Reconstructive vascular surgery and the extent of tissue damage due to diabetic foot ulcers relates to risk of new ulceration in patients with PAD.

OBJECTIVE: There is limited information regarding new ulceration following the healing of ischaemic foot ulcers in diabetic patients. Our aim is to study new ulcerations in the same foot as the previous ulcer(s) in patients with diabetes and severe peripheral artery disease (PAD). METHOD: Patients with diabetes and severe PAD who healed from previous ulcer(s) (Wagner grade 1-5, at or below the ankle), were recruited for the prospective study from the time of healing of their ulcer. Patients were followed up regarding new ulceration, and their treatments and ulcer status noted either directly or on examination of medical records. RESULTS: We analysed the data on 602 patients with diabetes and severe PAD with healed foot ulcers, either primarily (n=443, 74%) or after minor amputation (n=159, 26%). Of these 51% (n=305) had revascularisation before healing from the previous ulcer, 34% (n=202) developed a new ulcer on the same foot within 15 months (range 0-106). Amputation was required by 22% (n=45) of patients, with a new ulcer on the same foot. The median survival time of all patients (n=602) was 54 months. By regression analysis, a low maximal Wagner grade for the previous ulcer and reconstructive vascular surgery was related to a decreased risk of developing new ulcers in the same foot. CONCLUSION: Patients with diabetes and ischaemic foot ulcers have a high-risk for developing new ulcers and amputation in the same foot after healing. The extent of tissue involvement in the previous ulcer and reconstructive vascular surgery affected the risk for development of new ulcers.

Less pronounced response to exercise in healthy relatives to type 2 diabetic subjects compared with controls.

Healthy first-degree relatives with heredity of type 2 diabetes (FH+) are known to have metabolic inflexibility compared with subjects without heredity for diabetes (FH-). In this study, we aimed to test the hypothesis that FH+ individuals have an impaired response to exercise compared with FH-. Sixteen FH+ and 19 FH- insulin-sensitive men similar in age, peak oxygen consumption (V̇o2 peak), and body mass index completed an exercise intervention with heart rate monitored during exercise for 7 mo. Before and after the exercise intervention, the participants underwent a physical examination and tests for glucose tolerance and exercise capacity, and muscle biopsies were taken for expression analysis. The participants attended, on average, 39 training sessions during the intervention and spent 18.8 MJ on exercise. V̇o2 peak/kg increased by 14%, and the participants lost 1.2 kg of weight and 3 cm waist circumference. Given that the FH+ group expended 61% more energy during the intervention, we used regression analysis to analyze the response in the FH+ and FH- groups separately. Exercise volume had a significant effect on V̇o2 peak, weight, and waist circumference in the FH- group, but not in the FH+ group. After exercise, expression of genes involved in metabolism, oxidative phosphorylation, and cellular respiration increased more in the FH- compared with the FH+ group. This suggests that healthy, insulin-sensitive FH+ and FH- participants with similar age, V̇o2 peak, and body mass index may respond differently to an exercise intervention. The FH+ background might limit muscle adaptation to exercise, which may contribute to the increased susceptibility to type 2 diabetes in FH+ individuals.

Early revascularization after admittance to a diabetic foot center affects the healing probability of ischemic foot ulcer in patients with diabetes.

OBJECTIVES: There is limited information about whether time from recognition of decreased perfusion to revascularization affects the probability of healing in a patient with a diabetic foot ulcer. The aim of the present study was to examine whether time to revascularization after referral to a multidisciplinary foot center was related to the outcome of foot ulcers in patients with diabetes and severe peripheral arterial disease (PAD). METHODS: Patients with diabetes, a foot ulcer, and a systolic toe pressure <45 mmHg or an ankle pressure <80 mmHg were prospectively included at the foot center, and considered for revascularization according to a preset protocol. All patients underwent invasive revascularization, either percutaneous transluminal angioplasty (PTA) or reconstructive vascular surgery. All patients had continuous follow-up until healing or death irrespective of the type of revascularization. RESULTS: A total of 478 patients were included (age 74 [range 66-80] years, 60% males), of whom 315 patients (66%) had PTA, and 163 (34%) had reconstructive surgery. Of the 478 patients, 217 (45%) healed primarily, 88 (19%) healed after a minor amputation, 76 (16%) healed after a major amputation and 92 patients (19%) died unhealed. The median time from inclusion in the study to revascularization was 8 weeks (3-18 weeks). Time to vascular intervention within 8 weeks (p < .001), maximum Wagner grade reached <3 (p < .001), absence of peripheral edema (p = .033), and presence of intermittent claudication (p = .001) were related to a higher probability of healing. CONCLUSIONS: Time to revascularization and extent of tissue damage were related to the probability of healing of ischemic foot ulcer in patients with diabetes over time. In the presence of a decreased perfusion in a patient with diabetes and a foot ulcer not only revascularization per se but also timing of revascularization is important for the possibility of healing without a major amputation.

