Aryl hydrocarbon receptor interacting protein mutations seem not to associate with familial non-medullary thyroid cancer.

BACKGROUND: Over 95% of all thyroid malignancies are non-medullary thyroid carcinomas (NMTC). Familial NMTC are more aggressive and mortality is higher as compared with sporadic carcinomas. Known genetic factors do not explain all familial NMTC. Recently, thyroid disorders have been observed in families with germline mutations in aryl hydrocarbon receptor interacting protein (AIP) but, due to frequent occurrence of these conditions in the population, the significance of this co-occurrence is not clear. AIM, SUBJECTS AND METHODS: To examine whether AIP is involved in familial NMTC, we performed AIP mutation screening in 93 familial NMTC cases. In addition, the AIP status was studied in one follicular thyroid adenoma patient with a known AIP mutation from an additional cohort. RESULTS: No potentially pathogenic changes were identified, but two likely rare polymorphisms were detected. AIP mutation-positive patient's follicular thyroid adenoma showed no loss of heterozygosity or lack of immunohistochemical AIP staining. CONCLUSION: Our study indicates that germline AIP mutations are rare or do not exist in familial NMTC.

Mutation analysis of MEN1, HRPT2, CASR, CDKN1B, and AIP genes in primary hyperparathyroidism patients with features of genetic predisposition.

OBJECTIVE: Primary hyperparathyroidism (PHPT), a common endocrine condition, is usually caused by sporadically occurring parathyroid adenoma. A subset of patients carry germline mutations in genes such as MEN1 (multiple endocrine neoplasia type 1), HRPT2 (hyperparathyroidism 2), and CASR (calcium-sensing receptor) predisposing to syndromic forms of PHPT or familial isolated hyperparathyroidism (FIHP). Recently, germline mutations in two novel genes AIP (aryl hydrocarbon receptor-interacting protein) and CDKN1B (cyclin-dependent kinase inhibitor 1B) have been found to be associated with endocrine tumors. The purpose of this study was to evaluate the role of MEN1, HRPT2, CASR, AIP, and CDKN1B genes in PHPT patients with clinical features suggestive of genetic predisposition. PATIENTS AND DESIGN: Medical records of patients treated for PHPT from 1974 to 2001 at Oulu University Hospital were reviewed. Patients with multiglandular or recurrent/persistent disease, other MEN1- related manifestations, aged 40 yr or younger at onset or with a family history of PHPT/MEN1-related tumor were invited to the study. Twenty patients with previously diagnosed MEN1 were excluded. Participants were interviewed and blood samples obtained for biochemical screening and mutation analysis of MEN1, HRPT2, CASR, AIP, and CDKN1B. RESULTS: Of the 56 invited patients, 29 took part in the study. One patient was found to carry the c. 1356_1367del12 MEN1 founder mutation. Mutations in other genes were not detected. CONCLUSIONS: Apart from MEN1, mutations in other genes predisposing to PHPT seem to be rare or non-existing in Northern Finnish PHPT patients. No evidence was found for a role of AIP or CDKN1B in PHPT predisposition.

Effects of controlled hypoglycaemia on cardiac repolarisation in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Nocturnal hypoglycaemia may contribute to sudden death in diabetic patients. However, it is not well known why hypoglycaemia makes these patients prone to death. METHODS: We assessed the effects of controlled hypoglycaemia on cardiac repolarisation using novel electrocardiographic descriptors of T-wave and QRS complex morphology in 16 type 1 diabetic patients and eight healthy counterparts. Several electrocardiographic variables characterising repolarisation were analysed from digitised 12-lead electrocardiograms during a euglycaemic and a hypoglycaemic clamp. RESULTS: Hypoglycaemia did not result in significant changes either in the QT interval corrected for heart rate by the nomogram method or in QT dispersion. However, the morphology of the T-wave changed significantly during hypoglycaemia. The T-wave amplitude and area in precordial leads decreased significantly in both groups (p<0.05 to p<0.001). The spatial QRS-T angle (total cosine R to T) (p<0.05) and the height and the width of the T-wave loop (p<0.05 and p<0.01, respectively) were also reduced in the diabetic patients. The changes in the repolarisation parameters did not exhibit any significant association with changes in catecholamine levels or in heart rate variability in either group. CONCLUSIONS/INTERPRETATION: Hypoglycaemia results in distinct alterations in cardiac repolarisation, which may increase the vulnerability to arrhythmic events.

Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation.

