M.-R. Taskinen

Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society

Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.

Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial

BACKGROUND Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. METHODS The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50-75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. FINDINGS Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47-0.94; p=0.022). INTERPRETATION Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.

Overproduction of large VLDL particles is driven by increased liver fat content in man

Aims/hypothesisWe determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL1 production.MethodsA multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL1 and VLDL2 after a bolus of [2H3]leucine and [2H5]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI.ResultsUnivariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL1 TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL1 in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL1 TG and ApoB pool sizes, adiponectin was not linked to VLDL1 TG or ApoB production and thus was not a predictor of VLDL1 production. However, adiponectin correlated negatively with the removal rates of VLDL1 TG and ApoB.Conclusions/interpretationWe propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL1 particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.

Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM

Summary Insulin administration to healthy subjects inhibits the production of very low density lipoprotein (VLDL)1 (Svedbergs flotation (Sf) rate 60–400) without affecting that of VLDL2 (Sf 20–60) subclass. This study was designed to test whether this hormonal action is impaired in non-insulin-dependent diabetes mellitus (NIDDM). We studied six men with NIDDM (age 53 ± 3 years, body mass index 27.0 ± 1.0 kg/m2, plasma triglycerides 1.89 ± 0.22 mmol/l) during an 8.5 h infusion of saline (control) and then in hyperinsulinaemic (serum insulin ∼ 540 pmol/l) conditions during 8.5 h infusions of glucose and insulin to give either hyper- and normoglycaemic conditions. [3-2H]-leucine was used as tracer and kinetic constants derived using a non-steady-state multicompartmental model. Compared to the control study, patients with NIDDM reduced VLDL1 apo B production by only 3 ± 8 % after 8.5 h of hyperinsulinaemia (701 ± 102 vs 672 ± 94 mg/day respectively, NS) in hyperglycaemic conditions and by 9 ± 21 % under normoglycaemic conditions (603 ± 145 mg/day). In contrast, in normal subjects insulin induced a 50 ± 15 % decrement in VLDL1 apo B production (p < 0.05). Direct synthesis of VLDL2 apo B in patients with NIDDM was not markedly affected by insulin. We conclude that a contributory factor to hypertriglyceridaemia in NIDDM is the inability of insulin to inhibit acutely the release of VLDL1 from the liver, despite efficient suppression of serum non-esterfied fatty acids. [Diabetologia (1997) 40: 454–462]

Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM

SummaryInsulin is known to increase expression of the ob gene product leptin in adipose tissue of rodents. We determined whether insulin increases circulating leptin concentrations in humans, and whether this effect might be altered in patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma leptin concentrations were determined during an 8.5-h hyperinsulinaemic clamp (serum free insulin approximately 480 pmol/l) and during an 8.5-h infusion of physiological NaCl solution (saline) in eight normal subjects (age 51±3 years, BMI 26.3±0.6 kg/ m2, fasting plasma glucose 5.6±0.2 mmol/l) and seven patients with NIDDM (age 54±2 years, 27.0±0.9 kg/m2, 11.1±0.8 mmol/l). Fasting serum insulin level correlated with plasma leptin (r=0.72, p<0.005), even after adjusting for the percentage of body fat (p<0.005). During the insulin infusion, a significant increase in the plasma leptin concentration was observed after 6 h (37±14%; 5.2±0.8 vs 3.9±0.6 ng/ml, 6 vs 0 h, p<0.05) in the normal subjects and after 8.5 h (38±11%; 7.1±1.0 vs 5.5±0.9 ng/ml, 8.5 vs 0 h, p<0.05) in the patients with NIDDM. During the saline infusion, plasma leptin concentrations decreased significantly in the normal subjects by 11±1% (p<0.005) and in the patients with NIDDM by 14±1% (p<0.01) after 2 h. During the infusion of insulin as compared to saline, plasma leptin concentrations were 32±13 (p<0.05), 53±14 (p<0.001), 106±15 (p<0.001) and 165±21 (p<0.001)% higher at 2, 4, 6 and 8.5 h in the normal subjects, and 11±9 (p<0.05), 27±10 (p<0.05), 58±7 (p<0.001) and 106±13 (p<0.001)% higher in the patients with NIDDM, respectively. No differences were observed in plasma leptin concentrations between the normal subjects and patients with NIDDM, under any conditions. We conclude that prolonged exposure to insulin increases plasma leptin concentrations in humans implying a role for insulin in chronic but not acute regulation of plasma leptin concentrations. The decrease in plasma leptin concentrations during saline infusion was greater than that expected on the basis of change in serum insulin concentrations, suggesting that factors other than insulin also contribute to regulation of plasma leptin concentrations.

The metabolic syndrome influences the risk of chronic complications in patients with Type II diabetes

Abstract.Aims/hypothesis: We examined features of the metabolic syndrome to see if they modified the risk of chronic diabetic complications in patients with Type II (non-insulin-dependent) diabetes mellitus. Methods: A total of 85 randomly selected patients with the metabolic syndrome (WHO definition) were compared with 85 Type II diabetic patients matched for age, sex, duration of diabetes, glycaemic control and without the syndrome to assess the microvascular and macrovascular complications. Results: The patients with the metabolic syndrome had a higher prevalence of cardiovascular disease (52 vs 21 %, p < 0.001), microalbuminuria or macroalbuminuria (23 vs 7 %, p = 0.003) and distal neuropathy (16 vs 6 %, p = 0.048) than patients without the syndrome. The patients with the metabolic syndrome had smaller LDL particle size (25.4 ± 1.4 vs 26.4 ± 1.1 nm; p < 0.001), which correlated with the ratio of serum triglycerides to HDL cholesterol (r = –0.64, p < 0.001). In a multiple logistic regression analysis the metabolic syndrome was associated with coronary heart disease (RR 3.84, p < 0.001) and microalbuminuria (RR 3.99, p = 0.01). Small LDL particle size was independently associated with neuropathy (RR 0.58; p = 0.04), whereas a high HbA1 c was related to neuropathy (RR 1.69, p = 0.04), retinopathy (RR 1.53, p = 0.002) and microalbuminuria (RR 1.54, p = 0.01). Conclusion/interpretation: Although chronic hyperglycaemia is the main predictor of microvascular complications in patients with Type II diabetes, this risk is modified by some of the components of the metabolic syndrome. [Diabetologia (2001) 44: 1148–1154]

Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect.