Extensive changes in the transcriptional profile of human adipose tissue including genes involved in oxidative phosphorylation after a 6-month exercise intervention.

AIM: Adipose tissue has an important function in total energy homeostasis, and its dysregulation may contribute to lifestyle-related diseases such as type 2 diabetes, cancer and cardiovascular diseases. The aim of this study was to investigate genome-wide mRNA expression in adipose tissue in healthy men before and after an exercise intervention to identify genes or pathways that mediate the beneficial effect of regular exercise. We also investigated the difference in adipose tissue mRNA expression between individuals with or without a family history of type 2 diabetes. METHODS: The 6-month supervised exercise intervention was conducted in 47 healthy men (age 37.8 ± 4.3 years, BMI 28.5 ± 3.6 kg m(-2) ) with a previous low level of physical activity. RNA was analysed using GeneChip Human Gene 1.0 ST arrays (Affymetrix) before and after the exercise. RESULTS: We identified 2,560 significant transcripts differentially expressed before vs. after exercise with a false discovery rate (FDR) < 0.1%, including genes encoding the respiratory chain, histone subunits, small nucleolar RNAs and ribosomal proteins. Additionally, pathways enriched in response to exercise include the ribosome, oxidative phosphorylation, proteasome and many metabolic pathways, whereas the WNT and MAPK signalling pathways were down-regulated (FDR < 5%) after exercise. There were no significant differences in mRNA expression between individuals with or without a family history of type 2 diabetes. CONCLUSION: Exercise increased the expression of genes involved in oxidative phosphorylation, which is the opposite of what has been seen in adipose tissue from elderly or obese individuals with low physical fitness, and our study thereby demonstrates a mechanism for the beneficial effect of exercise.

Outcome of ischemic foot ulcer in diabetic patients who had no invasive vascular intervention.

OBJECTIVE/BACKGROUND: There is limited information regarding outcome in patients not available for revascularisation. Our aim was to identify factors related to ulcer healing in diabetic patients with severe peripheral arterial disease who were not available for revascularisation. METHODS: Diabetic patients with a foot ulcer, consecutively presenting at a multidisciplinary foot centre with systolic toe pressure <45 mmHg or an ankle pressure <80 mmHg were prospectively included. Patients who received revascularisation were excluded. All patients had continuous follow-up until healing or death. RESULTS: Out of 602 patients (median age: 76 years) included in this study, 50% healed either primarily (76%) or with a minor amputation (24%). Seventeen percent of patients healed after major amputation and 33% died unhealed. By regression analysis, rest pain, impaired renal function, ischemic heart disease, cerebral vascular disease, extent of tissue destruction, and ankle pressure >50 mmHg affected the outcome of the ulcers. CONCLUSION: Diabetic patients with ischemic foot ulcers not available for revascularisations are not excluded from healing without major amputation. Factors strongly related to outcome were co-morbidity, severity of peripheral arterial disease, and extent of tissue destruction. Our findings reinforce the need for a classification system considering these factors at decision-making for vascular intervention.

Telomere length in blood and skeletal muscle in relation to measures of glycaemia and insulinaemia.

