Fasting Non-esterified Fatty Acid Levels Research Articles

Abstract P308: The Determinants of Fasting and Post-Load Non-Esterified Fatty Acids in Older Adults: The Cardiovascular Health Study

Aim: Non-esterified fatty acids (NEFA) are associated with key cardiometabolic diseases of aging and are potential targets for prevention, but their population-level correlates remain uncertain. We sought to identify modifiable factors associated with higher fasting and post-load NEFA levels in older adults. Methods: We used linear multivariable regression models to determine the cross-sectional associations of demographic, anthropometric, lifestyle characteristics, and medication use with serum fasting and post-load NEFA concentrations amongst community-dwelling older adults enrolled in the Cardiovascular Health Study (n = 1,924). Results: In general, fasting NEFA levels demonstrated a broader set of determinants, while post-load NEFA were more consistently associated with metabolic factors. Waist circumference and weight were associated with higher fasting and post-load NEFA. Cigarette smoking and caffeine intake were associated with lower levels of both species, and moderate alcohol intake was associated with higher fasting levels whereas greater consumption was associated with lower post-load levels. Unique factors associated with higher fasting NEFA included female sex, higher age, loop and thiazide diuretic use and calcium intake, while factors associated with lower fasting levels included higher educational attainment, beta-blocker use, and protein intake. Hours spent sleeping during the daytime were associated with higher post-load NEFA, while DASH score were associated with lower levels. Conclusion: Fasting and post-load NEFA appear to have both common and unique modifiable risk factors, including sociodemographics, anthropometric, medications, and diet. Post-load NEFA were particularly sensitive to metabolic factors, while a broader range of determinants were associated with fasting levels. These factors warrant further study as targets for lowering levels of NEFA in older adults..

Sleep apnea in men is associated with altered lipid metabolism, glucose tolerance, insulin sensitivity, and body fat percentage

PurposeObstructive sleep apnea (OSA) is associated with obesity and risk for type 2 diabetes. In this community-based study, we thoroughly investigated fatty acid metabolism, incretin response, glucose tolerance, insulin secretion and insulin sensitivity, and autonomic nerve activity in men with or without OSA.MethodsFifteen men without diabetes but with signs of severe OSA, defined as apnea–hypopnea index (AHI) >30, and 15 age- and BMI-matched men without OSA (AHI < 5) were recruited from a community-based cohort. Assessments included clinical and anthropometric measurements, a 2-h oral glucose tolerance test (OGTT), and autonomic nerve activity using heart rate variability (HRV).ResultsMen with OSA had higher body fat % than BMI-matched men without OSA (p = 0.046) and it was associated with markers of insulin resistance. The area under the curve for nonesterified fatty acids (NEFA) during OGTT was higher in men with OSA (p = 0.021) and fasting NEFA levels were numerically higher (p = 0.097). The plasma glucose at fasting and during OGTT was higher in men with OSA (p < 0.001). Incretin response was similar between groups. Fasting and OGTT-derived indices indicated impaired insulin sensitivity in men with OSA. Compared with men without OSA, Matsuda index (p = 0.068) and Gutt index (p < 0.01) were lower in men with OSA. The HRV measures did not differ between groups.ConclusionsOur study suggests that fatty acid handling, glucose tolerance, and insulin sensitivity are impaired in men with severe OSA. This might partly be explained by the increased body fat percentage.

Subchronic sleep restriction causes tissue-specific insulin resistance.

