Structural and functional findings in patients with moderate diabetic retinopathy.

PURPOSE: To evaluate structural and functional ocular changes in patients with type 2 diabetes mellitus (DM2) and moderate diabetic retinopathy (DR) without apparent diabetic macular edema (DME) assessed by optical coherence tomography (OCT) and microperimetry. METHODS: This was a single-center cross-sectional descriptive study for which 75 healthy controls and 48 DM2 patients with moderate DR were included after applying exclusion criteria (one eye per patient was included). All eyes underwent a complete ophthalmic examination (axial length, macular imaging with swept-source OCT, and MAIA microperimetry). Macular thicknesses, ganglion cell complex (GCC) thicknesses, and central retinal sensitivity were compared between groups, and the relationships between the OCT and microperimetry parameters were evaluated. RESULTS: Macular thickness was similar in both groups (242.17 ± 35.0 in the DM2 group vs 260.64 ± 73.9 in the control group). There was a diminution in the parafoveal area thickness in the DM2 group in the GCC complex. Retinal sensitivity was reduced in all sectors in the DM2 group. The central global value was 24.01 ± 5.7 in the DM2 group and 27.31 ± 2.7 in the control group (p < 0.001). Macular integrity was 80.89 ± 26.4 vs 64.70 ± 28.3 (p < 0.001) and total mean threshold was 23.90 ± 4.9 vs 26.48 ± 2.6 (p < 0.001) in the DM2 and control group, respectively. Moderate correlations were detected between the central sector of MAIA microperimetry and retina total central thickness (- 0.347; p = 0.0035). Age, visual acuity, and hemoglobin A1c levels also correlated with retinal sensitivity. CONCLUSION: Macular GCC thickness and central retinal sensitivity were reduced in patients with moderate DR without DME, suggesting the presence of macular neurodegeneration.

Gene expression profile following an oral unsaturated fat load in abdominal obese subjects.

PURPOSE: Our aim was to evaluate the postprandial effect of an oral fat load test (OFLT) rich in unsaturated fatty acids on gene expression profile in peripheral blood mononuclear cells (PBMC) from subjects with abdominal obesity as an insulin resistance model and controls. METHODS: A total of 20 controls and 20 abdominal obese patients were studied. Metabolic parameters and oxidative stress markers were measured with standardized protocols. The whole gene expression at fasting state and after the OFLT (0, 4 and 8 h) was analysed using human HT-12-v4 expression beadchips, from Illumina. RESULTS: We found a significant decrease in plasma glucose, insulin and oxidative stress markers in abdominal obese patients and controls. We found beneficial metabolic postprandial gene expression in three genes: FKBP5, DDIT4 and DHRS9. Following an OFLT, the postprandial mRNA expression of FKBP5, and DDIT4 was downregulated while that of DHRS9 was overexpressed, both in nondiabetic normolipidemic subjects and in insulin-resistant subjects with abdominal obesity. CONCLUSIONS: Our results suggest that an OFLT rich in unsaturated fatty acids downregulates the expression of FKBP5, coding for the glucocorticoid receptor pathway, and that of DDIT4, involved in the oxidative stress response. These changes could favourably influence the insulin resistance and oxidative stress status in the postprandial state.

Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice.

Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care.

Establishing cut-off values for apolipoprotein B and non-HDL-C according to LDL-C values in a South European population.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) remains the primary target of therapy in most strategies of dyslipidaemia management focused on cardiovascular disease prevention. Different guidelines have identified specific LDL-C cut-off points as targets for therapeutic intervention. Many clinical situations characterised by dyslipidaemia and elevated triglycerides are common in our environment and in overall industrialised countries. Thus, lipid goals based only on LDL-C could misclassify an important percentage of subjects. The objective of the present study was to establish cut-off point values for apoB and non-HDL-C in relation to the identified LDL-C cut-off points for cardiovascular risk in a South European population. METHODS: We performed a cross-sectional study including 1501 subjects (770 women and 731 men) between 18 and 80 years of age. Samples were collected after 12-14 h of fasting. Cholesterol, HDL-C, triglycerides and apoB levels were measured using direct methods. LDL-C was calculated by the Friedewald formula. Non-HDL-C was calculated as total cholesterol minus HDL-C. RESULTS: The Spearman's rank correlations between apoB and LDL-C (r 0.86, p < 0.0001), and between apoB and non-HDL-C (r 0.91, p < 0.0001) were both significant. The proposed cut-off points for apoB, according to LDL-C goals (70, 100, 130 and 160 mg/dl) in our population are 70, 80, 100 and 115 mg/dl respectively. The proposed cut-off values for non-HDL-C are 100, 120, 150 and 190 mg/dl respectively. CONCLUSION: The established LDL-C cut-off values could not be accurate to estimate cardiovascular risk in subjects with mild hypertriglyceridaemia, as frequently occurs in our Mediterranean population. To take into consideration the burden of atherogenic particles and better classify patients at risk we propose cut-off values for apoB or the equivalent for non-HDL-C. Prospective trials including cardiovascular variables are needed to validate our assumption.