AIMS: Skeletal muscle is a major metabolic organ and plays important roles in glucose metabolism, insulin sensitivity and insulin action. Muscle telomere length reflects the myocyte's exposure to harmful environmental factors. Leukocyte telomere length is considered a marker of muscle telomere length and is used in epidemiologic studies to assess associations with ageing-related diseases where muscle physiology is important. However, the extent to which leucocyte and muscle telomere length are correlated is unknown, as are their relative correlations with glucose and insulin concentrations. The purpose of this study was to determine the extent of these relationships. METHODS: Leucocyte and muscle telomere length were measured by quantitative real-time polymerase chain reaction in participants from the Malmö Exercise Intervention (n = 27) and the Prevalence, Prediction and Prevention of Diabetes-Botnia studies (n = 31). Participants in both studies were free from Type 2 diabetes. We assessed the association between leucocyte telomere length, muscle telomere length and metabolic traits using Spearmen correlations and multivariate linear regression. Bland-Altman analysis was used to assess agreement between leucocyte and muscle telomere length. RESULTS: In age-, study-, diabetes family history- and sex-adjusted models, leucocyte and muscle telomere length were positively correlated (r = 0.39, 95% CI 0.15-0.59). Leucocyte telomere length was inversely associated with 2-h glucose concentrations (r = -0.58, 95% CI -1.0 to -0.16), but there was no correlation between muscle telomere length and 2-h glucose concentrations (r = 0.05, 95% CI -0.35 to 0.46) or between leucocyte or muscle telomere length with other metabolic traits. CONCLUSIONS: In summary, the current study supports the use of leucocyte telomere length as a proxy for muscle telomere length in epidemiological studies of Type 2 diabetes aetiology.

First-degree relatives of type 2 diabetic patients have reduced expression of genes involved in fatty acid metabolism in skeletal muscle.

CONTEXT: First-degree relatives of patients with type 2 diabetes (FH+) have been shown to have decreased energy expenditure and decreased expression of mitochondrial genes in skeletal muscle. In previous studies, it has been difficult to distinguish whether mitochondrial dysfunction and differential regulation of genes are primary (genetic) or due to reduced physical activity, obesity, or other correlated factors. OBJECTIVE: The aim of this study was to investigate whether mitochondrial dysfunction is a primary defect or results from an altered metabolic state. DESIGN: We compared gene expression in skeletal muscle from 24 male subjects with FH and 26 without FH matched for age, glucose tolerance, VO(2peak) (peak oxygen uptake), and body mass index using microarrays. Additionally, type fiber composition, mitochondrial DNA content, and citrate synthase activity were measured. The results were followed up in an additional cohort with measurements of in vivo metabolism. RESULTS: FH+ vs. FH- subjects showed reduced expression of mitochondrial genes (P = 2.75 × 10(-6)), particularly genes involved in fatty acid metabolism (P = 4.08 × 10(-7)), despite similar mitochondrial DNA content. Strikingly, a 70% reduced expression of the monoamine oxidase A (MAOA) gene was found in FH+ vs. FH- individuals (P = 0.0009). Down-regulation of the genes involved in fat metabolism was associated with decreased in vivo fat oxidation and increased glucose oxidation examined in an additional cohort of elderly men. CONCLUSIONS: These results suggest that genetically altered fatty acid metabolism predisposes to type 2 diabetes and propose a role for catecholamine-metabolizing enzymes like MAOA in the regulation of energy metabolism.

Evaluation of the effects of exercise on insulin sensitivity in Arabian and Swedish women with type 2 diabetes.

AIMS: The purpose of this study was to evaluate the effects of exercise on cardio-respiratory fitness and insulin sensitivity in sedentary, overweight Arabian and Swedish women with type 2 diabetes. METHODS: Eighteen Arabian and 14 Swedish women participated in a supervised 6-month resistance training and aerobic program of moderate intensity. Insulin sensitivity and VO(2max) were measured at entry to the study and after 3 and 6 months training. RESULTS: After 6 months exercise, insulin sensitivity (M-value) increased (2.7+/-1.4 mg kg(-1) min(-1) vs. 3.4+/-2 mg kg(-1) min(-1), p<0.05) in all patients and accounted for by an increase in non-oxidative glucose metabolism (0.3+/-1.1 mg kg(-1) min(-1) vs. 1.5+/-1.5 mg kg(-1) min(-1), p<0.005) with no significant difference between the ethnic groups. Notably, significant improvement in HbA1c was only seen in the Swedish patients who achieved greater exercise intensity (73.3+/-4.8% vs. 63.3+/-5.2% of maximum heart rate, p<0.005). No changes were observed regarding VO(2max) or lipid profile in either group. CONCLUSIONS: Although a 6-month exercise intervention of moderate intensity in Arabian and Swedish patients with type 2 diabetes can improve insulin sensitivity it is hampered by the metabolic inflexibility of switching between oxidation of glucose or fat.