Short sleep duration is associated with an increased risk of type 2 diabetes. Subchronic sleep restriction (SR) causes insulin resistance, but the mechanisms and roles of specific tissues are unclear. The purpose of this article was to determine whether subchronic SR altered (1) hepatic insulin sensitivity, (2) peripheral insulin sensitivity, and (3) substrate utilization. This was a randomized crossover study in which 14 subjects underwent 2 admissions separated by a washout period. Each admission had 2 acclimatization nights followed by 5 nights of either SR (4 hours time in bed) or normal sleep (8 hours time in bed). MAIN OUTCOME MEASURE/METHODS: Insulin sensitivity (measured by hyperinsulinemic-euglycemic clamp) and hepatic insulin sensitivity (measured by stable isotope techniques) were measured. In addition, we assayed stress hormone (24-hour urine free cortisol, metanephrine, and normetanephrine), nonesterified fatty acid (NEFA), and β-hydroxybutyrate (β-OH butyrate) levels. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured by indirect calorimetry. Compared to normal sleep, whole-body insulin sensitivity decreased by 25% (P = .008) with SR and peripheral insulin sensitivity decreased by 29% (P = .003). Whereas hepatic insulin sensitivity (endogenous glucose production) did not change significantly, percent gluconeogenesis increased (P = .03). Stress hormones increased modestly (cortisol by 21%, P = .04; metanephrine by 8%, P = .014; normetanephrine by 18%, P = .002). Fasting NEFA and β-OH butyrate levels increased substantially (62% and 55%, respectively). REE did not change (P = 0.98), but RQ decreased (0.81 ± .02 vs 0.75 ± 0.02, P = .045). Subchronic SR causes unique metabolic disturbances characterized by peripheral, but not hepatic, insulin resistance; this was associated with a robust increase in fasting NEFA levels (indicative of increased lipolysis), decreased RQ, and increased β-OH butyrate levels (indicative of whole-body and hepatic fat oxidation, respectively). We postulate that elevated NEFA levels are partially responsible for the decrease in peripheral sensitivity and modulation of hepatic metabolism (ie, increase in gluconeogenesis without increase in endogenous glucose production). Elevated cortisol and metanephrine levels may contribute to insulin resistance by increasing lipolysis and NEFA levels.

Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 μU/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g·min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km (P = .009), which were strongly correlated together in all PCOS/cp rats (ρ = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.

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

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

Opposite effects of pravastatin and atorvastatin on insulin sensitivity in the rat: Role of vitamin D metabolites

Recent studies indicate that pravastatin improves whereas other statins impair glucose homeostasis in humans, but the underlying mechanisms are not clear. We examined the effect of pravastatin and atorvastatin on insulin sensitivity in a rat model. Pravastatin (40 mg/kg/day) or atorvastatin (20mg/kg/day) were administered for 3 weeks and insulin sensitivity was assessed by measuring fasting plasma insulin, HOMA-IR, non-esterified fatty acids (NEFA) and glycerol levels, as well as by the hyperinsulinemic euglycemic clamp. Pravastatin had no effect on fasting insulin and HOMA-IR but significantly reduced plasma NEFA and glycerol levels and increased glucose infusion rate (GIR) during the hyperinsulinemic clamp. Increase in GIR induced by pravastatin was not abolished by NO synthase inhibitor, l-NAME, indicating that this effect did not result from the improvement of endothelial function. Atorvastatin increased fasting insulin, HOM-IR, NEFA and glycerol levels as well as reduced GIR. Statins had no effect on leptin, HMW adiponectin, resistin, visfatin, interleukin-6 and TNF-α. Pravastatin increased plasma concentrations of 25-hydroxy- and 1,25-dyhydroxyvitamin D(3) (25-OH-D(3) and 1,25-(OH)(2)-D(3)), and its effect on insulin sensitivity was mimicked by exogenous 1,25-(OH)(2)-D(3). Atorvastatin reduced plasma 25-OH-D(3) but had no effect on 1,25-(OH)(2)-D(3). Decrease in insulin sensitivity induced by atorvastatin was not corrected by supplementation of vitamin D(3) despite normalization of plasma 25-OH-D(3) level. Pravastatin and atorvastatin have opposite effects on insulin sensitivity and vitamin D(3) status. Pravastatin-induced increase in insulin sensitivity is mediated by elevation of 1,25-(OH)(2)-D(3). In contrast, atorvastatin-induced decrease in insulin sensitivity is independent of lowering 25-OH-D(3).

