Comparison of regional fat measurements by dual-energy X-ray absorptiometry and conventional anthropometry and their association with markers of diabetes and cardiovascular disease risk.

BACKGROUND/OBJECTIVES: Fat distribution is a strong and independent predictor of type 2 diabetes (T2D) and cardiovascular disease (CVD) and is usually determined using conventional anthropometry in epidemiological studies. Dual-energy X-ray absorptiometry (DXA) can measure total and regional adiposity more accurately. Nonetheless, whether DXA provides more precise estimates of cardiovascular risk in relation to total and regional adiposity is not known. We determined the strength of the associations between DXA- and conventional anthropometry determined fat distribution and T2D and CVD risk markers. SUBJECTS/METHODS: Waist (WC) and hip circumference (HC) and DXA was used to measure total and regional adiposity in 4950 (2119 men) participants aged 29-55 years from the Oxford Biobank without pre-existing T2D or CVD. Cross-sectional associations were compared between WC and HC vs. DXA-determined regional adiposity (all z-score normalised) with impaired fasting glucose, hypertriglyceridemia, hypertension and insulin resistance (IR). RESULTS: Following adjustment for total adiposity, upper body adiposity measurements showed consistently increased risk of T2D and CVD risk markers except for abdominal subcutaneous fat in both sexes, and arm fat in men, which showed protective associations. Among upper adiposity depots, visceral fat mass showed stronger odds ratios (OR) ranging from 1.69 to 3.64 compared with WC 1.07-1.83. Among lower adiposity depots, HC showed modest protection for IR in both sexes (men: OR 0.80 (95% confidence interval 0.67, 0.96); women: 0.69 (0.56, 0.86)), whereas gynoid fat and in particular leg fat showed consistent and strong protective effects for all outcomes in both men and women. The differential effect of body fat distribution on CVD and T2D were more pronounced at higher levels of total adiposity. CONCLUSIONS: Compared with DXA, conventional anthropometry underestimates the associations of regional adiposity with T2D and CVD risk markers. After correcting for overall adiposity, greater subcutaneous fat mass in particular in the lower body is protective relative to greater android or visceral adipose tissue mass.

What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?

Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals' overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one's own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess.

Regulation of human subcutaneous adipose tissue blood flow.

Subcutaneous adipose tissue represents about 85% of all body fat. Its major metabolic role is the regulated storage and mobilization of lipid energy. It stores lipid in the form of triacylglycerol (TG), which is mobilized, as required for use by other tissues, in the form of non-esterified fatty acids (NEFA). Neither TG nor NEFA are soluble to any extent in water, and their transport to and out of the tissue requires specialized transport mechanisms and adequate blood flow. Subcutaneous adipose tissue blood flow (ATBF) is therefore tightly linked to the tissue's metabolic functioning. ATBF is relatively high (in the fasting state, similar to that of resting skeletal muscle, when expressed per 100 g tissue) and changes markedly in different physiological states. Those most studied are after ingestion of a meal, when there is normally a marked rise in ATBF, and exercise, when ATBF also increases. Pharmacological studies have helped to define the physiological regulation of ATBF. Adrenergic influences predominate in most situations, but nevertheless the regulation of ATBF is complex and depends on the interplay of many different systems. ATBF is downregulated in obesity (when expressed per 100 g tissue), and its responsiveness to meal intake is reduced. However, there is little evidence that this leads to adipose tissue hypoxia in human obesity, and we suggest that, like the downregulation of catecholamine-stimulated lipolysis seen in obesity, the reduction in ATBF represents an adaptation to the increased fat mass. Most information on ATBF has been obtained from studying the subcutaneous abdominal fat depot, but more limited information on lower-body fat depots suggests some similarities, but also some differences: in particular, marked alpha-adrenergic tone, which can reduce the femoral ATBF response to adrenergic stimuli.

MicroRNAs in adipose tissue: their role in adipogenesis and obesity.

MicroRNAs (miRNAs) are endogenous small RNAs that posttranscriptionally regulate gene expression and that have been shown to have important roles in numerous disease processes. There is growing evidence for an important role of miRNAs in regulating the pathways in adipose tissue that control a range of processes including adipogenesis, insulin resistance and inflammation. Several high-throughput studies have identified differentially expressed miRNAs in adipose tissue pathology and during adipogenesis and a number of these have now been characterised functionally in terms of their actions and targets. This review will summarise the current literature on miRNAs in adipose tissue, as well as discussing the methodologies used in this area of research and the potential application of miRNAs as biomarkers and as therapeutic targets.

