Rogelio U. Almario

Metabolic and endocrine effects of long-chain versus essential omega-3 polyunsaturated fatty acids in polycystic ovary syndrome.

The objective of the study was to compare the effects of essential vs long-chain omega (n)-3 polyunsaturated fatty acids (PUFAs) in polycystic ovary syndrome. In this 6-week, prospective, double-blinded, placebo (soybean oil)-controlled study, 51 completers received 3.5 g n-3 PUFA per day (essential PUFA from flaxseed oil or long-chain PUFA from fish oil). Anthropometric variables, cardiovascular risk factors, and androgens were measured; oral glucose tolerance test (OGTT) and frequently sampled intravenous GTT (IVGTT) were conducted at baseline and 6 weeks. Between-group comparisons showed significant differences in serum triglyceride response (P = .0368), whereas the changes in disposition index also tended to differ (P = .0621). When within-group changes (after vs before intervention) were considered, fish oil and flaxseed oil lowered serum triglyceride (P = .0154 and P = .0176, respectively). Fish oil increased glucose at 120 minutes of OGTT (P = .0355), decreased the Matsuda index (P = .0378), and tended to decrease acute insulin response during IVGTT (P = .0871). Soybean oil increased glucose at 30 (P = .0030) and 60 minutes (P = .0121) and AUC for glucose (P = .0122) during OGTT, tended to decrease acute insulin response during IVGTT (P = .0848), reduced testosterone (P = .0216), and tended to reduce sex hormone-binding globulin (P = .0858). Fasting glucose, insulin, adiponectin, leptin, or high-sensitivity C-reactive protein did not change with any intervention. Long-chain vs essential n-3 PUFA-rich oils have distinct metabolic and endocrine effects in polycystic ovary syndrome; and therefore, they should not be used interchangeably.

Effects of protein versus simple sugar intake on weight loss in polycystic ovary syndrome (according to the National Institutes of Health criteria)

OBJECTIVE To compare the effects of protein vs. simple sugars on weight loss, body composition, and metabolic and endocrine parameters in polycystic ovary syndrome (PCOS). DESIGN A 2-month, free-living, randomized, single-blinded study. SETTING University PCOS clinic. PATIENT(S) Thirty-three patients with PCOS. INTERVENTION(S) To achieve a final energy reduction of 450 kcal/day, first the daily energy intake was reduced by 700 kcal; then a 240-kcal supplement containing either whey protein or simple sugars was added. MAIN OUTCOME MEASURE(S) Changes in weight, fat mass, fasting glucose and insulin, plasma lipoproteins, and sex steroids. RESULT(S) Twenty-four subjects (13 in the simple sugars group and 11 in the protein group) completed the study. The protein group lost more weight (-3.3 +/- 0.8 kg vs. -1.1 +/- 0.6 kg) and more fat mass (-3.1 +/- 0.9 kg vs. -0.5 +/- 0.6 kg) and had larger decreases in serum cholesterol (-33.0 +/- 8.4 mg/dL vs. -2.3 +/- 6.8 mg/dL), high-density lipoprotein cholesterol (-4.5 +/- 1.3 mg/dL vs. -0.4 +/- 1.3 mg/dL), and apoprotein B (-20 +/- 5 mg/dL vs. 3 +/- 5 mg/dL). CONCLUSION(S) In patients with PCOS, a hypocaloric diet supplemented with protein reduced body weight, fat mass, serum cholesterol, and apoprotein B more than the diet supplemented with simple sugars.

Serum fatty acid binding protein 4, free fatty acids, and metabolic risk markers.

Fatty acid binding protein (FABP) 4 chaperones free fatty acids (FFAs) in the adipocytes during lipolysis. Serum FFA relates to metabolic syndrome, and serum FABP4 is emerging as a novel risk marker. In 36 overweight/obese women, serum FABP4 and FFA were measured hourly during 5-hour oral glucose tolerance test. Insulin resistance was determined using frequently sampled intravenous glucose tolerance test. Serum lipids and inflammation markers were measured at fasting. During oral glucose tolerance test, serum FABP4 decreased by 40%, reaching its nadir at 3 hours (from 45.3 +/- 3.1 to 31.9 +/- 1.6 ng/mL), and stayed below the baseline at 5 hours (35.9 +/- 2.2 ng/mL) (P < .0001 for both, compared with the baseline). Serum FFA decreased by 10-fold, reaching a nadir at 2 hours (from 0.611 +/- 0.033 to 0.067 +/- 0.004 mmol/L), then rebounded to 0.816 +/- 0.035 mmol/L at 5 hours (P < .001 for both, compared with baseline). Both fasting FABP4 and nadir FABP4 correlated with obesity. Nadir FABP4 correlated also with insulin resistance parameters from frequently sampled intravenous glucose tolerance test and with inflammation. Nadir FFA, but not fasting FFA, correlated with the metabolic syndrome parameters. In conclusion, fasting FABP4 related to metabolic risk markers more strongly than fasting FFA. Nadir FABP4 and nadir FFA measured after glucose loading may provide better risk assessment than the fasting values.