Improving glycogenesis in Streptozocin (STZ) diabetic mice after administration of green algae Chlorella

Chlorella, a type of unicellular fresh water algae, has been a popular foodstuff in Japan and Taiwan. Studies have shown the hypoglycemic effects of Chlorella in alloxan-induced and Streptozocin (STZ)-induced diabetic animals. However, the mechanisms by which Chlorella treatment affects blood glucose homeostasis have not been studied. Diabetes in ICR mice was induced by injection of STZ. Lipogenesis in vivo was measured by incorporating 3H-H2O into lipids in brown and white adipose tissues. Glucose uptake in the liver and soleus muscles was measured by assaying 2-deoxy-D-[1,2-3H] glucose levels. The effects of Chlorella on serum non-esterified fatty acids (NEFA) were measured with commercial assay kits. Insulin-stimulated lipogenic rates in brown and white adipose tissues were unaffected by Chlorella. However, Chlorella increased 2-deoxyglucose uptake in the livers and soleus muscles in normal and STZ mice compared to that in their respective controls (p < 0.01). In addition, fasting NEFA levels were lower in Chlorella-treated STZ mice compared to H2O-treated STZ mice (p < 0.005). The current results suggest that the hypoglycemic effects of Chlorella are due to an enhancement of glucose uptake in the liver and in soleus muscles. The improved insulin sensitivity after Chlorella treatment could be also due to lower NEFA levels, since insulin sensitivity is usually blunted by elevated NEFA in diabetes.

Effects of a westernized lifestyle on the association between fasting serum nonesterified fatty acids and insulin secretion in Japanese men

The effects of the prolonged elevation of nonesterified fatty acid (NEFA) levels on insulin secretion have been controversial and thought to be sex-specific. To investigate the association between a westernized lifestyle and the effects of NEFA on insulin secretion in Japanese men, we examined 67 nondiabetic Japanese-American men and 220 nondiabetic native Japanese men who underwent a 75-g oral glucose tolerance test (OGTT). Most Japanese Americans we surveyed are genetically identical to Japanese living in Japan, but their lifestyle is more westernized. Sets of multiple regression analyses were performed to evaluate the relationship between the sum of the immunoreactive insulin (IRI) levels during the OGTT ((Sigma)IRI) and clinical parameters. Japanese Americans had higher levels of fasting IRI, (Sigma)IRI, and a higher insulin resistance index (homeostasis model assessment for insulin resistance [HOMA-IR]) than native Japanese, whereas there were no significant differences in fasting NEFA and triglyceride levels. A multiple regression analysis adjusted for age, fasting triglycerides, and body mass index (BMI) demonstrated that the fasting NEFA level was an independent determinant of the (Sigma)IRI only in Japanese-American men ( P = .001), but not in native Japanese men ( P = .054). Even when HOMA-IR was included in models instead of BMI, the NEFA level was a significant variable of (Sigma)IRI only in Japanese Americans ( P < .001), and not in native Japanese ( P = .098). In addition, a multiple regression analysis adjusted for age, fasting triglycerides, and BMI demonstrated that the fasting NEFA level was the only independent determinant of (Sigma)C-peptide in Japanese-American men ( P = .041). In conclusion, NEFA seems to be associated with insulin secretion independent of obesity or HOMA-IR. A westernized lifestyle may increase the effects of serum fasting NEFA levels on total insulin secretion after a glucose load in Japanese men.

The impact of acute elevation of non‐esterified fatty acids on insulin sensitivity and secretion in women with former gestational diabetes

Elevations in non-esterified fatty acids (NEFA) have been shown to decrease insulin action and secretion, and are a risk factor for the development of Type 2 diabetes. As women who have had gestational diabetes (GDM) are at increased risk of diabetes, we examined the effect of an acute elevation of NEFA on insulin secretion and action in these women. Nineteen women with recent former GDM and 19 age- and BMI-matched postpartum healthy control subjects underwent a 40-min intravenous glucose tolerance test, with and without a preceding 2-h infusion of 20% Intralipid. Insulin action was assessed by glucose disappearance (Kg) and insulin sensitivity (SI); insulin secretion by first phase insulin release (FPIR) and disposition index (DI). NEFA levels were similarly elevated in both groups by the Intralipid infusion (up to 1.140 +/- 0.03 mm). As expected, the lipid infusion significantly reduced Kg (2.15 +/- 0.13 vs. 1.69 +/- 0.09/min, P < 0.001) and SI (3.14 +/- 0.28 vs. 2.13 +/- 0.17/min/mUl/min, P < 0.001) in all subjects, and these were significant within the GDM and control subgroups. FPIR was elevated in the Intralipid study in the total group of women (4.50 +/- 0.50 vs. 5.02 +/- 0.53, P = 0.02), but DI was significantly reduced (12.13 +/- 1.1 vs. 8.83 +/- 0.7, P < 0.001). There was no significant difference, however, in the absolute or percentage change in Kg, SI or FPIR with lipid infusion between the GDM and control groups. GDM status was not a predictor of the response of Kg, SI or FPIR to lipid infusion, rather, adiposity (% fat), average fasting NEFA levels and basal disposition index were associated. These data suggest that women with former gestational diabetes, in contrast to other prediabetic states, are not more susceptible to the deleterious effects of an acute elevation in nonesterified fatty acids than matched control subjects.