Apolipoprotein M can discriminate HNF1A-MODY from Type 1 diabetes.

AIMS: Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a(-/-) mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA. METHODS: ApoM concentration was measured in subjects with HNF1A-MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated. RESULTS: Mean (standard deviation) serum apoM concentration (µmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10(-18) ) and control subjects [1.34 (0.22), P = 7.2 × 10(-19) ). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68). CONCLUSIONS: We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics.

Marked resistance of femoral adipose tissue blood flow and lipolysis to adrenaline in vivo.

AIMS/HYPOTHESIS: Fatty acid entrapment in femoral adipose tissue has been proposed to prevent ectopic fat deposition and visceral fat accumulation, resulting in protection from insulin resistance. Our objective was to test the hypothesis of femoral, compared with abdominal, adipose tissue resistance to adrenergic stimulation in vivo as a possible mechanism. METHODS: Regional fatty acid trafficking, along with the measurement of adipose tissue blood flow (ATBF) with (133)Xe washout, was studied with the arteriovenous difference technique and stable isotope tracers in healthy volunteers. Adrenergic agonists (isoprenaline, adrenaline [epinephrine]) were infused either locally by microinfusion or systemically. Local microinfusion of adrenoceptor antagonists (propranolol, phentolamine) was used to characterise specific adrenoceptor subtype effects in vivo. RESULTS: Femoral adipose tissue NEFA release and ATBF were lower during adrenaline stimulation than in abdominal tissue (p < 0.001). Mechanistically, femoral adipose tissue displayed a dominant α-adrenergic response during adrenaline stimulation. The α-adrenoceptor blocker, phentolamine, resulted in the 'disinhibition' of the femoral ATBF response to adrenaline (p < 0.001). CONCLUSIONS/INTERPRETATION: Fatty acids, once stored in femoral adipose tissue, are not readily released upon adrenergic stimulation. Femoral adipose tissue resistance to adrenaline may contribute to the prevention of ectopic fatty acid deposition.

Association of adipose tissue blood flow with fat depot sizes and adipokines in women.

OBJECTIVE: To explore possible associations between adipose tissue (AT) blood flow (ATBF), AT depot sizes and adipocyte-derived hormones (adipokines) in women. SUBJECTS: In all, 43 healthy women were divided into four groups: normal-weight (n=11) and obese (n=11) pre-menopausal women and normal-weight (n=10) and obese (n=11) post-menopausal women. METHODS: Fasting levels of adipokines were obtained, and a single-slice computed tomography scan at the level of L4-L5 was used to estimate fat depot sizes. ATBF was assessed by xenon washout while in a fasting state and after oral glucose load. We also measured glucose, insulin and non-esterified fatty acids. RESULTS: Total, subcutaneous and visceral AT areas strongly correlated with ATBF (all P<0.001). Circulating leptin levels strongly and inversely correlated with ATBF (P=0.001), but this association did not remain after adjustment for body mass index. Adiponectin was not associated with blood flow. CONCLUSION: ATBF is closely linked to subcutaneous and visceral AT size. Further analyses are needed to determine possible mediators of this association, including mechanistic studies to assess a putative role for leptin as a significant modulator of blood flow.

Gluteofemoral body fat as a determinant of metabolic health.

Body fat distribution is an important metabolic and cardiovascular risk factor, because the proportion of abdominal to gluteofemoral body fat correlates with obesity-associated diseases and mortality. Here, we review the evidence and possible mechanisms that support a specific protective role of gluteofemoral body fat. Population studies show that an increased gluteofemoral fat mass is independently associated with a protective lipid and glucose profile, as well as a decrease in cardiovascular and metabolic risk. Studies of adipose tissue physiology in vitro and in vivo confirm distinct properties of the gluteofemoral fat depot with regards to lipolysis and fatty acid uptake: in day-to-day metabolism it appears to be more passive than the abdominal depot and it exerts its protective properties by long-term fatty acid storage. Further, a beneficial adipokine profile is associated with gluteofemoral fat. Leptin and adiponectin levels are positively associated with gluteofemoral fat while the level of inflammatory cytokines is negatively associated. Finally, loss of gluteofemoral fat, as observed in Cushing's syndrome and lipodystrophy is associated with an increased metabolic and cardiovascular risk. This underlines gluteofemoral fat's role as a determinant of health by the long-term entrapment of excess fatty acids, thus protecting from the adverse effects associated with ectopic fat deposition.