Differential effects of walnuts vs almonds on improving metabolic and endocrine parameters in PCOS.

Background/Objectives:Polycystic ovary syndrome (PCOS) is commonly associated with insulin resistance, dyslipidemia and increased inflammation, which all benefit from dietary intake of monounsaturated and n-3 polyunsaturated fatty acids (MUFA and n-3 PUFA). Our goal was to compare the effects of MUFA-rich almonds vs n-3/n-6 PUFA-rich walnuts on metabolic and endocrine parameters in PCOS.Subjects/Methods:Thirty-one PCOS patients randomly received either walnuts or almonds containing 31 g of total fat per day for 6 weeks. At the beginning and at the end, anthropometric parameters, fasting lipids, phospholipid-fatty acids, inflammatory markers, androgens, oral glucose tolerance tests (OGTT) and frequently sampled intravenous-GTT were obtained.Results:Weight remained stable. Within group, walnuts increased the n-3/n-6 essential PUFA in the diet and plasma phospholipids. Walnuts decreased low-density lipoprotein-cholesterol by 6% from 3.76±0.27 to 3.38±0.22 mmol/l (P=0.05) and apoprotein B by 11% from 0.72±0.04 to 0.64±0.05 g/l (P<0.03). Although almonds also reduced low-density lipoprotein-cholesterol by 10% and apoprotein B by 9%, these were not significant. Walnuts increased insulin response during OGTT by 26% (P<0.02). Both walnuts and almonds increased adiponectin (walnuts from 9.5±1.6 to 11.3±1.8 μg per 100 ml, P=0.0241; almonds from 10.1±1.5 to 12.2±1.4 μg/dl, P=0.0262). Walnuts decreased HgBA1 from 5.7±0.1 to 5.5±0.1% (P=0.0006) with significant intergroup difference from almonds (P=0.0470). Walnuts increased sex hormone-binding globulin from 38.3±4.1 to 43.1±4.3 nmol/l (P=0.0038) and almonds reduced free androgen index from 2.6±0.4 to 1.8±0.3 (P=0.0470).Conclusion:Nut intake exerted beneficial effects on plasma lipids and androgens in PCOS.

Effects of dietary fat restriction on particle size of plasma lipoproteins in postmenopausal women

Hypertriglyceridemia is an independent risk factor for coronary artery disease (CAD) and is also commonly associated with other coronary risk factors, ie, small, dense low-density lipoprotein (LDL) particles and low plasma levels of high-density lipoprotein cholesterol (HDL-C). Dietary fat restriction is recommended for the prevention of nutrition-related cancers. Low-fat, high-carbohydrate intake can increase plasma triglyceride (TG) and decrease HDL-C. In general, plasma TG levels are inversely related to the particle size of LDL. We investigated the effects of dietary fat restriction on the concentration and particle size of plasma lipoproteins in 14 healthy postmenopausal women (aged 61 +/- 11 years). During a 4-month period of eucaloric controlled feeding, dietary fat was reduced stepwise from a habitual intake of 33% +/- 8% to 23% and then to 14% of daily energy. Changes in the plasma lipid level and particle size of very-low-density lipoprotein (VLDL), LDL, and HDL were determined at the end of each dietary phase. Increasing carbohydrate intake without weight loss was associated with an increase in plasma TG (1.86 +/- 0.30 v 2.47 +/- 0.37 mmol/L) and decreases in total cholesterol (5.82 +/- 0.25 v 5.40 +/- 0.21 mmol/L), LDL-C (3.07 +/- 0.18 v 2.61 +/- 0.21 mmol/L), HDL-C (1.42 +/- 0.1 v 1.24 +/- 0.1 mmol/L), and apolipoprotein (apo) A1 (5.14 +/- 0.25 v 4.61 +/- 0.36 mmol/L), whereas plasma apo B did not change. The particle size of VLDL increased (42.7 +/- 1.4 v 47.0 +/- 0.9 nm). However, there was no change in either LDL (25.1 +/- 0.2 v 25.3 +/- 0.2 nm) or HDL particle size. Although at each level of dietary fat intake LDL particle size correlated inversely with plasma TG and apo B, there was no relationship between the increase in plasma TG and LDL particle size. These results show that hypertriglyceridemia caused by a eucaloric high-carbohydrate intake is not associated with a decrease in LDL particle size. Therefore, carbohydrate-induced hypertriglyceridemia may not have the same atherogenic potential as genetic hypertriglyceridemias.