Circulating mononuclear cells nuclear factor-kappa B activity, plasma xanthine oxidase, and low grade inflammatory markers in adult patients with familial hypercholesterolaemia.

BACKGROUND: Few data are available on circulating mononuclear cells nuclear factor-kappa B (NF-kB) activity and plasma xanthine oxidase (XO) activity in heterozygous familial hypercholesterolaemia (FH). The goal of the study was to analyse circulating mononuclear cells NF-kB and plasma XO activities in FH patients. MATERIALS AND METHODS: Thirty FH index patients and 30 normoglycaemic normocholesterolaemic controls matched by age, gender, body mass index, abdominal circumference and homeostasis model assessment index were studied. Plasma XO and inflammatory markers were measured by standard methods. NF-kB was assayed in circulating mononuclear cells. RESULTS: Familial hypercholesterolaemia patients showed a significantly higher NF-kB (75.0 +/- 20.7 vs. 42.7 +/- 16.8 relative luminiscence units) and XO (0.44 +/- 0.13 vs. 0.32 +/- 0.09 mU mL(-1)) activities than controls. In addition, interleukin-1, interleukin-6, high sensitivity C reactive protein (hsCRP) and oxidized LDL (LDL-ox) were also significantly higher in FH patients. In the total group (FH and controls), XO was significantly associated with LDL-cholesterol (LDL-C), apolipoprotein B (apoB), NF-kB and hsCPR, and NF-kB activity was significantly associated with XO, hsCPR, LDL-ox, LDL-C and apoB plasma values. Using multiple regression analysis, XO was independently associated with hsCPR and NF-kB, and NF-kB activity in circulating mononuclear cells was independently associated with apoB and LDL-ox plasma values. CONCLUSION: Familial hypercholesterolaemia patients show increased activities of NF-kB and XO, and higher values of low grade inflammatory markers related to atherosclerosis. NF-kB activity was independently associated with apoB plasma values. These data could explain in part the high cardiovascular disease risk present in these patients.

Plasma homocysteine levels are associated with ulceration of the foot in patients with type 2 diabetes mellitus.

BACKGROUND: To examine the association of biochemical markers of risk (plasma Hcy, microalbuminuria, lipoprotein (a)(Lp(a)) and diabetic dyslipidaemia) with the prevalence of diabetic foot ulceration in type 2 diabetic patients. METHODS: Case/control study conducted in 198 type 2 diabetic patients. 89 patients have foot ulcers and 109 have no foot ulcers (control group), in order to establish ORs for diabetic foot ulceration. In all subjects plasma Hcy, Lp(a), total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein B, HbA(1c) and microalbuminuria were measured using standard procedures. RESULTS: Plasma Hcy, microalbuminuria, HbA(1c) and apolipoprotein B levels were significantly higher in patients with foot ulceration compared with the control group. Plasma lipids, Lp(a), vitamin B12 and folic acid values were similar in both groups. In the logistic regression model, plasma Hcy (OR 1.09; 95% CI 1.04-1.69), microalbuminuria (OR 1,01; 95% CI 1.01-1.17) and HbA(1c) levels (OR 1.33; 95% CI 1.04-1.69) were independent risk factors for the presence of diabetic foot ulceration. CONCLUSIONS: In our study, for each micromol increase in plasma Hcy levels there was a 10% increase in the risk of diabetic foot ulceration. In addition, plasma homocysteine, HbA(1c) and microalbuminuria accounted for 50% prevalence risk of diabetic foot ulceration. Further prospective studies should be conducted to confirm the association of plasma Hcy levels with the risk of foot ulceration.

Increased plasma xanthine oxidase activity is related to nuclear factor kappa beta activation and inflammatory markers in familial combined hyperlipidemia.