Using a new socioepidemiological questionnaire to analyse associations between intergenerational upward social mobility and body fat distribution: a pilot study with the Oxford BioBank cohort.

BACKGROUND: As measured through body mass index (BMI), obesity is more prevalent among upwardly mobile adults than among adults born into middle-class families. Although BMI reflects general adiposity, health risks are more strongly associated with abdominal adiposity. It is therefore important to investigate associations between upward mobility and fat distribution. METHODS: A socioepidemiological questionnaire was developed, qualitatively validated and piloted with Oxford BioBank participants. Sex-specific analyses of variance (ANOVA) investigated associations between participant occupational class and adiposity, paternal occupational class and adiposity, and upward occupational mobility and adiposity. The main aim was to observe whether the expected directional effect of adiposity in relation to paternal occupational class would emerge. RESULTS: 280 participants (166 women, 114 men; age 32-67 years) completed the questionnaire. Men with fathers of occupational class 2 or 3 had higher mean BMI, total body fat percentage, android fat mass and android-to-gynoid fat mass ratio than men with fathers of occupational class 1. Women with fathers of occupational class 2 or 3 had higher mean BMI, total body fat percentage, android fat mass and gynoid fat mass than women with fathers of occupational class 1. Among men, upward mobility was not associated with adiposity. Among women, upward mobility was associated with higher total body fat percentage, android fat mass and gynoid fat mass. CONCLUSION: The expected directional effect was found, thereby supporting the questionnaire's use. Upward mobility did not appear to change associations between paternal occupational class and participant adiposity. Future research using the socioepidemiological questionnaire should investigate associations between gender, educational mobility, adiposity and health.

Remodeling phenotype of human subcutaneous adipose tissue macrophages.

BACKGROUND: Adipose tissue macrophages (ATMs) have become a focus of attention recently because they have been shown to accumulate with an increase in fat mass and to be involved in the genesis of insulin resistance in obese mice. However, the phenotype and functions of human ATMs are still to be defined. METHODS AND RESULTS: The present study, performed on human subcutaneous AT, showed that ATMs from lean to overweight individuals are composed of distinct macrophage subsets based on the expression of several cell surface markers: CD45, CD14, CD31, CD44, HLA-DR, CD206, and CD16, as assessed by flow cytometry. ATMs isolated by an immunoselection protocol showed a mixed expression of proinflammatory (tumor necrosis factor-alpha, interleukin-6 [IL-6], IL-23, monocyte chemoattractant protein-1, IL-8, cyclooxygenase-2) and antiinflammatory (IL-10, transforming growth factor-beta, alternative macrophage activation-associated cc chemokine-1, cyclooxygenase-1) factors. Fat mass enlargement is associated with accumulation of the CD206+/CD16- macrophage subset that exhibits an M2 remodeling phenotype characterized by decreased expression of proinflammatory IL-8 and cyclooxygenase-2 and increased expression of lymphatic vessel endothelial hyaluronan receptor-1. ATMs specifically produced and released matrix metalloproteinase-9 compared with adipocytes and capillary endothelial cells, and secretion of matrix metalloproteinase-9 from human AT in vivo, assessed by arteriovenous difference measurement, was correlated with body mass index. Finally, ATMs exerted a marked proangiogenic effect on AT-derived endothelial and progenitor cells. CONCLUSIONS: The present results showed that the ATMs that accumulate with fat mass development exhibit a particular M2 remodeling phenotype. ATMs may be active players in the process of AT development through the extension of the capillary network and in the genesis of obesity-associated cardiovascular pathologies.

Metabolism of triglyceride-rich lipoproteins during alimentary lipemia.

