Metabolic outcomes 2 years following gastric bypass surgery in people with type 2 diabetes: an observational cohort study.

BACKGROUND: Gastric bypass surgery induces early remission or significant improvement in type 2 diabetes (T2D). AIM: To assess effectiveness of stopping glucose-lowering treatment at the time of surgery. DESIGN: Observational cohort analysis. METHODS: We identified 101 patients (62 women) with T2D who had undergone gastric bypass surgery at a mean (SD, standard deviation) age of 51.4 (9.0) years. We recorded weight, body mass index (BMI), glycosylated haemoglobin (HbA1c), blood pressure (BP), total and high-density lipoprotein (HDL) cholesterol preoperatively and at a median 4, 12 and 24 months postoperatively, and changes to glucose-lowering therapy. RESULTS: Mean (SD) baseline BMI was 50.3 (6.3) kg/m(2), HbA1c 65.3 (18.5) mmol/mol, systolic BP 146.0 (18.0) mmHg, diastolic BP 87.0 (10.8) mmHg and total cholesterol-to-HDL cholesterol ratio 4.0 (1.2). Mean (95% confidence interval) reduction in BMI was 16.4 (14.1-18.7) kg/m(2), HbA1c 23.6 (17.6-29.6) mmol/mol, systolic BP 12.9 (5.9-19.8) mmHg, diastolic BP 6.1 (1.8-10.5) mmHg and total cholesterol-to-HDL cholesterol ratio 1.1 (0.6-1.5) at 24 months (P < 0.001 for all measures). Although 91% of patients were receiving glucose-lowering therapies preoperatively, complete (HbA1c < 42 mmol/mol) and partial (HbA1c 42-48 mmol/mol) remissions of T2D were seen in 62.1% and 5.2% at 2 years postoperatively. CONCLUSIONS: Cessation of glucose-lowering therapies in people with T2D at the time of gastric bypass surgery was clinically effective. The majority of patients remained in complete or partial remission of diabetes up to 2 years postoperatively.

The effectiveness and cost of single and multi-factorial cardiovascular risk factor modification to guideline targets in type 2 diabetes.

AIMS: Cardiovascular disease is the main cause of morbidity and mortality in type 2 diabetes (T2DM), at huge cost to the NHS. We investigated the potential effect on population cardiovascular risk and associated costs of single and multi-factorial intervention, to target levels, in individuals with T2DM. METHODS: Baseline population means and proportions for cardiovascular risk factors were calculated for 159 patients with T2DM from 3 general practices. Predicted 10year cardiovascular risk, and associated costs were calculated using the LIP2687 risk calculator, based on Framingham and UKPDS equations. Systolic blood pressure, HbA(1C), total cholesterol and HDL-cholesterol were altered to NICE and SIGN target levels and the model run again. The difference in outcomes was observed. RESULTS: 45%, 76% and 38% of patients met NICE targets for cholesterol, systolic blood pressure and HbA1c, respectively. As expected, comparing the two guidelines, fewer patients met the 'stricter' targets (P=0.0001). Treatment-to-target produced no significant difference in cardiovascular risk or costs, although greater reductions in outcomes were seen with multi-factorial intervention. CONCLUSION: This small study suggests that intervention in only those patients with the highest cardiovascular risk brings little reduction in population cardiovascular risk and associated health costs. Multi-factorial intervention in all patients with T2DM, regardless of baseline values, is likely to bring greater reductions. This raises the question as to whether the current emphasis on treatment to target should be modified to encourage multi-factorial intervention in all patients with T2DM, even those with baseline values below target levels.

Trends in the association between blood pressure and obesity in a Taiwanese population between 1996 and 2006.