BACKGROUND AND AIMS: Xanthine oxidase (XO) has been described as one of the major enzymes producing free radicals in blood. Oxidative stress and inflammatory processes have been implicated in the pathogenesis of endothelial dysfunction and the progression of atherosclerosis but until now, there is little data about the influence of vascular prooxidant systems and inflammation in familial combined hyperlipidemia (FCH). Our goal was to evaluate whether XO activity was altered in FCH and if it was related to the inflammatory process represented by NFkB, IL-6 and hsCRP, and assessing the correlation between XO activity and insulin resistance (IR). METHOD AND RESULTS: 40 Non-related subjects with FCH and 30 control subjects were included, all of them non-diabetic, normotensive and non-smokers. We measured lipid profile, glucose, insulin, uric acid, XO activity, malondialdehyde (MDA), IL-6 and hsCRP in plasma and NFkB activity in circulating mononuclear cells. Patients with FCH showed significantly higher levels of uric acid, XO activity, MDA, NFkB activity, IL-6 and hsCRP than controls. XO activity was independently related to NFkB activity with an odds ratio of 4.082; to IL-6 with an odds ratio of 4.191; and to IR with an odds ratio of 3.830. Furthermore, mean NFkB activity, IL-6 levels, and IR were highest in the highest percentile of XO activity. CONCLUSIONS: Subjects with FCH showed increased XO and NFkB activities and low grade inflammatory markers related to atherosclerosis. XO activity was correlated with higher inflammatory activity and IR. These data could explain, in part, the high cardiovascular disease risk present in these patients.

LDL particle size and composition and incident cardiovascular disease in a South-European population: The Hortega-Liposcale Follow-up Study.

BACKGROUND: The association of low-density lipoprotein (LDL) particle composition with cardiovascular risk has not been explored before. The aim was to evaluate the relationship between baseline LDL particle size and composition (proportions of large, medium and small LDL particles over their sum expressed as small-LDL %, medium-LDL % and large-LDL %) and incident cardiovascular disease in a population-based study. METHODS: Direct measurement of LDL particles was performed using a two-dimensional NMR-technique (Liposcale®). LDL cholesterol was assessed using both standard photometrical methods and the Liposcale® technique in a representative sample of 1162 adult men and women from Spain. RESULTS: The geometric mean of total LDL particle concentration in the study sample was 827.2 mg/dL (95% CI 814.7, 839.8). During a mean follow-up of 12.4 ±â€¯3.3 years, a total of 159 events occurred. Medium LDL particles were positively associated with all cardiovascular disease, coronary heart disease (CHD) and stroke after adjustment for traditional risk factors and treatment. Regarding LDL particle composition, the multivariable adjusted hazard ratios for CHD for a 5% increase in medium and small LDL % by a corresponding decrease of large LDL % were 1.93 (1.55, 2.39) and 1.41 (1.14, 1.74), respectively. CONCLUSIONS: Medium LDL particles were associated with incident cardiovascular disease. LDL particles showed the strongest association with cardiovascular events when the particle composition, rather than the total concentration, was investigated. A change in baseline composition of LDL particles from large to medium and small LDL particles was associated with an increased cardiovascular risk, especially for CHD.

Absence of cardiovascular autonomic dysfunction and vagal pancreatic impairment in idiopathic achalasia of the oesophagus.

Extra-oesophageal autonomic dysfunction in idiopathic achalasia is not well documented, due to contradictory results reported. We aimed to study the cardiovascular and pancreatic autonomic function in patients with idiopathic achalasia. Thirty patients with idiopathic achalasia (16M/14F; 34.5 +/- 10.8 years) and 30 healthy volunteers (13M/17F; 34.8 +/- 10.7 years) were prospectively studied. Age >60 years and conditions affecting results of autonomic evaluation were excluded. Both groups underwent the sham feeding test and plasmatic levels of pancreatic polypeptide (PP) were determined by radioimmunoassay (basal, at 5, 10, 20 and 30 min). Cardiovascular parasympathetic (deep breathing, standing, Valsalva) and sympathetic function (postural decrease of systolic blood pressure, Handgrip test) were assessed. Statistical comparison of basal and increase levels of PP and parasympathetic/sympathetic cardiovascular parameters was performed between groups. Basal levels of PP were similar in controls and patients and maximum increase of PP during sham feeding test. A similar rate of abnormal cardiovascular tests was found between groups (P > 0.05). E/I ratio was the mostly impaired parameter (patients: 36.7% vs controls: 20%, P = 0.15, chi-squared test). Autonomic cardiovascular tests and pancreatic response to vagal stimulus are not impaired in patients with primary achalasia of the oesophagus.