Maturity-onset diabetes of the young (MODY) type 3 is a dominantly inherited form of diabetes, which is often misdiagnosed as non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM). Phenotypic analysis of members from four large Finnish MODY3 kindreds (linked to chromosome 12q with a maximum lod score of 15) revealed a severe impairment in insulin secretion, which was present also in those normoglycemic family members who had inherited the MODY3 gene. In contrast to patients with NIDDM, MODY3 patients did not show any features of the insulin resistance syndrome. They could be discriminated from patients with IDDM by lack of glutamic acid decarboxylase antibodies (GAD-Ab). Taken together with our recent findings of linkage between this region on chromosome 12 and an insulin-deficient form of NIDDM (NIDDM2), the data suggest that mutations at the MODY3/NIDDM2 gene(s) result in a reduced insulin secretory response, that subsequently progresses to diabetes and underlines the importance of subphenotypic classification in studies of diabetes.

Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes.

To study the effect of rigorous inslulin on serum llpoproteins in patients with noninsulin-dependent diabetes not controlled with oral only, we measured serum llpoproteins, apoproteins, lipolytic enzymes, and glucose disposal using anf insulin clamp technique before and after 4 weeks of insulin therapy. Lipoproteins were isolated by ultracentrifugation and high density llpoprotein (HDL) subfractions, by rate-zonal density graddient ultracetrifugation. The group included 11 subfractions, by rate-zonal density gradient ultracentrifugation. The group included 11 women and eight men (age 58 ± 1 years adn RBW 125 ± 4%). Body weight, glycosylated hemoglobin, mean dlurnal glucose, plasma free insulin, and glucose uptake (M-value) were 75 vs. 76 kg; 11.9 vs. 8.9%; 234 vs. 124 mg/di; 123 vs. 27 μU/ml; and 5.0 ± 0.4 vs. 7.1 ± 0.6 mg/kg/min before and after insulin therapy, respectively. After Insulin therapy there was decrease of very low density lipoprotein (VLDL) triglyceride (−60%, p < 0.001) but an increase of HDL2 cholesterol (+21%, p < 0.001); HDL2 phosphollpids (+38%, p < 0.001); HDL2 proteins (+23% p < 0.01); and HDL2 mass (127 ± 11 vs. 158 ± 12 mg/dl, p < 0.001). There was a decrease of HDL3 cholesterol (−13%, p < 0.05); HDL3 phosphollpids (+38%, p < 0.001); HDL2 proteins (+23%, p < 0.01); and HDL2 mass (127 ± 11 vs. 158 ± 12 mg/dl, p < 0.001). There was a decrease of HDL3 cholesterol (−13%, p < 0.025<; HDL3 phospholipids (−16%, p < 0.05); HDL3 proteins (−18%, p < 0.001); and HDL3 mass (179 ± 6 vs. 146 ± 6, p < 0.01). Zonel profiles showed a redisttribution of particles from HDL3 to HDL2. Serum apo A-l increased (p < 0.05), apo A-ll remained constant, but apo B decreased (−29%, p < 0.001). The most marked change during insulin therapy was a 2.3-fold increase in adlpose tissue fllploprotein llpase (LPL) activity (p < 0.001). The changes of VLDL and HDL subfractions were not explained by respective changes of the blood glucose, free insulin, or M-value. The data indicate that intensive insulin therapy induces antiatherogenic changes in serum lipids and lipoproteins and suggest that the induction of LPL by insulin is the major factor responsible for redistribution of HDL particles from HDL3 to HDL2

Smoking cessation improves insulin sensitivity in healthy middle‐aged men

Cigarette smokers have recently been shown to exhibit insulin resistance, dyslipidaemia and markers of the insulin resistance syndrome (IRS). The aim of this study was to examine the effects of smoking cessation on insulin sensitivity and IRS. Forty male, non‐obese healthy smokers participated in this open parallel study with 8 weeks of follow‐up. Seventeen subjects were able to stop smoking, while 23 subjects continued to smoke and served as a controls group. Anthropometric and metabolic data were measured. Degree of insulin sensitivity was determined with the euglycaemic hyperinsulinaemic clamp technique. Smoking cessation increased insulin sensitivity and improved the lipoprotein profile in spite of a modest increase in body weight. Initial smoking habits correlated positively with the increase in BMI as well as the improvements in the metabolic variables after smoking cessation. These data support the view that smoking causes insulin resistance and IRS, and also demonstrate that the beneficial metabolic effects of smoking cessation override the effects of an accompanying modest increase in body weight.

What does postprandial hyperglycaemia mean

Aims  The potential importance of postprandial glucose (PPG) control in the development of complications in Type 2 diabetes is much debated. The recent American Diabetes Association (ADA) consensus statement discussed the role of postprandial hyperglycaemia in the pathogenesis of diabetic complications and concluded that the relationship between PPG excursions and the well‐established risk factors for cardiovascular disease (CVD) should be further examined. Using the ADA statement as a starting point and including the more recent American College of Endocrinology guidelines on glycaemic control, a panel of experts in diabetes met to review the role of PPG within the context of the overall metabolic syndrome, in the development of complications in Type 2 diabetes.