In the last decades, the prevalence of obesity has increased in the Taiwanese population. This has the potential to impact on the risks of cardiovascular diseases and diabetes. This study investigated trends in the changes in several indices of obesity in the last decade, and the relationship between blood pressure (BP) and these obesity indices available in Mei-Jaw Corporation health-screening data from 1996/1998 to 2006. Three cross-sectional surveys among healthy individuals ages 20-59 years, in which 14,362 subjects examined in year 1996, 17,368 in 1998, and 28,524 in 2006, were included in the analysis. Body weight and height data were available from 1996, whereas %body fat, waist circumference and waist-hip ratio (Whratio) were only available from 1998 onwards. We found that the association between systolic BP and body weight, body mass index, %body fat, Whratio and waist became stronger for both men and women in 2006 than 1996 after adjustment for age, education level, alcohol intake, smoking and betel nut chewing. In contrast, non-obese people seemed to have lower diastolic BP in 2006 than in 1996. This trend is consistent irrespective of the index of obesity used. Among healthy individuals, the average values for the obesity indices increased in men but remained similar in women. However, in both men and women, the relationship between obesity and BP has changed. Further research is required to investigate the impact of these intriguing changes in the associations on the risk of cardiovascular diseases in the Taiwanese population.

The response of serum apolipoprotein H to an oral fat load.

BACKGROUND: We tested the hypothesis that serum apolipoprotein H (apo H) concentration increases after an oral fat load. Such a study would give valuable insight into whether apo H was influenced by the postprandial state. METHODS: Ten male subjects aged 24-48 years were fed 62.5 g of total fat (saturates 12 g, monounsaturates 35.3 g, polyunsaturates 12.5 g). Venous blood was sampled hourly for 5 h post-oral fat load. RESULTS: No significant change in serum apo H concentration occurred following the oral fat load. However, serum apo H in the baseline samples correlated significantly with subject body mass index (r = 0.683, P < 0.05), body fat mass (r = 0.778, P < 0.01), lean body mass (r = 0.693, P < 0.05), serum triglyceride (r = 0.732, P < 0.02), serum insulin (r = 0.808, P < 0.01) and insulin resistance index (r = 0.794, P < 0.01). In stepwise multiple linear regression model, with serum apo A1, apo B, lipoprotein(a), total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, plasma glucose and insulin and apo H as the dependent variable, insulin remained in the model (r = 0.81, P < 0.01). Conversely, with body mass index, body fat mass, lean body mass and waist/hip ratio in the model and apo H as dependent variable, only body fat mass remained in the model (r = 0.78, P < 0.01). CONCLUSIONS: Serum apo H may be involved in insulin resistance and relates to various indices of adipose tissue, including body fat mass. However, serum apo H concentrations do not significantly change postprandially.

Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity.

AIMS/HYPOTHESIS: British dietary recommendations are to decrease total fat intake to less than 30 % of daily energy intake and saturated fat to less than 10 %. In practice, it is difficult for people to make these changes. It may be easier to encourage people to switch from a diet rich in saturated fatty acids to one rich in polyunsaturated fatty acids. METHODS: A total of 17 subjects - six people with Type II (non-insulin-dependent) diabetes mellitus, six non-obese and five obese people without diabetes - were randomised to spend two 5-week periods on a diet rich in saturated or in polyunsaturated fatty acids, in a crossover design. At the start of the study and after each dietary period, we assessed abdominal fat distribution using magnetic resonance imaging, insulin sensitivity using hyperinsulinaemic-euglycaemic clamps and fasting lipid parameters. RESULTS: Dietary compliance, assessed by weekly 3-day dietary records and measurement of biochemical markers, was good. Energy and fat intake appeared to be reduced on the diet rich in polyunsaturated fatty acids although body weights did not change. Insulin sensitivity and plasma low density lipoprotein cholesterol concentrations improved with the diet rich in polyunsaturated fatty acids compared with the diet rich in saturated fatty acids. There was also a decrease in abdominal subcutaneous fat area. CONCLUSION/INTERPRETATION: If this result is confirmed in longer-term studies, this dietary manipulation would be more readily achieved by the general population than the current recommendations and could result in considerable improvement in insulin sensitivity, reducing the risk of developing Type II diabetes.