Oesophageal motility disorders in type 1 diabetes mellitus and their relation to cardiovascular autonomic neuropathy.

The relationship between cardiovascular autonomic neuropathy (CVAN) and oesophageal dysfunction in diabetes mellitus has not been well established because reports are contradictory. The aim of this study was to assess oesophageal function and its correlation with CVAN in type 1 diabetic patients without oesophageal symptoms. Forty-six type 1 diabetic patients without oesophageal symptoms (DG) and 34 healthy volunteers (CG) were studied. Both groups underwent CVAN tests and oesophageal manometry and pH-metry. Differences between groups regarding results of cardiovascular autonomic tests and oesophageal studies were statistically analysed. Compared with the CG, the DG group showed insufficient lower oesophageal sphincter (LOS) relaxation and a higher percentage of simultaneous waves (P < 0.01). Patients with CVAN (n = 22) showed a higher prevalence of pathological simultaneous contractions (>10%), and the prevalence of simultaneous waves related to the degree of autonomic neuropathy was: 9% of patients without CVAN, 7% of those suspected to have it and 50% of patients with CVAN (P < 0.001). Factors associated with the presence of pathological simultaneous waves (>10%) were the presence of CVAN and duration of diabetes (P < 0.05, logistic regression analysis). Increase in simultaneous waves and impaired relaxation of LOS are more frequent in diabetic patients with CVAN.

[Intraocular lenses with blue light filter]. / Lentes intraoculares con filtros para luz azul.

PURPOSE: To evaluate if a SN60AT <> IOL (Alcon) with IMPRUV filter (Alcon) offers any advantage in patients having cataract surgery, as compared with Acrysof SA60 IOL (Alcon). METHODS: This was a prospective analytical study. We studied sixty-four eyes from 32 patients with cataracts. After a random assignment, phacoemulsification with the implant was performed using the Acrysof SN60AT tinted lens in one eye and Acrysof SA60 in the other. A variety of variables was subsequently assessed: contrast sensitivity with a CSV 1000E test, colour perception through a Farnsworth 25 test and subjective measures by a patient survey. Differences between the groups were assessed statistically. RESULTS: The contrast sensitivity results were obtained for 3, 6, 12 and 18 cycles per degree (cpd) frequencies under scotopic conditions, with better results obtained following the use of SN60AT: 0.75 (CSV 1000E test units) for 3 cpd, 0.86 for 6 cpd, 0.54 for 12 cpd and 0.35 for 18 cpd. The differences were statistically significant between the two groups for 3 cpd and 6 cpd. A total of 62.5% of patients using a tinted lens and 50% with SA60 achieved good results in the Farnsworth test; 12.5% and 21% had fair results and 25% and 28.1% respectively had poor results. CONCLUSIONS: We obtained an improvement in favour of the tinted lens for all frequencies, with this being statistically significant at lower frequencies (3 and 6 cpd). No significant differences in the Farnsworth test performance or in the patient survey were found. The tinting provided by the IMPRUV filter brings an increase in contrast sensitivity without affecting colour perception.

Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis.

Mutations underlying FH in Spain are largely unknown because only a few and limited surveys have been carried out on Spanish FH patients up to now. To gain information on this issue, we have analysed a group of 113 unrelated Spanish FH patients from an eastern area of Spain (Valencian Community). We have screened the LDLR gene by Southern blot and PCR-SSCP analysis to detect large rearrangements and small mutations, respectively. In addition, we have screened the Apo B gene for mutations known to cause FDB by PCR-SSCP analysis. We have identified a total of 47 different mutations in the LDLR gene (5 large rearrangements, and 42 small mutations, which were characterized by DNA sequencing), 19 of which have not been described in other populations (Valencia-1 to -4, 112insA, P160R, 790DelATGA, 920insTCAG, G642E, and the ten novel mutations E246A, 884delT, I289T, S305F, Q328X, Y354C, I603del, 2312-3C>A, V779M, and N804K). Three of these mutations (15%) were present in more than 1 proband, being mutation 112insA the most prevalent (frequency approximately 8%) in our sample. The Apo B gene R3500Q mutation was found in only one patient and no underlying defect was found in about 27% of patients. Our data support the notion that Spaniards represent a heterogeneous population with its own spectrum of LDLR gene mutations and that, in our population, FDB has a lower frequency or a milder expression than in central Europe countries.

Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.

The aims of this study were to examine the presence of mutations in the low-density lipoprotein receptor gene among subjects clinically diagnosed with familial hypercholesterolemia and to analyze whether the molecular diagnosis helps to predict the response to simvastatin treatment in our familial hypercholesterolemia population. Fifty-five probands and 128 related subjects with familial hypercholesterolemia were studied. Genetic diagnosis was carried out following a three-step protocol based on Southern blot and PCR-single strand conformational polymorphism analysis. A randomized clinical trial with simvastatin was conducted in 42 genetically diagnosed subjects with familial hypercholesterolemia classified as carriers of null mutations (n = 22) and of defective mutations (n = 20). A mutation-causing familial hypercholesterolemia was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which have not been previously described. The remaining five probands (11%) were carriers of large rearrangements. Familial hypercholesterolemia with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and low-density lipoprotein cholesterol levels in these subjects were significantly lower (24.8 +/- 10.3 vs. 34.8 +/- 10.9, P = 0.04 and 30.0 +/- 39.8 vs. 46.1 +/- 18.2, P = 0.02, respectively) than in subjects with defective mutations. Baseline and posttreatment high-density lipoprotein cholesterol plasma values were significantly lower in subjects with familial hypercholesterolemia with null mutations (P < 0.001). In an outbreed Caucasian population, a three-step protocol for genetic screening detected a mutation in the low-density lipoprotein receptor gene in a high percentage (84%) of subjects with familial hypercholesterolemia. Subjects with familial hypercholesterolemia with null mutations (class I) showed lower plasma high-density lipoprotein cholesterol values and a poor low-density lipoprotein cholesterol response to simvastatin treatment.

Influence of genetic variation at the apo A-I gene locus on lipid levels and response to diet in familial hypercholesterolemia.

We have examined the apo AI - 75 (G/A) and apo AI + 83(MspI +/-) polymorphisms at the APOA1 gene locus for associations with plasma lipid levels and response to an NCEP-I diet in 69 (44 women, 25 men) heterozygotes for familial hypercholesterolemia (FH). Subjects were studied at baseline (after consuming for one month a diet with 35%, fat, 10% saturated, and 300 mg/day cholesterol) and after 3 months of an NCEP-I diet. No gender-related differences for any of the lipid variables examined were found and the data were analyzed for men and women combined. For the apo AI - 75 (G/A) polymorphism, there were 51 G/G and 18 G/A subjects. At baseline, G/A subjects showed significantly lower total cholesterol (p = 0.0036), and LDL-C (p = 0.0023), and apo B (p = 0.0209), than G/G individuals, but no differences were found for HDL-C, triglycerides and VLDL-C values. Following the NCEP-I diet these genotype-related differences remained significant for total and LDL-C. The MspI (-) allele at the apo AI + 83 polymorphism was detected in the heterozygous state in five subjects and its presence was not associated with altered baseline lipids nor with dietary response to the NCEP-I diet. Our results suggest that FH subjects carrying the A allele at the apoAI - 75 (G/A) polymorphism have significantly lower total and LDL-C and apo B baseline levels but respond to a low-fat diet with similar reductions in total and LDL-C when compared with homozygotes for the G allele at this polymorphic site.

Effect of olive and sunflower oils on low density lipoprotein level, composition, size, oxidation and interaction with arterial proteoglycans.