OBJECTIVE: The existence of genotype-phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations. DESIGN AND METHODS: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982-2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1. RESULTS: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27-8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29-9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31-35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73-131.9, P = 0.014). CONCLUSIONS: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.

Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population.

BACKGROUND: Large-scale mitochondrial DNA (mtDNA) deletions are associated with clinical conditions such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia in adults and Pearson syndrome in children. Reported case series have suggested that deletions are not uncommon in the population, but their prevalence has not been documented. METHODS: The authors ascertained patients with clinical features associated with mtDNA deletions in a defined adult population in northern Finland. Buccal epithelial samples were requested from each patient fulfilling the selection criteria, and full-length mtDNA was amplified using the long PCR method. Deletion breakpoints were identified using sequencing. Patients with deletions were examined clinically. RESULTS: The authors identified four patients with single large-scale mtDNA deletions. The prevalence of deletions was calculated to be 1.6/100,000 in the adult population in the province of Northern Ostrobothnia (0.0 to 3.2; 95% CI). Analysis of incident cases from a neighboring province revealed two patients with deletions and yielded a similar population frequency. CONCLUSIONS: The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.

Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.

Estimation of mortality and the natural course of a disease is usually based on information of carefully studied individuals with or at risk for a specific disease. Genealogical information has rarely been accurate enough for such studies. With the help of church records and multiple endocrine neoplasia type 1 (MEN1) family information of the two founder MEN1 mutations in Northern Finland (1466del12 and 1657insC), we could trace back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and find 67 probable gene carriers born between 1728 and 1929, which were identified among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age (+/- sd) of death of affected males (n = 16) was 61.1 +/- 12.0 yr vs. 65.8 +/- 15.3 yr for unaffected males (n = 16) and for affected females (n = 16) was 67.2 +/- 10.7 yr vs. 67.7 +/- 14.7 yr for unaffected females (n = 13). The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex-matched life expectancy estimates derived from Finnish national statistics. Causes of death differed significantly between female probands and spouses. In conclusion, obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 yr.

Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes.

OBJECTIVE: To assess whether there are any differences in genetic, autoimmune, or clinical features between type 1 diabetes presenting in childhood and that diagnosed later. RESEARCH DESIGN AND METHODS: We studied 352 individuals (252 children and adolescents <20 years of age and 100 adults > or =20 years of age) manifesting clinical signs of type 1 diabetes over a period of 7.5 years at a university hospital in northern Finland with a primary catchment area population of approximately 300,000. The patients were analyzed for susceptible and protective HLA-DQB1 alleles (*02, *0302, *0301, *0602, *0603, and *0604), islet cell antibodies (ICA), insulin autoantibodies, and antibodies to GAD and IA-2 (IA-2A). Their clinical symptoms and signs were recorded at diagnosis. RESULTS: The adult patients carried the high-risk DQB1*02/0302 genotype less frequently than the children and more often had protective genotypes. They also had a decreased frequency of all 4 single autoantibody specificities and of multiple (> or =3) autoantibodies. The proportion of patients testing negative for all autoantibodies was lower among the children than among the adults. IA-2A were associated with the DQB1*0302/x genotype in both the children and adults, and the same held true for ICA among the adults. The adults were characterized by a higher proportion of males, a longer duration of symptoms, and a lower frequency of infections during the preceding 3 months. In addition, they had a higher relative body weight on admission and milder signs of metabolic decompensation (higher pH, base excess, and bicarbonate concentrations) and a lower glycated hemoglobin level at diagnosis than the children. CONCLUSIONS: Clinical manifestation of type 1 diabetes before the age of 20 years is associated with a strong HLA-defined genetic disease susceptibility, an intensive humoral immune response to various beta-cell antigens, a higher frequency of preceding infections, and a shorter duration of symptoms and more severe metabolic decompensation at diagnosis. Taken together, these observations suggest that the age at clinical onset of type 1 diabetes is determined by the intensity of the beta-cell-destructive process, which is modulated by both genetic and environmental factors.

Microcirculatory response of skin to benzoic acid and methyl nicotinate in patients with diabetes.