Lipids enhance α 1-adrenoceptor pressor sensitivity in patients with chronic kidney disease

Dyslipidemia in patients with chronic kidney disease (CKD) may contribute to hypertension (HT) by altering neurocirculatory control. To test this notion, we quantified the effects of acutely increasing levels of nonesterified fatty acids (NEFAs) and triglycerides on alpha1-adrenergic pressor sensitivity and baroreflex sensitivity (BRS) in subjects without diabetes with CKD. Alpha1 pressor sensitivity was determined before and after increasing NEFA and triglyceride levels with a fat emulsion and heparin infusion in 8 subjects with stage 2 to 3 CKD (glomerular filtration rate, 56 +/- 6 mL/min by 125 I-iothalamate clearance). Seven subjects with HT and 8 normotensive control (CO) subjects with normal renal function and matched to patients with CKD also were studied. Fasting NEFA levels were greater in patients with CKD than in CO subjects (585 +/- 98 versus 321 +/- 32 micromol/L; P < 0.01), but not different from those in subjects with HT (501 +/- 68 micromol/L). Alpha1 pressor sensitivity, defined as the phenylephrine dose that increased mean blood pressure (BP) by 20 mm Hg, was greatest (lowest dose) in subjects with CKD (0.83 +/- 0.11 microg x kg(-1) x min(-1)), followed by those with HT (1.08 +/- 0.19 microg x kg(-1) x min(-1)) and CO subjects (1.34 +/- 0.19 microg x kg(-1) x min(-1); P < 0.05 versus CKD group). BRS, measured as the ratio of change in R-R interval to change in systolic BP during the phenylephrine infusion, was lowest, intermediate, and highest in the CKD, HT, and CO groups, respectively. Increasing NEFA and triglyceride levels significantly enhanced alpha1 pressor sensitivity in all 3 groups and reduced BRS in the CKD and CO groups. These observations suggest that the dyslipidemia prevalent in patients with stage 2 to 3 CKD may contribute to HT by enhancing alpha1 pressor sensitivity and impairing baroreflex function.

Hypertension and its treatment influence changes in fasting nonesterified fatty acid concentrations: A link between the sympathetic nervous system and the metabolic syndrome?

In previous studies, a cross-sectional association has been described between blood pressure (BP) and nonesterified fatty acid (NEFA) concentrations. The direction of causality, and thus, the mechanism explaining this relationship, remains uncertain. Therefore, we analyzed a prospective population-based cohort of 937 subjects who underwent an oral glucose tolerance test (OGTT) on two occasions separated by 4.5 years. In cross-sectional analysis, NEFA measures were correlated with systolic and diastolic BP, both at baseline and at follow-up study. In longitudinal analysis, baseline systolic and diastolic BP predicted changes in fasting NEFA levels (both P < .01). However, baseline NEFA levels did not predict change in BR In multivariate analysis, the relationship between baseline BP and change in fasting NEFA was independent of age and sex. Obesity and its interaction with BP did not explain this association. Absolute changes in NEFA concentrations were greater among subjects who were hypertensive at baseline compared with the normotensive individuals. This change was greater in subjects treated with diuretics compared with those treated with beta-adrenergic antagonists (P < .01), an observation that provides support for a role of sympathetic nervous system (SNS) activity in explaining the relationship between BP and NEFA concentration.

Cross-sectional but not longitudinal associations between non-esterified fatty acid levels and glucose intolerance and other features of the metabolic syndrome.

