The metabolic syndrome

Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.

Methods We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. Results The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P = 0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P = 0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P = 0.057 for interaction). Conclusions The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

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Effects of combination lipid therapy in type 2 diabetes mellitus.

Objectives Despite nearly 40 years of research, the role of plasma triglyceride as a risk factor for cardiovascular disease remains elusive. The objectives of the present study were to quantify the...

Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.

The VFA, also known as short-chain fatty acids, are produced in the gastrointestinal tract by microbial fermentation of carbohydrates and endogenous substrates, such as mucus. This can be of great advantage to the animal, since no digestive enzymes exist for breaking down cellulose or other complex carbohydrates. The VFA are produced in the largest amounts in herbivorous animal species and especially in the forestomach of ruminants. The VFA, however, also are produced in the lower digestive tract of humans and all animal species, and intestinal fermentation resembles that occurring in the rumen. The principal VFA in either the rumen or large intestine are acetate, propionate, and butyrate and are produced in a ratio varying from approximately 75:15:10 to 40:40:20. Absorption of VFA at their site of production is rapid, and large quantities are metabolized by the ruminal or large intestinal epithelium before reaching the portal blood. Most of the butyrate is converted to ketone bodies or CO2 by the epithelial cells, and nearly all of the remainder is removed by the liver. Propionate is similarly removed by the liver but is largely converted to glucose. Although species differences exist, acetate is used principally by peripheral tissues, especially fat and muscle. Considerable energy is obtained from VFA in herbivorous species, and far more research has been conducted on ruminants than on other species. Significant VFA, however, are now known to be produced in omnivorous species, such as pigs and humans. Current estimates are that VFA contribute approximately 70% to the caloric requirements of ruminants, such as sheep and cattle, approximately 10% for humans, and approximately 20-30% for several other omnivorous or herbivorous animals. The amount of fiber in the diet undoubtedly affects the amount of VFA produced, and thus the contribution of VFA to the energy needs of the body could become considerably greater as the dietary fiber increases. Pigs and some species of monkey most closely resemble humans, and current research should be directed toward examining the fermentation processes and VFA metabolism in those species. In addition to the energetic or nutritional contributions of VFA to the body, the VFA may indirectly influence cholesterol synthesis and even help regulate insulin or glucagon secretion. In addition, VFA production and absorption have a very significant effect on epithelial cell growth, blood flow, and the normal secretory and absorptive functions of the large intestine, cecum, and rumen. The absorption of VFA and sodium, for example, seem to be interdependent, and release of bicarbonate usually occurs during VFA absorption.(ABSTRACT TRUNCATED AT 400 WORDS)

Energy contributions of volatile fatty acids from the gastrointestinal tract in various species

A 59-year-old man with severe hypertriglyceridemia and no post-heparin lipolytic activity was studied because of a marked fall in plasma triglyceride concentrations after a blood transfusion. An apolipoprotein activator (apolipoprotein C-II) for lipoprotein lipase could not be detected by polyacrylamide-gel electrophoresis of apoproteins, immunodiffusion of the plasma against anti-apolipoprotein CII or activation assays for lipoprotein lipase. Furthermore, the patient's triglyceride-rich lipoproteins would not serve as substrate for lipoprotein lipase. The patient had latent post-heparin lipolytic activity, which appeared after the addition of apolipoprotein CII to the post-heparin plasma. After a transfusion of 1 unit of plasma from a normal subject the patient's plasma triglycerides fell, within one day, from 1000 to 250 mg per deciliter and remained below preinfusion concentrations for six days. We conclude that this patient's hyperlipoproteinemia resulted from a deficiency of apolipoprotein C-II.

Hypertriglyceridemia associated with deficiency of apolipoprotein C-II.

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.

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Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.

Postprandial lipoproteins and progression of coronary atherosclerosis

OBJECTIVE: Because women with systemic lupus erythematosus (SLE) are 5-8 times more likely to develop coronary heart disease (CHD) than are women in the general population, we assessed the prevalence of classic risk factors for CHD in women with SLE. METHODS: Consecutive female patients with SLE who were without evidence of CHD and were attending a large lupus clinic in Toronto were studied. The control population was recruited from among age-matched subjects attending a family practice unit for an annual physical examination. The prevalence of classic CHD risk factors and the 10-year risk of a CHD-related event were determined using the Framingham risk assessment formula. Lipid subfractions, other metabolic risk factors, lifestyle variables, and demographic characteristics were also compared between the 2 groups. RESULTS: We studied 250 SLE patients and 250 controls whose mean +/- SD age was 44.8 +/- 12 years and 44.3 +/- 15 years, respectively. Hypertension and diabetes were significantly more common among the SLE patients. Although the SLE patients had a higher mean number of CHD risk factors per patient, the 10-year risk of a CHD-related event, using the Framingham multiple risk factor assessment, was the same in SLE patients and controls (3.2%). Compared with controls, SLE patients had higher levels of very low-density lipoprotein cholesterol and total triglycerides, and had higher levels of homocysteine despite having higher folate levels. Premature menopause, sedentary lifestyle, and an at-risk body habitus were also more prevalent in SLE patients. CONCLUSION: Women with SLE have a range of detectable coronary risk factors that are not fully reflected in the Framingham risk factor formula. These factors are likely to contribute to the loss of protection from CHD that has been observed in SLE.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.11296

Risk factors for coronary heart disease in women with systemic lupus erythematosus: The Toronto Risk Factor Study

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 · min −1 ) in 17 women (8 chronically hyperinsulinemic obese, BMI = 357 kg/m2; 9 normal weight, BMI = 225 kg/m 2 ) During acute hyperinsulinemia, plasma FFA decreased by ∼ 95% within 1 h in both groups VLDL triglyceride production decreased 66% in the control subjects ( P = 00003) and 67% in obese subjects ( P = 00003) ApoB production decreased 53% in control subjects ( P = 003) but only 8% in obese (NS) Plasma triglycerides decreased by 40% from baseline in control subjects ( P 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 = 0003) 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

George Steiner

Papers

Hypertriglyceridemia associated with deficiency of apolipoprotein C-II.

Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.

Postprandial lipoproteins and progression of coronary atherosclerosis

Risk factors for coronary heart disease in women with systemic lupus erythematosus: The Toronto Risk Factor Study

Effects of Acute Hyperinsulinemia on VLDL Triglyceride and VLDL ApoB Production in Normal Weight and Obese Individuals