AIMS: In view of the relationship between microvascular pathology and organ complications in diabetes mellitus, the aim of the present study was to examine the microvascular response of upper arm skin to non-immunological contact irritants in 17 insulin-dependent diabetic patients and 11 non-diabetic controls. METHODS: Non-immunological contact urticaria, an inflammatory reaction mediated in a unique way, not previously studied in diabetic patients, was examined. The test agents were benzoic acid and methyl nicotinate. The intensity of the reactions was measured using laser-Doppler flowmetry and colorimetry. The patients were divided into two groups, depending on whether they had had diabetes for less or more than 10 years. RESULTS: There were no differences in the maximal blood flow responses between the groups, but the diabetic patients showed increased blood flow responses to the lowest irritant concentrations compared to the controls. The reactions in the two groups of diabetic patients were similar. CONCLUSIONS: The present study suggests that the microvascular reactivity of diabetic skin to non-immunological contact irritants is increased.

Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-related symptoms.

PURPOSE: To evaluate the prolonged release (PR) of the long-acting somatostatin analog lanreotide in patients with gastrointestinal neuroendocrine tumors and its effect on hormone-related symptomatology, tumor markers, tumor size, tolerability, and quality of life (QOL). PATIENTS AND METHODS: Eligible patients had the following substantial daily symptoms: for patients with carcinoid tumors, three or more stools and/or 1.5 or more flushing episodes; for patients with gastrinoma, greater than 50% elevated basic acid output; and for patients with vasoactive intestinal peptide-secreting tumors (VIPomas), four or more stools and/or a stool volume of >/= 800 mL, a measurable tumor, and an elevated biochemical tumor marker (>/= two times the upper limit of the normal reference range). Lanreotide PR was administered intramuscularly every 14 days at 30 mg for 6 months. We measured efficacy by studying symptoms, tumor markers, tumor size, and QOL. Side effects were scored according to the National Cancer Institute's toxicity grading system and ultrasound examination of the gallbladder. RESULTS: Fifty-five patients were included in the study (48 patients with carcinoid tumors, six patients with gastrinoma, and one patient with VIPoma). Symptomatic improvement (> 50% reduction) occurred in 38% of the assessable patients with carcinoid tumors, in 67% of the gastrinoma patients, and in the VIPoma patient. Tumor markers normalized in two of 45 assessable patients, 19 patients exhibited a reduction (> 50%), 19 patients exhibited no change, and tumor markers rose by more than 50% in five patients. Tumor size was reduced in two of 31 assessable patients and remained stable in 25 patients; four patients experienced progression. QOL assessments after 1 month showed improvements in emotional and cognitive function, and diminished fatigue, sleeping disorders, and diarrhea. Eight of 30 assessable patients developed gallstones. CONCLUSION: Lanreotide PR is a well-tolerated somatostatin analog with significant clinical, biochemical, and antitumor effects that bring about a significant improvement in QOL for patients with neuroendocrine tumors.

Delayed restoration of epidermal barrier function after suction blister injury in patients with diabetes mellitus.

AIMS: Diabetes mellitus is a risk factor for compromised wound healing. The present study examines the restoration of the epidermal barrier function using the suction blister wound model. METHODS: The healing process was evaluated over time by measuring water evaporation (WE) and blood flow (BF) in the wound area. Seventeen Type 1 diabetic males and 11 non-diabetic control males were studied. RESULTS: At the onset, the WE of diabetic patients was 116 +/- 11 g x m(-2) x h(-1) and that of controls 95 +/- 13 g x m(-2) x h(-1) (P < 0.001). On the second day, the WE of diabetic patients was 90 +/- 21 g x m(-2) x h(-1) and that of controls 60 +/- 24 g x m(-2) x h(-1) (P < 0.02). The most profound difference was encountered during the fourth day, when the WE of diabetic patients was 40 +/- 17 g x m(-2) x h(-1) and that of controls 14 +/- 8 g x m(-2) x h(-1) (P < 0.001). The value recorded on the fourth day was 37% of the onset value in diabetic patients and 16% in controls (P < 0.001). Eight days after wounding the values were close to that of normal skin in both diabetic and control subjects. At the onset, the BF was 93 +/- 20 (arbitrary units) in diabetic men and 112 +/- 18 in controls (P = 0.02). On the second, fourth and eighth day there was no significant differences. CONCLUSIONS: The results suggest that restoration of the epidermal barrier function is delayed in the patients with diabetes. There were also a trend toward an initially weaker inflammatory response.

Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults.