The metabolism of chylomicron remnants and VLDL was studied in healthy controls and normo- (NTG) and hypertriglyceridemic (HTG) patients with coronary artery disease after intake of an oral fat load. Specific determination of apo B-48 and B-100 enabled separation of the respective contribution of the two lipoprotein species. The postprandial plasma levels of small (Sf 20-60) and large (Sf 60-400) chylomicron remnants increased in controls and NTG patients. In contrast, only large chylomicron remnants increased in the HTG patients. An increase of large VLDL was seen in response to the oral fat load in all groups, whereas small VLDL were either unchanged in the controls and the NTG patients, or decreased in the HTG patient group. The whole plasma concentration of C apolipoproteins was essentially uninfluenced by the oral fat load, whereas the content in large triglyceride-rich lipoproteins paralleled the apo B elevations in controls and NTG patients. An even more prominent increase of apo B in large triglyceride-rich lipoproteins in the HTG group was not accompanied by an increase of C apolipoproteins. These findings indicate that chylomicrons compete with VLDL for removal of triglycerides by lipoprotein lipase and that the postprandial metabolism of triglyceride-rich lipoproteins is severely defective in hypertriglyceridemia.

Inequality and childhood overweight and obesity: a commentary.

Statements on childhood overweight and obesity (COO) have focused on different avenues for prevention and treatment, critical stages of the life cycle, including pregnancy and lactation, individual, family, school and community-based interventions, multidisciplinary family programmes and multicomponent interventions. This commentary is concerned with the less-addressed relationship between COO and inequality. It describes current global patterns of inequality and COO and the ways in which those inequalities are linked to COO at micro-level, meso-level and macro-level. It then describes current programmatic approaches for COO inequality, preventive and medical, and considers important pitfalls in the framing of the problem of COO and inequality. It ends with describing how childhood and adolescent overweight and obesity prevention and treatment programmes might be formulated within broader socio-political frameworks to influence outcomes.

Studies on the lecithin: cholesterol acyltransferase substrate properties of HDL as determined by its subclass distribution analysed by gradient gel electrophoresis.

In order to study the impact of high-density lipoproteins (HDL) subclasses on the ability of HDL to act as substrate for lecithin: cholesterol acyltransferase (LCAT), we isolated HDL from nine normolipidemic male subjects. The HDL particle size distribution was analysed by gradient gel electrophoresis and the esterification rate of the isolated homologous HDL was compared with a pool of HDL where all the nine subjects took part. It was found that the strongest determinant for HDL cholesterol esterification rate was the inhibitory action of HDL subclass 2B.

Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men.

BACKGROUND: Alimentary lipemia has been associated with coronary heart disease and common carotid artery intima-media thickness (IMT). This study was designed to investigate the relations of subclasses of postprandial triglyceride-rich lipoproteins (TRLs) with IMT. METHODS AND RESULTS: Ninety-six healthy 50-year-old men with an apolipoprotein (apo) E3/E3 genotype underwent an oral fat tolerance test and B-mode carotid ultrasound examination. The apo B-48 and apo B-100 contents of each fraction of TRLs were determined as a measure of chylomicron remnant and VLDL particle concentrations. In the fasting state, LDL cholesterol (P<0.05) and basal proinsulin (P<0. 05) were significantly related to IMT, whereas HDL cholesterol, plasma triglycerides, and insulin were not. In the postprandial state, plasma triglycerides at 1 to 4 hours (P<0.01 at 2 hours), total triglyceride area under the curve (AUC) (P<0.05), incremental triglyceride AUC (P<0.01), and the large VLDL (Sf 60 to 400 apo B-100) concentration at 3 hours (P<0.05) were significantly related to IMT. Multivariate analyses showed that plasma triglycerides at 2 hours, LDL cholesterol, and basal proinsulin were consistently and independently related to IMT when cumulative tobacco consumption, alcohol intake, waist-to-hip circumference ratio, and systolic blood pressure were included as confounders. CONCLUSIONS: These results provide further evidence for postprandial triglyceridemia as an independent risk factor for early atherosclerosis and also suggest that the postprandial triglyceridemia is a better predictor of IMT than particle concentrations of individual TRLs.

Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT).