Sequelae following sural nerve biopsy in type 1 diabetic subjects.

OBJECTIVES: To detect post-operative sequelae of sural nerve biopsy. MATERIALS AND METHODS: A questionnaire mailed to type 1 diabetic patients (n = 24; male/female 23/1; reply n = 23) 2 years after biopsy. RESULTS: Type 1 diabetic patients (age 56 [11]; median [interquartile range]) had a long duration of diabetes (DM; 20 [19] years) and all had neuropathy. Three out of 24 patients developed infection (two superficial and one deep) and one had a post-operative bleeding. Less frequent pain among the patients were reported from one centre. About one-third or more of the patients still complained of pain, mostly mild, in the biopsy area and paraesthesia in the foot 2 years after surgery. More than two-thirds of the patients were reluctant for further biopsy; a crucial information in drug trial planning. CONCLUSIONS: Sequelae of a sural nerve biopsy occur in type 1 DM. The risk for wound infections should be considered.

Vibrotactile sense in median and ulnar nerve innervated fingers of men with Type 2 diabetes, normal or impaired glucose tolerance.

AIMS: To investigate vibrotactile sense (large fibre neuropathy) at different frequencies in index and little fingers (median and ulnar nerves, respectively) of subjects with diabetes, or impaired (IGT) or normal glucose tolerance (NGT). METHODS: Vibration thresholds (tactilometry at seven frequencies (8, 16, 32, 64, 125, 250 and 500 Hz)) and median nerve function (electrophysiology) were examined in men (age 73.4 +/- 0.12 years; n = 58, mean +/- sd) with persistent NGT (n = 28) or IGT (n = 7) or with Type 2 diabetes mellitus (T2DM) (n = 23) for > 15 years. RESULTS: HbA1c was increased and vibrotactile sense (sensibility index) was impaired in index and little fingers in men with T2DM. Vibration thresholds were particularly increased at 16, 250 and 500 Hz in the little finger (ulnar nerve). T2DM subjects showed electrophysiological (gold standard) signs of neuropathy in the median nerve. Although subjects with persistent IGT had higher HbA1c, vibrotactile sensation and electrophysiology remained normal. HbA1c did not correlate with vibrotactile sense or electrophysiology, but the latter two correlated with respect to Z-score (sign of neuropathy) in forearm (NGT) and at wrist level (NGT and DM). CONCLUSIONS: Vibration thresholds are increased in the finger pulps in T2DM subjects, particularly at specific frequencies in ulnar nerve innervated finger pulps. Neuropathy is not present in IGT. Tactilometry, with a multi-frequency approach, is a sensitive technique to screen for large fibre neuropathy in T2DM. Frequency-related changes may mirror dysfunction of various receptors.

Inflammatory markers and IL-6 polymorphism in peripheral arterial disease with and without diabetes mellitus.