OBJECTIVE: To study the effects of GH treatment for up to 42 months on bone mineral density (BMD) and bone turnover. DESIGN AND METHODS: BMD with dual energy X-ray absorptiometry, serum type I procollagen carboxy-terminal propeptide (PICP), serum type I collagen carboxy-terminal telopeptide (ICTP) and serum IGF-I were assessed in 71 adults with GH deficiency. There were 44 men and 27 women, aged 20 to 59 (median 43) years. Thirty-two patients completed 36 months and 20 patients 42 months of treatment. RESULTS: The BMD increased for up to 30-36 months and plateaued thereafter. In the whole study group, the maximum increase of BMD was 5.0% in the lumbar spine (P<0. 001), 5.9% (P<0.01) in the femoral neck, 4.9% (NS, P>0.05) in the Ward's triangle and 8.2% (P<0.001) in the trochanter area. The serum concentrations of PICP (202.6+/-11.5 vs 116.3+/-5.4 microg/l; mean+/-s.e.m.) and ICTP (10.5+/-0.6 vs 4.4+/-0.3 microg/l) doubled (P<0.001) during the first 6 months of GH treatment but returned to baseline by the end of the study (130.0+/-10.4 and 5.6+/-0.7 microg/l respectively), despite constantly elevated serum IGF-I levels (39. 6+/-4.1 nmol/l at 42 months vs 11.9+/-0.9 nmol/l at baseline; P<0.001). The responses to GH treatment of serum IGF-I, PICP, ICTP (P<0.001 for all; ANOVA) and of the BMD in the lumbar spine (P<0.05), in the femoral neck and the trochanter (P<0.001 for both) were more marked in men than in women. At the end of the study the BMD had increased at the four measurement sites by 5.7-10.6% (P<0.01-0.001) in patients with at least osteopenia at baseline and by 0.1-5.3% (NS P<0.05) in those with normal bone status (P<0.001 for differences between groups; ANOVA). Among patients who completed 36-42 months of treatment, the number of those with at least osteopenia was reduced to more than a half. The response of BMD to GH treatment was more marked in young than in old patients at three measurement sites (P<0. 05-<0.001; ANOVA). In the multiple regression analysis the gender and the pretreatment bone mass appeared to be independent predictors of three measurement sites, whereas the age independently determined only the vertebral BMD. CONCLUSIONS: GH treatment in GH-deficient adults increased BMD for up to 30-36 months, with a plateau thereafter. Concurrently with the plateau in BMD the bone turnover rate normalized. From the skeletal point of view GH-deficient patients exhibiting osteopenia or osteoporosis should be considered as candidates for GH supplementation of at least 3-4 years.

Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population.

Mitochondrial diseases are characterized by considerable clinical variability and are most often caused by mutations in mtDNA. Because of the phenotypic variability, epidemiological studies of the frequency of these disorders have been difficult to perform. We studied the prevalence of the mtDNA mutation at nucleotide 3243 in an adult population of 245,201 individuals. This mutation is the most common molecular etiology of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), one of the clinical entities among the mitochondrial disorders. Patients with diabetes mellitus, sensorineural hearing impairment, epilepsy, occipital brain infarct, ophthalmoplegia, cerebral white-matter disease, basal-ganglia calcifications, hypertrophic cardiomyopathy, or ataxia were ascertained on the basis of defined clinical criteria and family-history data. A total of 615 patients were identified, and 480 samples were examined for the mutation. The mutation was found in 11 pedigrees, and its frequency was calculated to be >=16. 3/100,000 in the adult population (95% confidence interval 11.3-21. 4/100,000). The mutation had arisen in the population at least nine times, as determined by mtDNA haplotyping. Clinical evaluation of the probands revealed a syndrome that most frequently consisted of hearing impairment, cognitive decline, and short stature. The high prevalence of the common MELAS mutation in the adult population suggests that mitochondrial disorders constitute one of the largest diagnostic categories of neurogenetic diseases.

Improved metabolic control in patients with non-insulin-dependent diabetes mellitus is associated with a slower accumulation of glycation products in collagen.