Roles of Circulating WNT-Signaling Proteins and WNT-Inhibitors in Human Adiposity, Insulin Resistance, Insulin Secretion, and Inflammation

Wingless-type MMTV integration site family member (WNT) signaling and WNT-inhibitors have been implicated in regulation of adipogenesis, insulin resistance, pancreatic function, and inflammation. Our goal was to determine serum proteins involved in WNT signaling (WNT5 and WISP2) and WNT inhibition (SFRP4 and SFRP5) as they relate to obesity, serum adipokines, insulin resistance, insulin secretion, and inflammation in humans. Study population comprised 57 insulin resistant women with polycystic ovary syndrome (PCOS) and 27 reference women. In a cross-sectional study, blood samples were obtained at fasting, during oral, and frequently sampled intravenous glucose tolerance tests. Serum WNT5, WISP2, and SFRP4 concentrations did not differ between PCOS vs. reference women. Serum WNT5 correlated inversely with weight both in PCOS and reference women, and correlated directly with insulin response during oral glucose tolerance test in PCOS women. Serum WISP2 correlated directly with fatty acid binding protein 4. Serum SFRP5 did not differ between obese (n=32) vs. nonobese (n=25) PCOS women, but reference women had lower SFRP5 (p<5×10(-6) as compared to both PCOS groups). Serum SFRP5 correlated inversely with IL-1β, TNF-α, cholesterol, and apoprotein B. These findings demonstrated that WNT5 correlated inversely with adiposity and directly with insulin response, and the WNT-inhibitor SFRP5 may be anti-inflammatory. Better understanding of the role of WNT signaling in obesity, insulin resistance, insulin secretion, lipoprotein metabolism, and inflammation is important for prevention and treatment of metabolic syndrome, diabetes and cardiovascular disease.

Lignan Content of the Flaxseed Influences Its Biological Effects in Healthy Men and Women

Objective: The omega-3 polyunsaturated fatty acid (n-3 PUFA) as well as lignan components of flaxseed (FLX) can have beneficial effects. In this 6-week-long, randomized, double-blinded, placebo-controlled study, we investigated the effects of FLX lignans on cardiovascular risk factors. Methods: Thirty-seven subjects (13 men and 24 women, age: 54 ± 7 years, body mass index [BMI]: 29.7 ± 1 kg/m2) consumed nutrition bars with similar macronutrient contents. The fatty acid composition and the lignan contents of the bars differed significantly. Two FLX bars both contained 3.0 g of alpha linolenic acid (ALA: 18:3 n-3) but different amount of lignans (0.15 g vs. 0.41 g). Results: High-lignan FLX decreased total cholesterol (C) by 12% (p = 0.044), LDL-C by 15% (p = 0.022), and oxidized (Ox)-LDL by 25% (p = 0.035). Regular FLX tended to increase Ox-LDL by 13% (p = 0.051). The difference between the effects of high-lignan vs. regular lignan FLX on Ox-LDL was highly significant (p = 0.004). Conclusion: High-lignan FLX has the unique property of decreasing Ox-LDL, which is an independent risk factor for cardiovascular disease.

In polycystic ovary syndrome, adrenal steroids are regulated differently in the morning versus in response to nutrient intake

OBJECTIVE To investigate adrenal steroid regulation in polycystic ovary syndrome. DESIGN Five-hour oral glucose tolerance test (OGTT) and frequently sampled-intravenous gluclose tolerance test. SETTING University research center. PATIENT(S) Thirty patients. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Anthropometrics, leptin, cortisol, DHEAS, glucose, insulin. RESULT(S) Morning cortisol correlated with sensitivity index (SI, r = .540), DHEAS correlated inversely with age (r = -.6359), body mass index (BMI, r = -.6199), fat mass (r = -0.630), and leptin (r = -0.5676). Between the second and fourth hour of OGTT, cortisol changes (Delta) exhibited three patterns: I, responders (n = 9, Delta: 10.7 +/- 1.0 microg/dL); II, nonresponders (n = 10, Delta: -3.5 +/- 0.6 microg/dL); III, intermediates (n = 11, Delta: 4.3 +/- 1.0 microg/dL). Compared with nonresponders, responders were more obese (BMI: 37.0 +/- 1.6 vs. 31.7 +/- 1.8 kg/m(2)); had higher leptin (28.9 +/- 1.7 vs. 24.1 +/- 1.1 ng/mL), and lower DHEAS (133 +/- 12 vs. 236 +/- 32 ng/mL), higher glucose at 1 h of OGTT (195 +/- 13 vs. 131 +/- 12 mg/dL), higher area under the curve (AUC)(Glucose) (332 +/- 20 vs. 265 +/- 17 mg/dL), higher AUC(Insulin) (244 +/- 50 vs. 125 +/- 30 muU/mL), and lower nadir glucose (61 +/- 2 vs. 70 +/- 2 mg/dL). CONCLUSION(S) Obesity and insulin resistance are associated with lower morning cortisol and DHEAS but increased cortisol and DHEA responses after glucose ingestion. Morning steroid levels may not reflect the day-long exposure.