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis, recognized as an inflammatory disease of the vessel wall, probably accelerated by diabetes mellitus (DM). Elevated interleukin (IL)-6 levels have been associated with increased cardiovascular morbidity and a common polymorphism has been identified in the promoter region of the IL-6 gene. The aim of this prospective study was to investigate inflammatory mediators in PAD patients (+/- DM) and to investigate a possible relationship to the IL-6 gene polymorphism. Five groups of patients (DM, intermittent claudication +/- DM, critical limb ischemia (CLI) +/- DM) and a control group of 20 individuals each were included. Hemoglobin, high sensitive C-reactive protein (hsCRP), creatinine, blood lipids, white blood cells (WBC); CD11b/CD18; vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1), sE-selectin, sP-selectin; IL-6, IL-8, tumour necrosis factor (TNF)alpha, sTNFalpha-R1 and sTNFalpha-R2 were analysed. The IL-6 gene polymorphism was determined in all groups and also compared with 200 healthy controls from a larger study of blood donors. In a multiple regression analysis, adjusted for gender, smoking and age, the effect of CLI was significantly (p < 0.05) associated with elevated levels of the WBC count, hsCRP, proinflammatory cytokines (IL-6, TNFalpha-R1-2) and endothelial (sICAM, sVCAM) and WBC (CD11b gran) markers. The effect of less advanced PAD (intermittent claudication) was related to an increased concentration of sVCAM-1 and the number of monocytes and granulocytes. DM or leg ulcers were not significantly related to any of the markers. No significant difference in frequency of the various IL-6 genotypes was found between the groups or when compared with the group of 200 blood donors (p> 0.3). Activation of cytokines, endothelial cells and WBC was related to the Fontaine stage of PAD but not to the presence of DM or ulcers. No association was found between the polymorphism in the IL-6 promoter region and PAD.

Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes.

AIMS/HYPOTHESIS: The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 ( CAPN10). METHODS: We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-(3)H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l). RESULTS: There was a linear increase in NEFA levels ( p<0.0005) and WHR ( p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance ( r=-0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity ( r=-0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations ( r=-0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3+/-0.4 vs 7.2+/-0.4 mg.ffm kg(-1).min(-1).mU.l(-1); p<0.005). CONCLUSIONS/INTERPRETATION: We conclude that the pre-diabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes.

Hyperinsulinaemia as long-term predictor of death and ischaemic heart disease in nondiabetic men: The Malmö Preventive Project.

OBJECTIVES: Prospective studies have indicated that hyperinsulinaemia/insulin resistance is a risk factor for ischaemic heart disease (IHD), the risk decreasing with time of follow-up. Few studies have so far investigated the role of hyperinsulinaemia in the prediction of long-term total mortality. SETTING: Section of Preventive Medicine, Department of Medicine, University Hospital, Malmö, Sweden. SUBJECTS: A total of 6074 nondiabetic, middle-aged, healthy Swedish males. SCREENING EXAMINATION: We determined IHD risk factors including blood glucose and plasma insulin before and 2 h after an oral glucose tolerance test (OGTT). Total follow-up time was 19 years. Hyperinsulinaemia was defined as values above the 10th decentile of fasting or 2 h insulin concentration. MAIN OUTCOME MEASURES: Total mortality and cardiac event (CE) rate for IHD. RESULTS: Unadjusted relative risks (RRs) for both death and CE were J-shaped with the highest relative risk (RR: 1.4-1.6) in the hyperinsulinaemic group compared with all other men. The RRs for death and CE were significant for fasting insulin but became nonsignificant after adjustment for other risk factors and also with a longer follow-up. The risk of death in hyperinsulinaemic men, defined on the basis of 2-h insulin level, increased with time of follow-up and was still significantly increased after 19 years [RR: 1.32 (95% CI: 1.05-1.65], even after adjustment for other risk factors. CONCLUSIONS: Fasting hyperinsulinaemia was a predictor of total mortality and IHD in nondiabetic men, although not more significantly after adjustment for other risk factors and with lengthening of follow-up time. The 2-h postglucose hyperinsulinaemia appeared to be a stronger and independent predictor of mortality over long-term follow-up. These findings support the view that insulin resistance with associated cluster of risk factors predicts increased long-term risk of mortality and IHD.

Influence of plasma fibrinogen levels on the incidence of myocardial infarction and death is modified by other inflammation-sensitive proteins: a long-term cohort study.