Twenty-one patients with non-insulin-dependent diabetes in poor metabolic control were subjected to intensified therapy, in most cases with insulin, to investigate whether it is possible to slow down the accumulation of advanced glycosylation end products of collagen by improving glycaemic control. Fasting and mean daily blood glucose, serum fructosamine and glycohaemoglobin levels, as well as glycation of collagen were measured before and after 1.5 years of intensified therapy. All these parameters except for fructosamine correlated significantly with fasting blood glucose and glycohaemoglobin when measured before the insulin therapy was started, when the patients had had poor but stable metabolic control for a long period of time. After 1.5 years of intensified therapy the level of glycation of collagen did not significantly correlate with the fasting blood glucose or glycohaemoglobin levels, suggesting that the non-enzymatic glycosylation of collagen reflects a longer period of metabolic control of diabetes than the glycohaemoglobin level. Intensified treatment improved previously poor metabolic control in patients with non-insulin-dependent diabetes, and this improvement was reflected in a decrease in fasting and mean daily blood glucose levels, serum fructosamine and glycohaemoglobin concentrations, and in the level of early products of glycation of collagen. The average content of advanced glycosylation end products of collagen, assayed in terms of collagen-linked fluorescence did not decrease. However, they accumulated more slowly in the patient tercile with the greatest decrease in the level of fasting blood glucose than in the tercile with the smallest decrease, and even a decrease in fluorescence was observed in the patients with the greatest improvement in the metabolic control.(ABSTRACT TRUNCATED AT 250 WORDS)

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene associated with macroangiopathy and blood pressure in patients with non-insulin-dependent diabetes mellitus.

In the search for new risk factors for diabetic macroangiopathy the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene was studied in 237 consecutive patients (125 men and 112 women) with non-insulin-dependent diabetes. The female population showed an excess of ischemic electrocardiographic changes or definite myocardial infarctions in the patients homozygous for the deletion [D/D; odds ratio (OR) 2.8; 95% confidence interval (CI) 1.4-5.3] and in the insertion/deletion heterozygotes (I/D; OR 1.8; CI 1.1-3.1) compared with the patients homozygous for the insertion (I/I). In the total series coronary heart disease, cerebrovascular disease, and claudication were more often observed in the patients with I/D (OR 1.5; CI 1.0-2.2) or the D/D genotype patients (OR 1.7; CI 1.1-2.6) than in those with the genotype I/I. The systolic blood pressure was lower in patients with genotype I/I (138 +/- 19 mmHg) than in those with the genotype I/D (149 +/- 22 mmHg) or D/D (150 +/- 21 mmHg; P < 0.02). The prevalence of hypertension and the median urinary albumin excretion rate also tended to be lowest in the I/I genotype patients. Multiple logistic analysis revealed that in women the angiotensin-converting enzyme D/D genotype is independently associated with coronary heart disease. Our findings suggest that variation at the angiotensin-converting enzyme gene locus is one of the factors involved in the predisposition of diabetic patients to the development of arterial disease and hypertension.

DNA polymorphisms at the lipoprotein lipase gene are associated with macroangiopathy in type 2 (non-insulin-dependent) diabetes mellitus.

We studied the effect of variation at the lipoprotein lipase (LPL) gene locus on the susceptibility of individuals with Type 2 diabetes mellitus to atherosclerotic vascular disease in a population of 126 male and 114 female patients. The prevalence of any evidence of coronary heart disease (CHD) (presence of ischaemic ECG changes or definite myocardial infarction) was low in the patients who were homozygous for the presence of the PvuII restriction site (genotype 2-2) (40.9%) compared with those who were heterozygous (genotype 1-2) (57.9%; P = 0.05) or homozygous for the absence of it (genotype 1-1) (61.9%; P < 0.04). In men, a clear gene dosage effect on CHD was seen, the genotype 2-2 patients having the lowest (39.1%), the 1-2 patients an intermediate (49.3%) and the 1-1 patients the highest (61.1%) frequency of coronary disease. Patients with the genotype 2-2 of the HindIII polymorphism (absence of the restriction site) had the highest prevalence of any evidence of CHD (90.0%) compared with the genotype 1-2 (heterozygotes for the presence of the restriction site) (55.4%) or 1-1 (presence of the restriction site) (54.6%; P < 0.03). Stepwise discriminant analysis revealed that in the whole diabetic population the PvuII genotype of the LPL gene was independently and significantly associated with CHD but its effect decreased when the plasma lipids were taken into account. Overall, this study demonstrates the role of the PvuII polymorphism in the LPL gene to modulate the risk for diabetic macroangiopathy in patients with Type 2 diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA polymorphisms at the locus for human cholesteryl ester transfer protein (CETP) are associated with macro- and microangiopathy in non-insulin-dependent diabetes mellitus.

