, less than 1.7 mmol/L), 7 untreated NIDDM subjects with moderate hypertriglyceridemia (HTG; triglycerides, 1.7-4.7 mmol/L), and 8 age- and weight-matched normotriglyceridemic nondiabetic controls. The postprandial triglyceride increment was greater in NIDDM with HTG (P = 0.0001) and correlated strongly in all groups with the fasting triglyceride concentration (r = 0.83; P = 0.0001). Retinyl palmitate measured in whole plasma, an Sf greater than 1000 chylomicron fraction, and an Sf less than 1000 nonchylomicron fraction was also significantly greater in NIDDM with HTG, but did not differ significantly between NIDDM with NTG and controls. In NIDDM with HTG, chylomicrons appeared to be cleared at a slower rate, as evidenced by the significantly later intersection of the chylomicron and nonchylomicron retinyl palmitate response curves (13.7 h in HTG NIDDM vs. 8.5 h in NTG NIDDM vs. 7.3 h in controls; P less than 0.01). Although fasting FFA levels were similar in all three groups, the HTG diabetic subjects had a late postprandial surge in FFAs that lasted for up to 14 h. The postprandial FFA elevation in all groups correlated with the fasting triglyceride concentration (r = 0.57; P less than 0.002) and postprandial triglyceride increment (r = 0.80; P = 0.0001). The fasting core triglyceride content of the HDL particles in NIDDM with HTG was significantly elevated compared to those in NIDDM with NTG and controls (21.0% vs. 14.0% vs. 14.1% respectively; P less than 0.05), and this increased proportionately in all groups after the meal at the expense of cholesteryl ester, the increase correlating with total plasma postprandial triglyceride increment (r = 0.51; P less than 0.01). We conclude that moderate fasting hypertriglyceridemia in NIDDM is predictive of a constellation of postprandial changes in lipids and lipoproteins that may potentiate the already unfavorable atherogenic fasting lipid profile in these subjects.

Abnormalities in fasting lipid and lipoprotein levels are known to occur in obesity and other hyperinsulinemic states. However, postprandial lipoprotein metabolism has not been studied systematically in obese subjects using sensitive techniques to distinguish between triglyceride-rich lipoprotein particles derived from the intestine and the liver. In the present study the vitamin A fat-loading test was used to label intestinally derived triglyceride-rich lipoprotein particles in the postprandial state. Lipid parameters in seven normolipidemic obese subjects [body mass index, 43.7 +/- 2.81 kg/m2 (mean +/- SEM)] were compared to those in eight matched normal weight controls (body mass index, 23.6 +/- 0.72 kg/m2) during the 24-h period following ingestion of a mixed meal with a high fat content to which vitamin A had been added. Although subjects were selected for normal fasting lipid levels, in the obese group fasting triglycerides were significantly higher (1.35 +/- 0.12 vs. 0.68 +/- 0.08 mmol/L; P less than 0.0005) and high density lipoprotein (HDL) cholesterol was lower (0.94 +/- 0.08 vs. 1.35 +/- 0.11 mmol/L; P less than 0.01). The obese subjects had a greater postprandial triglyceride response to the test meal (P less than 0.05). The cumulative increment in total plasma triglycerides was 3.35-fold greater in obese than control subjects, while that of retinyl ester was only 1.63-fold greater, suggesting that a significant portion of the postprandial triglyceride response is due to endogenous hepatic lipoproteins. Postprandial plasma triglyceride and retinyl ester increment correlated with basal triglycerides (r = 0.72; P less than 0.005 and r = 0.57; P less than 0.03, respectively) and negatively with fasting HDL (r = -0.51; P less than 0.05 and r = -0.60; P less than 0.02, respectively). In the obese, the HDL triglyceride content increased maximally 4 h postprandially (4.1% to 6.1%; P less than 0.005) and phospholipid at 12 h (25.8% to 28.7%; P less than 0.05), with lower cholesteryl ester (21.1% to 17.5%; P less than 0.002) at 8 h, reflecting exchange of surface and core lipids with triglyceride-rich particles after the meal. In obese and control subjects the magnitude of HDL triglyceride enrichment after the meal correlated positively with the postprandial triglyceride increment (r = 0.74; P less than 0.007) and negatively with the fasting HDL cholesterol concentration (r = -0.80; P = 0.002). We conclude that even normolipidemic obese subjects have greater postprandial lipemia and triglyceride enrichment of HDL after ingestion of a high fat meal.(ABSTRACT TRUNCATED AT 400 WORDS)

Nineteen healthy adult volunteers were studied to define the nature of and threshold for the cognitive dysfunction that occurs during insulin-induced hypoglycemia. The P300 cerebral event-related potential is an electrophysiological correlate of cognitive decision-making processes that can be measured in response to either an auditory or visual stimulus. P300 and reaction time (RT) were recorded from a visual stimulus under euglycemic conditions and at plasma glucose concentrations of 3.3 and 2.6 mM during insulin infusion in 10 subjects. Reducing plasma glucose levels to 3.3 mM was not associated with an increase in either the latency or amplitude of the P300 component or a change in RT. However, further lowering of plasma glucose to 2.6 mM resulted in an increase in the latency of P300 and a prolongation in RT. Similar changes were seen for the auditory P300 in experiments performed on 9 additional subjects in which both auditory and visual stimuli were presented. The prolongation of P300 did not correct immediately when plasma glucose was raised to basal levels with intravenous glucose but returned to normal 45-75 min later, after ingestion of a carbohydrate-containing meal. Analysis of another event-related potential, P140 (a measure of the sensory processes), showed no change in response to hypoglycemia. Prolongation of RT paralleled the prolongation of P300 latency, suggesting that motor processes were not altered. Therefore, hypoglycemia appears to induce abnormalities in decision-making processes.(ABSTRACT TRUNCATED AT 250 WORDS)