Inflammation may play an important role in atherosclerotic disease. Plasma fibrinogen is an established predictor of cardiovascular events. The aim of this study was to evaluate whether other inflammation-sensitive plasma proteins modify this prediction. We studied the incidence of cardiac events and death in men in relation to fibrinogen levels alone and in combination with other proteins. The study was based on 6075 men, who were, on average, 46 years old at the time of the screening examination, which included the quantitative assessment of plasma levels of fibrinogen, orosomucoid, alpha(1)-antitrypsin, haptoglobin, and ceruloplasmin. The concentration of each protein was divided into quartiles for each. This classification made it possible to identify 4 groups, ie, men in the first fibrinogen quartile and at the same time either not belonging to the fourth quartile of any of the other proteins (Q1/No group) or also belonging to the fourth quartile of >/=1 of the additional proteins (Q1/Yes group) and corresponding groups in the fourth fibrinogen quartile (Q4/No and Q4/Yes groups). During the follow-up, which occurred at an average of 16 years, 439 (7.2%) men experienced a cardiac event, and 653 (10.7%) died; 278 of these men died of cardiovascular diseases, with 206 deaths attributed to ischemic heart disease. From the lowest to the highest quartile, there was for each protein a stepwise increase in the incidence of cardiac events and mortality. All-cause mortality and cardiovascular mortality were significantly higher in the Q4/Yes group compared with the Q4/No group, but they were similar in the Q4/No and Q1/Yes groups. The incidence of cardiac events was significantly higher in the Q1/Yes and Q4/Yes groups compared with the Q1/No and Q4/No groups, respectively. The increased cardiovascular mortality and cardiac event rates remained after adjustment for several confounders when the Q4/Yes and Q4/No groups were compared. The results suggest that the incidence of cardiac events and death due to cardiovascular diseases in middle-aged men predicted by plasma levels of fibrinogen is modified by other inflammation-sensitive proteins.

Homocysteine is related to neopterin and endothelin-1 in plasma of subjects with disturbed glucose metabolism and reference subjects.

Hyperhomocysteinemia is an independent risk factor for vascular disease. In order to evaluate relations between hyperhomocysteinemia and endothelial and leukocyte function, the investigators related homocysteine to indices of endothelial function (plasma endothelin-1 [p-ET-1] and intraplatelet levels of the nitric oxide [NO] and prostacyclin mediators 3'-5' guanosine monophosphate [cGMP] and cyclic 3'-5' adenosine monophosphate [cAMP]) and the monocyte-derived inflammatory mediator neopterin in 168 men (mean age 69, range 49-72 years) with disturbed glucose metabolism and a reference group of 52 male subjects (mean age 70, range 61-79 years). Among the 168 patients with disturbed glucose metabolism plasma (p)-homocysteine correlated significantly with age (r=0.20; p<0.01), glycosylated hemoglobin (HbA1c) (r=0.17; p<0.05), triglycerides (r=0.20; p<0.05), intraplatelet GMP (r=0.16; p<0.05), p-ET-1 (r=0.21; p<0.05), and p-neopterin (r=0.31; p<0.001). The correlation between p-homocysteine and p-ET-1 persisted (p<0.01) in multiple regression analysis. Among the 52 reference subjects p-homocysteine correlated significantly with p-ET-1 (r=0.32; p<0.05) and p-neopterin (r=0.37; p<0.01). The correlation between p-homocysteine and p-neopterin persisted (p<0.05) in multiple regression analysis. In conclusion, homocysteine is related to neopterin and endothelin-1 in plasma of subjects with disturbed glucose metabolism and in reference subjects, suggesting that homocysteine exerts its deleterious effects on vascular function through interference with endothelial and leukocyte function.

Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance.