The atherogenicity of low density lipoproteins (LDL) may be modulated by its serum levels, structure and affinity for components of the intima, all properties that can be altered by diet. Linoleic acid-rich diets (n-G, 18:2) reduce the levels of LDL whereas those rich in oleic (n-9,18:1) are considered 'neutral'. However, LDL enriched in linoleic acid have been reported to be more vulnerable to free radical-mediated oxidation than those enriched in oleic, a potentially atherogenic property. The effect of dietary fats on other properties of LDL that may also modulate atherogenesis, such as size and capacity to interact with intima components, are not well established. We explored here how a change from an olive oil-rich diet (OO) to a sunflower oil-rich one (SFO) affects these parameters in a community with a traditional Mediterranean diet. Eighteen free-living volunteers were placed for 3 weeks on a diet with 31% of caloric intake as sunflower oil and then shifted for an additional 3 weeks to a diet in which OO provided 30.5% of the calories. The LDL after SFO had a fatty acids ratio of (18:2 + 18:3 + 20:4) to (16:0 + 16:1 + 18:0 + 18:1) of 1.06 +/- 0.11 compared to 0.73 +/- 0.06 after the OO period. Serum LDL was significantly lower after SFO than after OO. Unexpectedly, copper-catalyzed oxidation of LDL from the SFO period was significantly less than that of the particles from the OO period. The resistance to oxidation of LDL of the SFO and OO period related to alterations in content of the antioxidants alpha-tocopherol, beta-carotene and retinol, in addition to changes in size and fatty acids composition. In vitro binding of LDL to human arterial proteoglycans was also significantly lower for the SFO-LDL than the OO-LDL, a result that can also be attributed to the larger size of the SFO-LDL. Therefore, three properties of LDL: circulating levels, oxidizability, and affinity with intima proteoglycans, that may modulate its atherogenicity, were shifted in a favorable direction by diets rich in linoleic acid and natural antioxidants.

Insulin resistance in patients with familial combined hyperlipidemia and coronary artery disease.

The minimum model modified by the administration of insulin provides an objective and relatively easily measured index of peripheral sensitivity to insulin which was significantly lower (p <0.02) in familial combined hyperlipidemia (FCH) with ischemic heart disease (IHD) than in FCH without IHD and in control subjects (1.2 +/- 0.6, 1.9 +/- 1.0, 2.9 +/- 1.2 x 10(-4) mU/L/ min, respectively). In patients with FCH, insulin resistance explains, at least in part, their metabolic alterations (hypertension, abnormal glucose tolerance, hyperinsulinemia) and elevated IHD.

Lipoprotein phenotype and insulin resistance in familial combined hyperlipidemia.

The study objective was to investigate the relationship of insulin resistance (IR) with the lipoprotein phenotype in familial combined hyperlipidemia (FCH). Thirty-seven FCH men diagnosed by clinical and biochemical criteria and classified as lipoprotein phenotype IIa (n = 9), IIb (n = 17), or IV (n = 11) were compared with a healthy control group of 30 men of similar age, body mass index (BMI), waist to hip ratio (WHR), and systolic and diastolic blood pressure. In all subjects, the plasma lipoprotein profile and baseline and post-oral glucose tolerance test (OGTT) glucose and insulin plasma values were measured. An intravenous glucose tolerance test was performed and IR was studied by the peripheral insulin sensitivity index (Si). After the OGTT, significantly higher values for insulinemia (at 0, 60, 90, and 120 minutes) and the area under the curve (AUC) of insulin secretion were observed in FCH. The AUC of insulin was greater in FCH subjects with the hypertriglyceridemic phenotype as compared with the controls and significantly lower Si levels, indicating greater IR, were found in the three FCH groups (control, 3.48 +/- 1.87 mU/L/min; FCH IIa, 2.09 +/- 1.08; FCH IIb, 1.54 +/- 0.77; FCH IV, 1.47 +/- 0.93; P < .001). The prevalence of IR (Si < 2 x 10(-4) mU/L/min) was greater in FCH, independent of the lipoprotein phenotype, as compared with the controls (P < .0001). Higher plasma glucose and insulin levels at 120 minutes and lower Si values were found in the FCH IIa group compared with the controls (P < .05), indicating a state of IR in this subgroup of normotriglyceridemic subjects. In conclusion, IR was found in the three FCH lipoprotein phenotypes, being more severe in subjects with hypertriglyceridemia. Hence, the therapeutic goals in FCH should include measures to normalize plasma lipids and improve peripheral insulin sensitivity.

Association between the TaqIB polymorphism in the cholesteryl ester transfer protein gene locus and plasma lipoprotein levels in familial hypercholesterolemia.