The response of serum sialic acid and other acute phase reactants to an oral fat load in healthy humans.

BACKGROUND: Elevated serum total sialic acid (TSA) has been shown to be associated with increased cardiovascular mortality. It has been postulated that atherogenesis is a postprandial phenomenon. We tested the hypothesis that serum TSA and other acute phase proteins, namely C-reactive protein (CRP) and fibrinogen, may be related to the postprandial state. METHODS: Ten healthy male subjects, aged 24-48 years, were fed 62.5 g of total fat (saturates 12 g, monounsaturates 35.3 g and polyunsaturates 12.5 g) in the form of strawberry flavoured Calogen. Venous blood was sampled hourly for 5 h. Concentrations of serum triglyceride, TSA and acute phase proteins were measured. RESULTS: Serum triglyceride concentration increased postprandially, peaking at 240 min. Serum CRP and plasma fibrinogen did not significantly increase after the oral fat load. However, serum TSA did increase from baseline (0.599+/-0.051 g/l) in response to the oral fat load, peaking at 120 min post-oral fat load (0.633+/-0.066 g/l, P<0.02). There was a significant correlation between serum TSA and plasma fibrinogen at baseline (rho=0.62, P=0.05) but not for serum CRP (rho=-0.22) or triglyceride (rho=0.21). CONCLUSIONS: We conclude that serum TSA increases postprandially and this finding gives further insight as to why the former is considered to be a cardiovascular risk factor.

The effect on adipose tissue blood flow of isoenergetic meals containing different amounts and types of fat.

OBJECTIVE: To investigate the factors regulating the increase in adipose tissue blood flow following meals. DESIGN: Eight subjects were fed three isoenergetic meals; two high-fat meals rich in either saturated or polyunsaturated fatty acids and one low-fat, high-carbohydrate meal. MEASUREMENTS: Blood samples were taken and adipose tissue blood flow was measured before and for 6 h after the meal. Plasma glucose, insulin, non-esterified fatty acid, total and chylomicron-triacylglycerol and catecholamine concentrations were measured. RESULTS: Adipose tissue blood flow rose to a peak after all three meals (P<0.05 for each). The three meals stimulated adipose tissue blood flow at similar times. There was a marked and statistically significant similarity in the time course of changes in blood flow and insulin concentrations. In contrast, noradrenaline concentrations peaked later than adipose tissue blood flow (P=0.014). CONCLUSION: Adipose tissue blood flow may be 'carbohydrate-stimulated' rather than 'fat-stimulated', with insulin having a vasodilatory role in adipose tissue as in skeletal muscle.

Uptake of individual fatty acids into adipose tissue in relation to their presence in the diet.

BACKGROUND: The fatty acid composition of adipose tissue triacylglycerol reflects, but is not identical to, the fatty acid composition of the habitual diet. OBJECTIVE: We investigated whether the fatty acid composition of adipose tissue is explained by differences between fatty acids in early storage in adipose tissue after a meal. DESIGN: Nine healthy men ate a meal containing several fatty acids. Blood samples were taken for 6 h after the meal from an arterialized hand vein and a vein draining the anterior abdominal subcutaneous adipose tissue. RESULTS: Net storage of fatty acids in adipose tissue occurred between 1 and 4 h after the meal. In relation to the amount fed, storage of fatty acids differed (P < 0. 01) between classes (n-3 polyunsaturated < saturated < n-6 polyunsaturated < monounsaturated); oleic acid was stored in the greatest amounts. These differences agreed closely with published data, except for n-3 polyunsaturated fatty acids. The only individual metabolic step at which significant differences between fatty acids was shown was incorporation of fatty acids into chylomicron triacylglycerol. Differences between fatty acids in rate of extraction from chylomicron triacylglycerol and net uptake into adipose tissue in the postprandial period were significant (P < 0. 01), but not when expressed in relation to proportions in chylomicron triacylglycerol. CONCLUSIONS: The characteristic fatty acid pattern of adipose tissue may predominantly reflect the early metabolic handling of different fatty acids. Adipose tissue uptake of n-3 polyunsaturated fatty acids is slow in relation to that of other fatty acids.