Cross-sectional studies have demonstrated an association between high non-esterified fatty acid (NEFA) concentrations and glucose intolerance. However, the direction of causality in these studies is uncertain. The aim of this study was to examine whether NEFA levels predicted the development of glucose intolerance in a prospective population-based cohort study. Four hundred and eighty-one women and 345 men participated in a prospective cohort study in which NEFA concentrations and glucose tolerance were measured at baseline and then repeated at follow-up 4.5 years later. The data do not show longitudinal relationships between baseline NEFA levels and either glucose intolerance or other features of the metabolic syndrome at follow-up. In contrast, strong cross-sectional associations were observed between NEFA measures and glucose intolerance (and other features of the metabolic syndrome) in both baseline and follow-up studies. At follow-up, fasting NEFA levels and two measures of NEFA suppression were markedly different in subjects with features of the metabolic syndrome, compared to subjects with normal glucose tolerance (NGT) (NGT vs. metabolic syndrome for each NEFA value, P< 0.001). These results support the hypothesis that plasma NEFA levels change as a consequence of the metabolic syndrome and do not support the notion that increased NEFA levels cause either the metabolic syndrome or diabetes.

Inhibition of carbohydrate-mediated glucagon-like peptide-1 (7-36)amide secretion by circulating non-esterified fatty acids.

Two studies were performed to assess the entero-insular axis in simple obesity and the possible effect of variations in the level of circulating non-esterified fatty acids (NEFA) on one of the components of the entero-insular axis, glucagon-like peptide-1 [(7-36) amide]. In the first study, we compared the entero-pancreatic hormone response to oral carbohydrate in obese and lean women. Obese subjects demonstrated hyperinsulinaemia and impaired glucose tolerance but this was not associated with an increased secretion of either glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 (GLP-1). These findings therefore provide no support for the hypothesis that overactivity of the entero-insular axis contributes to the hyperinsulinaemia seen in obesity. Indeed, the plasma GLP-1 response to carbohydrate was markedly attenuated in obese subjects, confirming previous observations. In the second study, in which carbohydrate-stimulated GLP-1 responses were again evaluated in obese and lean women, circulating NEFA levels were modulated using either heparin (to increase serum NEFA) or acipimox (to reduce serum NEFA). Treatment with acipimox resulted in complete suppression of NEFA levels and in a markedly higher GLP-1 response than the response to carbohydrate alone or to carbohydrate plus heparin. We suggest that higher fasting and postprandial NEFA levels in obesity may tonically inhibit nutrient-mediated GLP-1 secretion, and that this results in attenuation of the GLP-1 response to carbohydrate. However, although serum NEFA levels post-acipimox were similarly suppressed in both lean and obese subjects, the GLP-1 response was again significantly lower in obese subjects, suggesting the possibility of an intrinsic defect of GLP-1 secretion in obesity. The reduction of GLP-1 levels in obesity may be important both in relation to its insulinotropic effect and to its postulated role as a satiety factor.

Impact of nicotinic acid treatment on insulin secretion and insulin sensitivity in low and high insulin responders.

The aim of the study was to evaluate the effect of nicotinic acid (NA) on glucose tolerance, insulin secretion and sensitivity in relation to perturbations of non-esterified fatty acids (NEFA) and previously characterized insulin responses. Healthy subjects (n = 12) were treated for 14 days with incremental doses of NA reaching 2 g day-1. Before NA and on day 14 a hyperglycaemic clamp (11 mmol l-1) was performed with arginine (5 g i.v.) stimulation before and during the clamp. Fasting serum levels of NEFA were evanescently decreased on day 3 (-38%; p < 0.01) and day 7 (-33%; p < 0.05), but not on day 14 (-14%; NS). NA treatment did not significantly affect levels of fasting blood glucose, insulin, C-peptide, proinsulin or glucagon. NA treatment lowered the amount of infused glucose necessary to achieve clamp levels 48 (8) vs. 61 (10) mumol kg-1 min-1 (p < 0.01). Incremental increases in fasting NEFA levels correlated (r = -0.72) with decreased insulin sensitivity as reflected by M/I ratios (the amount of glucose infused, minus glucosuria, divided by the mean insulin level) (p < 0.01). Insulin and glucagon responses to arginine and glucose were similar before and after NA in subgroups with initially low and high insulin responses to glucose. NA-induced insulin resistance in this study is (a) less than previously reported; (b) not associated with changes in insulin secretory responsiveness, but is (c) influenced by an individually variable NA effect on fasting NEFA levels. Our results do not indicate that NA treatment can be used to test the capacity of B cells to cope with insulin resistance.