Cholesteryl ester transfer protein (CETP) facilitates the exchange of triglycerides (TG) and cholesteryl ester between lipoprotein particles. Subjects with familial hypercholesterolemia (FH) have been reported to have higher CETP activities, which could contribute to the lower high-density lipoprotein-cholesterol (HDL-C) levels and increased cardiovascular risk observed in some of these patients. Several polymorphisms have been reported in the CETP locus; the common TaqlB polymorphism is associated, in normolipidemic subjects, with decreased CETP activity and levels and with increased HDL-C levels. No data is available on the influence of this polymorphism in FH subjects. We have examined the TaqIB polymorphism in a group of 101 FH heterozygotes from Valencia, Spain. We have observed a frequency of 0.43 for the B2 allele, similar to those reported in the general population. Based on analysis of variance (ANOVA), we found significant associations between the presence of the B2 allele and increased plasma HDL-C (P <.04) and apolipoprotein A-I (apoA-I) levels (P <.01). An opposite association was observed for low-density lipoprotein-cholesterol (LDL-C) levels, with the B2/B2 subjects having lower levels than B1/B1 and B1/B2 subjects. The plasma apoB levels followed the same trend as those for LDL-C. In addition, the response to a National Cholesterol Education Program (NCEP)-I diet was studied in 77 of these subjects. The TaqlB polymorphism did not have a significant effect over the individual dietary response for any of the variables examined, as demonstrated by the lack of significant gene by diet interactions. In summary, the CETP TaqlB polymorphism is associated with a less atherogenic lipid profile, consisting of lower LDL-C, higher HDL-C levels, and a lower LDL-C/HDL-C ratio in heterozygous FH subjects. Moreover, the B2 allele was associated with a lower appearance of arcus cornealis, xanthomata, and clinical arteriosclerotic disease in these subjects.

A study of insulin resistance using the minimal model in nondiabetic familial combined hyperlipidemic patients.

The presence of insulin resistance in 20 male nondiabetic patients with familial combined hyperlipidemia (FCH) and 20 controls of similar age and body mass index (BMI) was investigated using the minimal model method modified by the administration of insulin and an oral glucose tolerance test. The peripheral sensitivity of insulin, expressed as the insulin sensitivity index (Si), was 1.91+/-1.05 and 2.86+/-1.19 x 10(-4) x min(-1) x mU/L in FCH patients and controls, respectively (P < .01), and the corresponding value for the peripheral utilization of glucose independently of insulin (Sg) was 1.70+/-1.13 in FCH patients and 2.35+/-0.60 x 10(-2) x min(-1) in controls (P < .02). In the FCH group, the Si value correlated significantly (P < .05) with the waist to hip ratio (WHR), plasma triglycerides (TG), free fatty acids (FFA), and the area under the curve of glucose (AUCg) and insulin (AUCi). In the control group, the correlation also reached statistical significance (P < .05) with age, BMI, WHR, blood pressure, TG, AUCg, and AUCi. Subgrouping the subjects with respect to central obesity defined as a WHR of 0.95 or greater, we observed lower Si values in obese and non-obese FCH subjects relative to controls (P < .02). The mean Si value in obese subjects was significantly lower than in non-obese FCH subgroups (1.40+/-0.79 v 2.68+/-0.95 x 10(-4) x min(-1) x mU/L, respectively, P < .01). In conclusion, a higher degree of insulin resistance relative to control values appears to be an integral part of the metabolic derangements observed in FCH, and central-trunk obesity exacerbates the insulin resistance syndrome.

Cardiovascular autonomic neuropathy in type 1 diabetic patients with and without peripheral neuropathy.

One hundred Type 1 diabetic patients (54 men, 46 women) mean age 28.9+/-8.4 years, were selected from among individuals referred to our hospital, with no previous diagnosis of diabetic chronic complications including diabetic neuropathy. After clinical and physical examinations, subjects were divided into two groups: with (n = 37) and without (n = 63) peripheral neuropathy. The percentage of subjects with cardiovascular autonomic neuropathy (AN), diagnosed by positive results to at least two of the five cardiovascular tests (Valsalva ratio, EI ratio, 30/15 ratio, blood-pressure response to standing up and handgrip test), was 40%: 72.9% in the group with peripheral neuropathy and 20.6% in the group without peripheral neuropathy (P < 0.0001). The prevalence of cardiovascular AN was related to the duration of the diabetes (P < 0.0001) and to HbA1c (P < 0.02). The presence of microalbuminuria and the existence of retinopathy were higher (P < 0.01 ) in group 1 (with peripheral neuropathy). Logistic regression analysis showed that only the presence of higher excretion of albumin is independently related to the presence of peripheral neuropathy. In conclusion, cardiovascular AN is frequent in Type 1 diabetes; furthermore, prevalence increases with the existence of peripheral neuropathy and with duration of the diabetes.