Impaired postprandial tissue regulation of blood flow in insulin resistance: a determinant of cardiovascular risk?

The insulin resistant state is a major risk factor for coronary artery disease. This increased risk is likely to be due to associated lipid and coagulation abnormalities rather than just abnormalities in glucose metabolism or hyperinsulinaemia alone. Exaggerated postprandial lipaemia is a well-recognised associate of insulin resistance and postprandial hypertriglyceridaemia is particularly important in the development of coronary atheroma. It seems likely that insulin is one of the hormonal regulators of adipose tissue and skeletal muscle blood flow. The reduced blood flow and blunting of the postprandial rise of peripheral blood flow in insulin resistance may decrease chylomicron-triglyceride delivery to muscle in subjects with insulin resistance. This, in turn, will lead to increased production of atherogenic particles. We propose that impaired postprandial vasodilation, already recognised as a key feature of glucose intolerance, is also the cause of impaired lipid metabolism in insulin resistant subjects and predisposes them to cardiovascular disease.

Use of structured triacylglycerols containing predominantly stearic and oleic acids to probe early events in metabolic processing of dietary fat.

Early events in the metabolic processing of dietary triacylglycerol may have an important impact on subsequent development of risk factors for coronary heart disease. We have used structured triacylglycerols containing predominantly stearic or oleic acids at the sn -2 position to probe aspects of the processing of dietary fatty acids presented to adipose tissue in chylomicron-triacylglycerol. Studies were conducted on 14 healthy women who were given meals containing 85 g carbohydrate and 60 g of either of the two structured triacylglycerols in random order. Systemic concentrations and arterio-venous differences across adipose tissue for plasma triacylglycerol and non-esterified fatty acids were measured, together with analysis of the fatty acid composition of the relevant fractions. The stereo-specific structure of the ingested triacylglycerol was largely preserved in chylomicron-triacylglycerol. Systemic concentrations of total and individual non-esterified fatty acids were not significantly different after ingestion of the two fats, nor were their rates of release across adipose tissue. The composition of non-esterified fatty acids released from adipose tissue changed after the meal to reflect more closely the composition of the triacylglycerol ingested, but again no significant differences were observed between the two test meals. There was no detectable release of monoacylglycerol from adipose tissue after either test meal. We conclude that the environment for lipoprotein lipase action in adipose tissue in vivo is likely to be highly organized, such that there is no release of monoacylglycerol, nor preferential uptake or release of fatty acids from chylomicron-triacylglycerol according to the nature or the position within triacylglycerol of the fatty acid.

The use of microdialysis to monitor rapid changes in glucose concentration.

As a result of the Diabetes Control and Complications Trial, there is increased emphasis on the importance of blood glucose concentration self-monitoring for people with diabetes. The current methods for this are not ideal, and there are many other possible techniques currently under investigation. One of these techniques is microdialysis, which can be used to analyse subcutaneous interstitial glucose concentrations. A system with high recovery has recently been used to monitor glucose concentrations with sampling over one- or two-hour periods. We have investigated whether this system can be used to monitor rapid changes in blood glucose concentration in healthy volunteers with collection intervals of only ten minutes. The results show that microdialysis can be used to monitor rapidly changing blood glucose concentration, but in some subjects, dialysate glucose lagged behind the whole blood and plasma glucose concentrations to a degree that would be clinically significant. It would therefore be necessary to assess the system, comparing dialysate with plasma glucose concentrations in each individual, prior to use in a clinical setting.

Lipoprotein lipase transport in plasma: role of muscle and adipose tissues in regulation of plasma lipoprotein lipase concentrations.