AIMS: Sorbitol and myo-inositol levels and morphology of sural nerve were compared with nerve function and clinical neuropathy in men with diabetic, impaired (IGT), and normal glucose tolerance. METHODS: After neurography of sural nerve and determinations of sensory thresholds for vibration, warm and cold on the foot, whole nerve sural nerve biopsy was performed in 10 men with Type 1 diabetes mellitus, 10 with IGT, and 10 with normal glucose tolerance. Polyol levels were assessed by gas-liquid chromatography/mass spectrometry. RESULTS: Sural nerve amplitudes were significantly lower and sorbitol levels significantly higher in diabetic patients (median (interquartile range)) (3.7 (3.5) microV and 643 (412) pmol/mg protein, respectively) both compared with IGT (11.3 (10.6)microV; P = 0.04 and 286 (83) pmol/mg protein; P = 0.0032, respectively) and normally glucose tolerant (10.0 (11.6); P = 0.0142 and 296 (250) pmol/mg protein; P = 0.0191, respectively) subjects. There were no differences in nerve morphology between the three groups. Nerve myo-inositol levels correlated, however, positively with cluster density (rs = 0.56; P = 0.0054). In diabetic and IGT subjects, sural nerve amplitudes (2.6 (3.8) vs. 12.1 (10.6) microV; P = 0.0246) and myelinated nerve fibre density (MNFD; 4,076 (1091) vs. 5,219 (668) nerve fibres/mm2; P = 0.0021) were significantly lower in nine subjects with clinical neuropathy than in 10 without. CONCLUSIONS: Nerve degeneration (i.e. MNFD) correlated with clinical neuropathy but not with glucose tolerance status whereas nerve myo-inositol levels positively correlated with signs of nerve regeneration (i.e. increased cluster density).

Long-term outcome of the Malmö preventive project: mortality and cardiovascular morbidity.

OBJECTIVES: To analyse the effects on mortality and cardiovascular morbidity in a population-based sample, invited to an intervention programme incorporating a baseline screening examination and treatment programmes for subjects with cardiovascular risk factors, high alcohol intake and, in women, suspicion of breast cancer on mammography. SETTING: Section of Preventive Medicine, Department of Medicine, University Hospital, Malmö, Sweden. SUBJECTS: Birth cohorts (aged 32-51 years) invited to screening examination (men = 9. 923; women = 4.422) were compared to birth cohorts not invited (men = 6.655; women = 4.290). Mean participation rate in the invited cohorts was 71% (range 64-78%). SCREENING EXAMINATION: Between 1974 and 1992 a baseline screening including a physical examination, blood pressure, a questionnaire regarding, e.g. family history, lifestyle, and socio-economic factors, laboratory tests of serum cholesterol, triglycerides, gamma-glutamyl-transferase, blood glucose before and after an oral glucose load, as well as a mammography examination in women, was performed. INTERVENTIONS: Subjects with hypertension; hyperlipidaemia; diabetes or glucose intolerance; high alcohol intake; or, in women, suspicion of breast cancer were referred to special outpatient clinics. MAIN OUTCOME MEASURES: Total and cause-specific mortality, nonfatal myocardial infarction, and stroke, from the screening examination until the end of 1995, was followed in both the intervention and control groups, using national and/or local registries. RESULTS: Total mortality did not differ significantly between the intervention group and control group. Cause-specific deaths were also similar except for 'other' deaths amongst men being significantly lower in the intervention group, mainly due to a lower mortality from 'other' causes (suicide, alcohol related deaths) in men under 40 years of age at baseline. Women under 40 years of age had a significantly lower mortality from cancer in the intervention group than in the control group. Nonfatal myocardial infarction and stroke did not differ between intervention and control group in either sex. Within the invited birth cohorts, nonparticipants had a higher total and cause-specific mortality. CONCLUSIONS: Risk factor screening for major diseases such as cardiovascular disease, alcohol abuse, diabetes mellitus and breast cancer, and subsequent treatment of the detected risk factors/diseases - The Malmö Preventive Project - did not reduce total mortality in the intervention group as a whole. In subjects under 40 years of age at entry, total mortality was lower in the intervention group than in the control group. In men, this seemed to be due to a reduction of alcohol-related deaths, whilst in women death from cancer was reduced.

Gliadin antibodies in adult insulin-dependent diabetes--autoimmune and immunogenetic correlates.