OBJECTIVES: To investigate the mechanisms by which bezafibrate retarded the progression of coronary lesions in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), we examined the relationships of on-trial lipoproteins and lipoprotein subfractions to the angiographic outcome measurements. BACKGROUND: BECAIT, the first double-blind, placebo-controlled, randomized serial angiographic trial of a fibrate compound, showed that progression of focal coronary atherosclerosis in young survivors of myocardial infarction could be retarded by bezafibrate treatment. METHODS: A total of 92 dyslipoproteinemic men who had survived a first myocardial infarction before the age of 45 years were randomly assigned to treatment for 5 years with bezafibrate (200 mg three times daily) or placebo; 81 patients underwent baseline and at least one post-treatment coronary angiography. RESULTS: In addition to the decrease in very low density lipoprotein (VLDL) cholesterol (-53%) and triglyceride (-46%) and plasma apolipoprotein (apo) B (-9%) levels, bezafibrate treatment resulted in a significant increase in high density lipoprotein-3 (HDL3) cholesterol (+9%) level and a shift in the low density lipoprotein (LDL) subclass distribution toward larger particle species (peak particle diameter +032 nm). The on-trial HDL3 cholesterol and plasma apo B concentrations were found to be independent predictors of the changes in mean minimum lumen diameter (r=-0.23, p < 0.05), and percent (%) stenosis (r = 0.30, p < 0.01), respectively. Decreases in small dense LDL and/or VLDL lipid concentrations were unrelated to disease progression. CONCLUSIONS: Our results suggest that the effect of bezafibrate on progression of focal coronary atherosclerosis could be at least partly attributed to a rise in HDL3 cholesterol and a decrease in the total number of apo B-containing lipoproteins.

Exercise prevents the accumulation of triglyceride-rich lipoproteins and their remnants seen when changing to a high-carbohydrate diet.

We tested the hypothesis that daily aerobic exercise opposes the fasting hypertriglyceridemia and exaggerated postprandial lipemia observed after substituting dietary fat with carbohydrate. Eight healthy postmenopausal women aged 51 to 66 years consumed the same high-fat mixed meal on 3 occasions: (1) after 3 days on a low-carbohydrate diet (35%, 50%, and 15% energy from carbohydrate, fat, and protein, respectively); (2) after 3 days on an isoenergetic high-carbohydrate diet (corresponding values 70%, 15%, and 15%); and (3) after 3 days on the same high-carbohydrate diet with 60 minutes of brisk walking daily. Plasma triglycerides were higher after the high-carbohydrate diet than after the low-carbohydrate diet: fasting, 1.58+/-0.19 versus 0.96+/-0.12 mmol/L, respectively; 6-hour postprandial area under concentration versus time curve, 13.74+/-1.57 versus 10.12+/-1.15 (mmol/L)xhour, respectively (both P<0.01). In the fasted and postprandial states, concentrations of apolipoproteins B-48 and B-100 in the triglyceride-rich lipoprotein fraction were significantly higher after the high-carbohydrate diet, as was the concentration of remnant-like lipoprotein particle cholesterol (a measure of lipoprotein remnants). These carbohydrate-induced increases in the number of circulating triglyceride-rich particles and their remnants were abolished when subjects had exercised daily during the high-carbohydrate diet.

The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients.

OBJECTIVE: To investigate the long-term antidiabetogenic effect of glucagon-like peptide 1 (GLP-1) and its influence on diabetic dyslipoproteinemia, patients with NIDDM were treated with GLP-1 subcutaneously for 1 week. RESEARCH DESIGN AND METHODS: Twelve patients participated in the study. The 1st week of the study, all of them were on intensive insulin treatment and from day 8, four were randomized to a control group continuing with insulin, and eight to a treatment group where GLP-1 was given at meals together with regular insulin from day 8 to 12. On days 13 and 14, they were only given GLP-1 at meals. NPH insulin at bedtime was given throughout the study. RESULTS: In the GLP-1-treated patients, the doses of regular insulin, given to keep a satisfactory blood glucose control, were reduced compared with treatment with insulin only. GLP-1 virtually inhibited the early increase in blood glucose after the meals, whereas an increase of approximately 2 mmol was seen during an optimized insulin treatment. In agreement with the short half-life of the peptide, 2-h postprandial plasma insulin levels were significantly decreased both at day 12 and 14, suggesting that there was not enough GLP-1 left to stimulate endogenous insulin release and compensate for the decrease in the dose of exogenous insulin. Therefore, the effect of GLP-1 was lost before the next meal, resulting in increased preprandial blood glucose values at lunch and dinner. The concentration of VLDL triglycerides decreased already during the 1st week. This decrease persisted during the 2nd week when GLP-1 was included in the treatment. No changes were observed in the levels of LDL and HDL cholesterol. The LDL particle diameter increased from a mean of 22.3 to 22.6 nm (P < 0.01) in response to insulin treatment. A further increment to 22.9 nm (P < 0.05) was seen after GLP-1 treatment. The LDL particle size did not change in the control group. Lipoprotein lipase activity was decreased by 27% and hepatic lipase was reduced by 13% in the GLP-1-treated group. CONCLUSIONS: We confirm the antidiabetogenic effect of GLP-1 in NIDDM patients. This effect was maintained during 7 days, which implies that the patients did not develop tolerance during this treatment period. Intensive insulin treatment, leading to normotriglyceridemia, increased the mean LDL particle diameter, which is likely to lower the risk of future coronary heart disease in patients with NIDDM. Furthermore, an additive effect of GLP-1 is indicated. Hence, this study gives additional evidence that GLP-1 may be useful as an agent for treating NIDDM.