Lipoprotein lipase (LPL) is synthesized in tissues involved in fatty acid metabolism such as muscle and adipose tissue. LPL is also found in the circulation, but is mostly lipolytically inactive. The proportion of active circulating LPL increases after a fatty meal. We investigated the release of active and inactive LPL from adipose tissue and muscle in the fasting and postprandial states. Arteriovenous concentration gradients of LPL across adipose tissue and forearm muscle were measured in male subjects before and after a fat-rich meal (n = 7) and before and during infusion of a triacylglycerol emulsion (Intralipid) (n = 6). Plasma LPL activity rose after the meal and more so during Intralipid infusion. Plasma LPL mass (>95% inactive LPL) increased after the meal but decreased after Intralipid infusion. In the fasting state (n = 13) muscle efflux of LPL activity was 0.263 +/- 0.098 mU/min per 100 ml of muscle tissue whereas there was an influx of LPL activity to adipose tissue of 0.085 +/- 0.100 mU/min per 100 g of adipose tissue (P < 0. 02 muscle vs. adipose tissue). Similarly in the postprandial state only muscle released LPL activity. Both tissues released LPL mass. In the fasting state efflux was 17.8 +/- 8.8 ng/min per 100 ml muscle and 55.2 +/- 21.3 ng/min per 100 g of adipose tissue (P < 0. 05 muscle vs. adipose tissue). Release of LPL, either active or inactive, was not correlated with levels of non-esterified fatty acids or plasma triacylglycerol. In conclusion, there is a substantial release of LPL from adipose tissue and muscle, most of which is inactive. A small proportion of active LPL seems to be redistributed from muscle to adipose tissue.

Peripheral fat metabolism during infusion of an exogenous triacylglycerol emulsion.

OBJECTIVE: To test the hypothesis that intravenous infusion of lipid would bring about changes in adipose tissue metabolism, which would tend to spare net fat mobilization, and to attempt to identify the mediators of such responses. DESIGN: The triacylglycerol (TG) emulsion, Intralipid, was infused and metabolic changes in subcutaneous adipose tissue and forearm muscle were assessed by measurements of arterio-venous differences. SUBJECTS: Six normal male subjects aged 21-37 y, with body mass index (BMI) 23.0-25.9 kg/m2. RESULTS: Plasma TG and non-esterified fatty acid (NEFA) concentrations rose during infusion as expected. The rise in systemic plasma NEFA concentration occurred despite decreased NEFA release from adipose tissue. Intralipid infusion resulted in a suppression of intracellular lipolysis in adipose tissue, by mechanisms which are not clear. Plasma leptin concentrations, measured in a search for the regulator of lipolysis, showed consistent leptin release from adipose tissue which did not change significantly with time. CONCLUSION: The suppression of intracellular lipolysis in adipose tissue during Intralipid infusion is a new observation and may reflect a novel mechanism for regulation of fat storage.

Adipose tissue metabolism in the postprandial period: microdialysis and arteriovenous techniques compared.

We investigated whether two different methods of studying metabolism in adipose tissue, microdialysis and the arteriovenous technique, produced comparable results during the postprandial period. Interstitial glycerol concentrations measured by microdialysis are usually used as an index of intracellular lipolysis, and it is not known whether they also reflect the intravascular action of lipoprotein lipase in the postprandial period. The two techniques were compared in 10 healthy subjects fed mixed meals. Interstitial glycerol concentrations reflected those measured in adipose tissue venous plasma. However, the calculation of the rate of glycerol release from adipose tissue using the microdialysis data differed systematically from that using arteriovenous difference measurement. The former method gave, on average, 40% lower values than the latter one. The difference is probably due to the assumptions that had to be made for the calculation of glycerol release. The two techniques have complementary places in the study of postprandial adipose tissue metabolism, with microdialysis reflecting intracellular hormone-sensitive lipase action rather than intravascular lipoprotein lipase.

Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period.