Glucose-lowering effect of whey protein depends upon clinical characteristics of patients with type 2 diabetes

Objective Whey protein (WP) intake has been shown to reduce postprandial glycemia. Majority of WP research in type 2 diabetes (T2DM) involved acute challenge or weight loss studies. It is not known if WP supplementation can provide sustained glucose lowering. Our goal was to investigate the effects of WP on glycemia comprehensively by using continuous glucose monitoring (CGM) while avoiding the confounding effects of variable food intake through controlled feeding. Research design and methods This double-blinded and placebo (PL)-controlled study included 22 patients with T2DM patients (11 male, 11 female; age 57.1±12.6 years) on diet or metformin monotherapy. First, one serving (21 g) of WP was compared with PL in parallel-armed acute challenge studies. Next, in a crossover design, each patient underwent CGM twice, over 2 consecutive weeks, 3.5 days each week. Identical diets were provided by the study during both CGM periods. During the first CGM, one serving of either WP or PL was consumed before breakfast and another before dinner. During the second CGM, participants switched to the alternate supplement. Order of the supplements was randomized. Results During acute challenge studies, WP stimulated insulin and glucagon-like peptide (GLP)-1 secretion; suppressed ghrelin (all p<0.05), while PL had no effect. During CGM, glucose response to WP varied depending on the baseline characteristics of the patients. When evaluated using linear regression, the most predictive baseline variables were body mass index (BMI) (p=0.0006), triglycerides (p=8.3×10−5) and GLP-1 (p=0.006). Lower BMI, triglyceride and GLP-1 predicted decreased glucose levels on WP. Obesity, hypertriglyceridemia and high fasting GLP-1 concentrations predicted increased glucose levels. Conclusions Effects of WP supplementation on glycemia in T2DM depend on the baseline characteristics. Lower body weight, normal triglyceride and lower GLP-1 levels predict glucose lowering. In contrast, obesity, hypertriglyceridemia and high baseline GLP-1 predict increased glucose response.

Hepatic microsomal triglyceride transfer protein gene expression in carbohydrate-induced hypertriglyceridemia

The microsomal triglyceride transfer protein (MTP) facilitates the assembly of very low density lipoproteins (VLDL). To investigate the effects of carbohydrate (CHO)-induced hypertriglyceridemia (HTG) on the hepatic expression of the MTP gene, Golden Syrian hamsters were fed fructose (FR) and sucrose (SUC) enriched diets. Changes in fasting plasma glucose (FPG), insulin, free fatty acids (FFA), TG, VLDL-TG and VLDL-protein were determined. Abundance of hepatic MTP-mRNA was compared to those of albumin (ALB)-mRNA and glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-mRNA. Hepatic secretion rates (SR) of VLDL-TG and VLDL-PR were assessed after intravenous Triton WR-1339 injection. Lipoprotein lipase (LpL) activity of the epididymal fat pads was determined. As compared to the control and SUC, FR increased plasma insulin (FR = 238+24, SUC = 115±17, control = 82±16 μU/ml, p < 0.0001), FFA (FR = 1.93±0.24, SUC = 1.35±0.1, control = 1.47±0.13 mEq/L, p < 0.03) and TG (FR = 215±47, SUC = 93±7, control = 71±16 mg/dl, p < 0.01), without affecting FPG. There was no change in LpL activity. Fructose-feeding increased VLDL-TG-SR (FR = 2.95±0.26, SUC = 1.28±0.34, control = 2.18±0.26 mg/kg.wt/h−1, p < 0.004), but not VLDL-protein-SR. MTP-mRNA abundance did not change when compared to albumin mRNA, however FR-fed hamsters had lower MTP mRNA abundance when compared to GAPDH mRNA (FR = 0.96±0.13, SUC = 1.15±0.14, control = 1.49±0.14 MTPGAPDH-mRNA, p < 0.05). The finding that FR-feeding increased VLDL-TG secretion without any increase in MTP mRNA proves that CHO-induced HTG can occur without an increase in hepatic MTP gene expression.