Gliadin antibody (GA) tests used in screening for coeliac disease (CD) frequently yield positive GA results without accompanying CD in cases of diabetes mellitus type 1 (DM-1). To enlighten this phenomenon we screened 848 DM-1 patients for IgA- and IgG-GA. Subsequently, 16 out of 19 high titre GA patients (6 with CD) were compared with 37 low titre DM-1 patients matched for sex, age and disease duration, for autoimmune and immunogenetic markers. Chronic thyroiditis and thyroid peroxidase (TPO) antibody positivity were more frequent in the GA-positive than in the GA-negative sub-group (38 vs. 2.7%, p = 0.003, and 69 vs. 27%, p < 0.00, respectively). The tissue transglutaminase (tTg) IgA titres correlated with CD but not with GA. tTg IgG titres were lower in GA-positive individuals (p = 0.0012). GA-positivity correlated with a higher titre of factor XIII IgA antibodies (p < 0.001). GA-positive DM-I patients were characterised by a distinct immunogenetic profile; the risk of HLA DQB1*02 was lower among GA-positive patients than among GA-negatives (OR 0.4, preventive fraction 0.43). All CD patients were HLA DRB1*03-DQB1* 02-positive, but none of the five patients with normal biopsies. GA-positive patients instead had HLA DRB1*13 in 37.5% as compared to 8.6% in GA-negative (OR 6.4, etiologic fraction 0.32). Thus, the occurrence of positive GA in DM-1 is correlated to TPO antibody positivity, thyroiditis and factor XIII IgA antibodies, but inversely correlated to tTg IgG, and seems to be associated with another HLA haplotype than that previously found to be associated with CD.

Alcohol consumption and disability pension among middle-aged men.

PURPOSE: To analyze the relation between alcohol consumption and the risk of disability pension among middle-aged men. METHODS: In the mid-seventies, complete birth-year cohorts of middle-aged male residents in Malmö, Sweden, were invited to participate in a general health survey. The 3751 men with complete data who constituted the cohort in this study were followed for 11 years. Alcohol consumption was estimated from the scores obtained from a test designed to identify subjects with alcohol related problems. RESULTS: Of the 498 men granted disability pension during follow-up, 48 stated to be teetotalers. The cumulative incidence of disability pension among teetotalers was 19%, whereas, it was 12% and 16%, respectively, among men with low and high alcohol consumption. The adjusted relative risk (RR) for acquiring a disability pension (using the group with low alcohol consumption as reference) was 1.8 among abstainers and 1.3 among men with high alcohol consumption. CONCLUSIONS: Alcohol overconsumption, as well as teetotalism, showed a positive relation to disability pension, and a moderate alcohol intake was found to be beneficial with respect to the risk of future disability pension.

Insulin-regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle.

To identify abnormally expressed genes contributing to muscle insulin resistance in type 2 diabetes, we screened the mRNA populations from normal and diabetic human skeletal muscle using cDNA differential display and isolated abnormally expressed cDNA clones of mitochondrial-encoded NADH dehydrogenase 1 (ND1), cytochrome oxidase 1, tRNA(leu), and displacement loop. We then measured mRNA expression of these mitochondrial genes using a relative quantitative polymerase chain reaction method in biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and 12 matched control subjects and in muscle biopsies taken after an insulin clamp from 13 subjects with type 2 diabetes, 15 subjects with impaired glucose tolerance, and 14 subjects with normal glucose tolerance. Insulin infusion increased mRNA expression of ND1 from 1.02 +/- 0.04 to 2.55 +/- 0.30 relative units (P < 0.001) and of cytochrome oxidase 1 from 0.80 +/- 0.01 to 1.24 +/- 0.10 relative units (P < 0.001). The ND1 response to insulin correlated with glucose uptake (r = 0.46, P = 0.002). Although the rate of insulin-mediated glucose uptake was decreased in the diabetic versus the nondiabetic twins (5.2 +/- 0.7 vs. 8.5 +/- 0.8 mg x kg(-1) fat-free mass x min(-1), P < 0.01), insulin-stimulated ND1 expression was not significantly different between them (2.4 +/- 0.5 vs. 2.7 +/- 0.5 relative units). Neither was there any significant intrapair correlation of ND1 expression between the monozygotic twins (r = -0.15, NS). We conclude that insulin upregulates mitochondrial-encoded gene expression in skeletal muscle. Given the positive correlation between ND1 expression and glucose uptake and the lack of intrapair correlation between monozygotic twins, mitochondrial gene expression may represent an adaptation to intracellular glucose flux rather than an inherited trait.