The objective of this study was to determine whether Acylation Stimulating Protein (ASP) is generated in vivo by human adipose tissue during the postprandial period. After a fat meal, samples from 12 subjects were obtained (up to 6 h) from an arterialized hand vein and an anterior abdominal wall vein that drains adipose tissue. Veno-arterial (V-A) gradients across the subcutaneous adipose tissue bed were calculated. The data demonstrate that ASP is produced in vivo (positive V-A gradient) With maximal production at 3-5 h postprandially. The plasma triacylglycerol (TAG) clearance was evidenced by a negative V-A gradient. It increased substantially after 3 h and remained prominent until the final time point. There was, therefore, a close temporal coordination between ASP generation and TAG clearance. In contrast, plasma insulin and non-esterified fatty acid (NEFA) had an early (1-2 h) postprandial change. Fatty acid incorporation into adipose tissue (FIAT) was calculated from V-A glycerol and non-esterified fatty acid (NEFA) differences postprandially. FIAT was negative during the first hour, implying net fat mobilization. FIAT then became increasingly positive, implying net fat deposition, and overall followed the same time course as ASP and TAG clearance. There was a direct positive correlation between total ASP production and total FIAT (r = 0.566, P < 0.05). These data demonstrate that ASP is generated in vivo by human adipocytes and that this process is accentuated postprandially, supporting the concept that ASP plays an important role in clearance of TAG from plasma and fatty acid storage in adipose tissue.

The effect of triacylglycerol-fatty acid positional distribution on postprandial metabolism in subcutaneous adipose tissue.

We hypothesized that fatty acids at the sn-2 position of chylomicron triacylglycerol are preferentially released into the venous plasma (rather than being taken up and stored in the adipocytes) after hydrolysis by lipoprotein lipase (EC 3.1.1.34) in adipose tissue. Arteriovenous differences across adipose tissue were studied in eight healthy subjects on two occasions for 6 h after ingestion of different structured triacylglycerols rich in palmitic acid either at the sn-2 or the sn-1,3 positions. In particular the specific fatty acids making up lipoprotein fractions and plasma non-esterified fatty acids were analysed. After the different meals there were no differences between either postprandial arterialized or venous plasma metabolite concentrations. Chylomicron triacylglycerol extraction in adipose tissue was the same following the two types of fat. There was no difference between the specific fatty acid composition of the postprandial non-esterified fatty acid release from adipose tissue after ingestion of the two triacylglycerols, indicating that there was no preferential release of a saturated fatty acid at the sn-2 position.

Clearance of lipoprotein remnant particles in adipose tissue and muscle in humans.

A major proportion of triglycerides in plasma triglyceride-rich lipoproteins (TRL) are removed in peripheral tissues by lipoprotein lipase, and hypothetically a minor proportion can also be removed by whole-lipoprotein particle uptake. This second removal pathway has not previously been directly demonstrated in humans. Simultaneous blood samples were drawn from arterialized blood, a vein draining the subcutaneous abdominal adipose tissue, and a deep antecubital vein of the forearm to provide arterio-venous gradients from blood-draining adipose tissue and muscle in seven male subjects. The men were given a fat-rich mixed meal containing vitamin A and the triglyceride and retinyl palmitate (RP) concentrations were quantified in the plasma. Density gradient ultracentrifugation was used to isolate TRL fractions, in which triglycerides, RP, apoB-48, and apoB-100 were quantified. There was clearance of triglycerides in muscle and adipose tissue and, in addition, removal of RP. By analysis of the TRL subfractions, the RP removal was likely to be confined to the largest chylomicron remnant particles. For the Sf > 400 fraction, the area under curve (AUC) relative to arterial for triglycerides were 79% (66-91%) and 81% (72-89%) in adipose tissue and muscle venous outflow, respectively (each P < 0.02 versus arterial). The corresponding values for RP were 87% (73-101%) and 85% (69-100%), respectively, (each P < 0.05 versus arterial). In the Sf 60-400 fraction there was further uptake of triglycerides, but not of RP. We hypothesize that the periphery could be of importance for removal of the largest chylomicron remnants, as their size might partially exclude them penetrating the fenestrated hepatic sinusoidal endothelium to reach the hepatic chylomicron remnant receptors.