Relation of plasma triglyceride and apoB levels to insulin-mediated suppression of nonesterified fatty acids. Possible explanation for sex differences in lipoprotein pattern.

To test whether a sex difference in insulin-mediated suppression of nonesterified fatty acids (NEFAs) could account for sex differences in plasma triglyceride levels, we studied 632 normoglycemic men and women of European and South Asian descent aged 40 to 69 years. Mean fasting NEFA levels were 19% higher in women than in men. Between fasting and 2 hours after a 75-g oral glucose load, NEFA levels fell by 69% in women and 55% in men, so that mean NEFA levels at 2 hours after loading were 19% lower in women than in men. Plasma triglyceride and apolipoprotein B levels were correlated with 2-hour NEFA levels in each sex and ethnic group, and these associations were independent of glucose, insulin, and central obesity. These results are consistent with experimental studies of the effects of insulin and NEFAs on hepatic production of triglycerides and apolipoprotein B. Suppression of NEFA levels in response to insulin is greater in women than in men, and this may account for some of the sex differences in lipoprotein pattern and coronary heart disease risk.

The metabolic and hormonal responses to a mixed meal in unrestrained pancreatectomised dogs chronically treated by portal or peripheral insulin infusion.

The metabolic and hormonal consequences of long term intravenous insulin replacement were studied in 11 pancreatectomised dogs. Insulin was delivered into the portal circulation of six animals for 164-224 days and into the peripheral circulation of the remainder for 123-365 days. Infusion rates were initially adjusted to achieve normoglycaemia in the fasting (0.37 +/- 0.01 mU Kg-1 min-1 portal; 0.45 +/- 0.03 mU kg-1 min-1 peripheral) and post-prandial states (2.57 +/- 0.07 mU kg-1 min-1 for 7 1/2 h portal; 3.16 +/- 0.18 mU kg-1 min-1 for 7 h peripheral). Animals were fed their usual mixed diet and blood samples were drawn from indwelling catheters at regular intervals for 24 h. A matched group of six normal dogs was similarly studied. Significantly less insulin was needed for glycaemic normalisation with portal (1.05 +/- 0.03 U kg-1 day-1) compared with peripheral (1.27 +/- 0.08 U kg-1 day-1) infusions, but post-prandial insulin levels were not normalised. Glucagon levels were normal and unaffected by the route of insulin infusion. Lactate and pyruvate responses were exaggerated post-prandially in the diabetic compared with the normal dogs. Fasting non-esterified fatty acid levels were suppressed with peripheral but normal with portal insulin infusion. There were only minor differences in the branched chain, essential and other non-essential amino acids except for alanine which was significantly above normal in the diabetic animals. Fasting levels of insulin, lactate, pyruvate and non-esterified fatty acids were normalised only with portal infusion while glucose, glucagon, 3-hydroxybutyrate and most amino acids were normalised regardless of the route of infusion. We conclude that the metabolic regulation achieved with portal insulin replacement is closer to normal than that achieved with peripheral infusion.

Human growth hormone levels during the menstrual cycle

The normal patterns of human growth hormone (HGH) secretion in an ovulatory mentrual cycle were studied. Nineteen normal subjects recorded daily basal body temperatures (BBT). Their mean day of BBT rise was 15.6. They were each studied on day 5 and day 25 of the cycle with an insulin tolerance test in a fasting ambulatory state using 0.1 unit of regular insulin per kilogram as a stimulus. Measurements of blood glucose and plasma HGH showed no significant difference between the two tests. Fasting nonesterified fatty acid levels (NEFA) were also measured and these were not different. One subject was followed through an ovulatory cycle with daily fasting basal blood samples and these were analyzed for their glucose and HGH content. Although the glucose level did not change the HGH level rose at ovulation and premenstrually. It is concluded that HGH secretion does not change significantly between the proliferative and the secretory phases of the menstrual cycle.