The effect of variation at the cholesteryl ester transfer protein (CETP) gene locus and in the apolipoprotein (apo) AI-CIII-AIV gene cluster on the susceptibility of individuals with non-insulin-dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 136 male and 122 female patients with NIDDM. The prevalence of myocardial infarction was high (38%) in patients with the EcoNI genotype 2-2 of the CETP gene locus (= 2-2; subjects homozygous for the absence of the restriction site) compared with patients with the genotype 1-1 (= 1-1; subjects homozygous for the presence of the restriction site) (18%, p < 0.02). The prevalence of any evidence of coronary heart disease (CHD) (presence of ischaemic ECG changes or definite myocardial infarction) was high in 2-2 (73%) compared with the genotype 1-2 (= 1-2; heterozygous for the presence of the restriction site) (52%, p < 0.02) and genotype 1-1 (p = 0.06). CHD was more prevalent in men with 2-2 (70%) than in those with 1-1 (42%, p < 0.05), but in women no significant differences were found in the prevalences of CHD between the EcoNI genotypes. Neuropathy was more often present in the patients with 2-2 (31%) than in those with 1-1 (12%, p < 0.02) or 1-2 (14%, p < 0.01). Plasma total cholesterol and total- and VLDL-triglycerides were higher in women with the EcoNI genotype 1-1 than in those with the genotype 1-2. In men no significant differences in plasma lipids were found. In addition, the prevalence of cerebrovascular disease was high (21%) in the patients with the genotype 1-1 of the TaqIB polymorphism compared with the genotype 2-2 (6%, p < 0.02). None of the alleles defined by four polymorphisms in the apo AI-CIII-AIV gene region were associated with an increased risk for macroangiopathy. The PstI polymorphism had an effect on plasma triglyceride levels. At the CETP locus one pair of loci (TaqIB and EcoNI) and three pairs of loci at the apo AI-CIII-AIV gene cluster (SacI and MspI, SacI and PvuII and MspI and PvuII) showed significant allelic association. In conclusion, the variation of CETP locus modulates the risk for diabetic complications in patients with NIDDM and the effect seems to be different between men and women. In contrast, the AI-CIII-AIV gene cluster polymorphisms seem not to be related to the risk of CHD in NIDDM.(ABSTRACT TRUNCATED AT 400 WORDS)

Apolipoprotein B gene DNA polymorphisms are associated with macro- and microangiopathy in non-insulin-dependent diabetes mellitus.

The relationship between diabetic macroangiopathy or microangiopathy and apolipoprotein B (apoB) polymorphism was studied in 139 male and 129 female patients with non-insulin-dependent diabetes (NIDDM) mellitus, comprising consecutive patients with poor diabetic control (HBA1 13.2% +/- 2.7 (SD)) referred to our hospital. Plasma cholesterol and triglyceride concentrations were higher in the patients who were homozygous for the X2 allele (presence of XbaI cleavage site). Patients with the X1 allele (absence of XbaI cleavage site) tended to have a higher frequency of macroangiopathy, although the differences were not statistically significant. There was no difference in the prevalence of microangiopathy between the groups. In subjects with only an R1 allele (= R+; homozygous for the presence of EcoRI cleavage site) the prevalence of coronary heart disease (CHD) was observed to be high (61.9%) as compared to the subjects possessing an R2 allele (= R-; homozygous or heterozygous for the absence of the EcoRI cleavage site) (46.7%; p < 0.02). When the polymorphisms XbaI (subjects homozygous for the absence of the cutting site = X+; subjects homozygous or heterozygous for the presence of the cutting site = X-) and EcoRI were combined, the prevalence of macroangiopathy was observed to be high in X+R+ (80.0%) as compared with X+R- (44.2%), X-R+ (56.8%) and X-R- (50.0%) (p < 0.03). The prevalence of macroangiopathy tended to be particularly high in patients with the apoprotein E4 allele (phenotype E4/4 or E4/3), combined with either X+ or R+.(ABSTRACT TRUNCATED AT 250 WORDS)

Pregnancy is not a risk factor for a deterioration of autonomic nervous function in diabetic women.

Pregnancy may have an untoward effect on diabetic retinopathy and nephropathy and symptoms of autonomic neuropathy may also be exacerbated during pregnancy. To test the hypothesis that previous pregnancies during the diabetic state are associated with increased risk of development of autonomic dysfunction, autonomic nervous function and pregnancy history were assessed in 117 women with long-standing Type 1 diabetes mellitus. Thirty-eight women (32%) had autonomic dysfunction, defined as at least one abnormal cardiovascular test. The presence of autonomic dysfunction was not related to the number of pregnancies during the disease state. Thus, this cross-sectional study suggests that pregnancies do not represent a risk factor for a deterioration of autonomic nervous function and development of autonomic neuropathy in diabetic women.