Risk of fatal stroke in patients with treated familial hypercholesterolemia: a prospective registry study.

BACKGROUND AND PURPOSE: Although it is recognized that in heterozygous familial hypercholesterolemia, large extracranial carotid vessels are affected by atherosclerosis, the risk of fatal stroke after treatment with cholesterol-lowering therapy remains uncertain. The goal of this study was to determine the risk of fatal stroke in patients with treated familial hypercholesterolemia. METHODS: A cohort of 1405 men and 1466 women with definite or possible heterozygous familial hypercholesterolemia was recruited from 21 outpatient lipid clinics in the United Kingdom. Patients were followed up prospectively from 1980 to 1998 for 22 992 person-years for a median duration of 7.9 years (interquartile range, 4.9 to 12.0 years). The mortality rate was calculated, and the standardized mortality ratio for men and women 20 to 79 years of age was derived from the ratio of the observed deaths to the number expected in the general population of England and Wales (standardized mortality ratio=100 for the standard population). RESULTS: A total of 169 deaths occurred; 9 (5.3%) were a result of stroke. The mortality rate from stroke was 0.39 per 1000 person-years (95% confidence interval, 0.18 to 0.74), and the standardized mortality ratio for fatal stroke was nonsignificantly lower than in the general population (79; 95% CI, 36 to 150). CONCLUSIONS: The results suggest that patients with treated familial hypercholesterolemia are not at increased risk of fatal stroke. However, the possibility cannot be excluded that untreated individuals are at increased risk, which would be consistent with the evidence that familial hypercholesterolemia is a panvascular disease.

Dyslipoproteinemic changes in borderline hypertension.

The present study examined plasma lipoprotein, lipoprotein lipase, hepatic lipase, and insulin levels in men with borderline hypertension (diastolic blood pressure 85 to 94 mm Hg) compared with age-matched normotensive control subjects (diastolic blood pressure less than or equal to 80 mm Hg, n = 75 + 75). High-density lipoprotein (HDL) subclasses were determined in a subset (n = 45 + 45). While total and low-density lipoprotein cholesterol levels were similar, levels of very-low-density lipoprotein (VLDL) cholesterol and triglycerides (0.46 versus 0.41 mmol/L, P = .027, and 1.0 versus 0.85 mmol/L, P = .031) and total triglycerides (1.53 versus 1.33 mmol/L, P = .009) were elevated and HDL cholesterol was reduced in the borderline group compared with the normotensive group (1.17 versus 1.26 mmol/L, P = .043). The HDL subclass HDL2b concentration was lower (0.16 versus 0.24 mmol/L, P = .006), while HDL3b and HDL3c concentrations were higher in the borderline group (0.38 versus 0.32 mmol/L, P = .016, and 0.19 versus 0.16 mmol/L, P = .042). Significantly higher activities of hepatic lipase in the borderline group (282 versus 232 mU/mL, P = .024) and significant correlations between lipoprotein lipase activity and VLDL and HDL concentrations suggest an involvement of these enzymes in the development of these differences. When adjusted for body mass index or insulin level, all differences disappeared, except for HDL3b and HDL3c concentrations, which remained significantly elevated. These results indicate that dyslipoproteinemic changes are present in early hypertension. Although most of these changes are related to obesity, alterations in HDL profile were not explained by influences of body mass index and insulin.