Increased uptake of oxLDL does not exert lipotoxic effects in insulin-secreting cells.

Modified lipoproteins can negatively affect beta cell function and survival. However, the mechanisms behind interactions of modified lipoproteins with beta cells - and in particular, relationships to increased uptake - are only partly clarified. By over-expressing the scavenger receptor CD36 (Tet-on), we increased the uptake of fluorescent low-density modified lipoprotein (oxLDL) into insulin-secreting INS-1 cells. The magnitude of uptake followed the degree of CD36 over-expression. CD36 over-expression increased concomitant efflux of 3H-cholesterol in proportion to the cellular contents of 3H-cholesterol. Exposure to concentrations of oxLDL from 20 to 100 µg/mL dose-dependently increased toxicity (evaluated by MTT) as well as apoptosis. However, the increased uptake of oxLDL due to CD36 over-expression did not exert additive effects on oxLDL toxicity - neither on viability, nor on glucose-induced insulin release and cellular content. Reciprocally, blocking CD36 receptors by Sulfo-N-Succinimidyl Oleate decreased the uptake of oxLDL but did not diminish the toxicity. Pancreatic islets of CD36-/- mice displayed reduced uptake of 3H-cholesterol-labeled oxLDL vs wild type but similar toxicity to oxLDL. OxLDL was found to increase the expression of CD36 in islets and INS-1 cells. In summary, given the experimental conditions, our results indicate that (1) increased uptake of oxLDL is not responsible for toxicity of oxLDL, (2) increased efflux of the cholesterol moiety of oxLDL counterbalances, at least in part, increased uptake and (3) oxLDL participates in the regulation of CD36 in pancreatic islets and in INS-1 cells.

Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA).

BACKGROUND: A family history of diabetes (FHD) is a strong predictor of diabetes risk, yet has rarely been investigated in latent autoimmune diabetes in adults (LADA). This study therefore investigated the risk of LADA and type 2 diabetes (T2D) in relation to FHD, taking into account the type of diabetes in relatives. METHODS: Data from a population-based study were used, including incident cases of LADA [glutamic acid decarboxylase antibody (GADA)-positive, n=378] and T2D (GADA-negative, n=1199), and their matched controls (n=1484). First-degree relatives with disease onset at age<40 years and taking insulin treatment were classified as type 1 diabetes (T1D) or, if otherwise, as T2D. Odds ratios (ORs) were adjusted for age, gender, BMI, education and smoking. Cases were genotyped for high- and low-risk HLA genotypes. RESULTS: Both FHD-T1D (OR: 5.8; 95% CI: 3.2-10.3) and FHD-T2D (OR: 1.9; 95% CI: 1.5-2.5) were associated with an increased risk of LADA, whereas the risk of T2D was associated with FHD-T2D (OR: 2.7; 95% CI: 2.2-3.3), but not FHD-T1D. In LADA patients, FHD-T1D vs FHD-T2D was associated with higher GADA but lower C-peptide levels, lower prevalence of low-risk HLA genotypes (5.0% vs 28.6%, respectively; P=0.038) and a tendency for higher prevalence of high-risk genotypes (90.0% vs 69.1%, respectively; P=0.0576). CONCLUSION: The risk of LADA is substantially increased with FHD-T1D but also, albeit significantly less so, with FHD-T2D. This supports the idea of LADA as a mix of both T1D and T2D, but suggests that the genes related to T1D have greater impact. LADA patients with FHD-T1D had more T1D-like features, emphasizing the heterogeneity of LADA.

Use of Swedish smokeless tobacco (snus) and the risk of Type 2 diabetes and latent autoimmune diabetes of adulthood (LADA).

AIMS: It has been suggested that moist snuff (snus), a smokeless tobacco product that is high in nicotine and widespread in Scandinavia, increases the risk of Type 2 diabetes. Previous studies are however few, contradictory and, with regard to autoimmune diabetes, lacking. Our aim was to study the association between snus use and the risk of Type 2 diabetes and latent autoimmune diabetes of adulthood (LADA). METHOD: Analyses were based on incident cases (Type 2 diabetes, n = 724; LADA, n = 200) and population-based controls (n = 699) from a Swedish case-control study. Additional analyses were performed on cross-sectional data from the Norwegian HUNT study (n = 21 473) with 829 prevalent cases of Type 2 diabetes. Odds ratios (OR) were estimated adjusted for age, BMI family history of diabetes and smoking. Only men were included. RESULTS: No association between snus use and Type 2 diabetes or LADA was seen in the Swedish data. For Type 2 diabetes, the OR for > 10 box-years was 1.00 [95% confidence interval (CI), 0.47 to 2.11] and for LADA 1.01 (95% CI, 0.45 to 2.29). Similarly, in HUNT, the OR for Type 2 diabetes in ever-users was estimated at 0.91 (95% CI, 0.75 to 1.10) and in heavy users at 0.92 (95% CI, 0.46 to 1.83). CONCLUSION: The risk of Type 2 diabetes and LADA is unrelated to the use of snus, despite its high nicotine content. This opens the possibility of the increased risk of Type 2 diabetes seen in smokers may not be attributed to nicotine, but to other substances in tobacco smoke.

Autoimmune diabetes in adults and risk of myocardial infarction: the HUNT study in Norway.

BACKGROUND: The long-term consequences of autoimmune diabetes in adults (AIDA) are largely unexplored. OBJECTIVE: To investigate the risk of myocardial infarction (MI) in AIDA compared to type 2 diabetes, taking into consideration the effects of socio-economic and lifestyle factors, the metabolic syndrome and glycaemic control. METHODS: A total of 62 995 participants including 207 individuals with AIDA (onset ≥35 years and anti-GAD positive) and 2322 individuals with type 2 diabetes (onset ≥35 years and anti-GAD negative), from the population-based Norwegian HUNT study, were followed for a first MI during the period 1995-2008. We identified 2614 MIs by hospital records or the National Cause of Death Registry. Cox proportional hazard models were used to estimate the risk of MI by diabetes subgroups after adjustment for age and socio-economic and lifestyle factors. RESULTS: AIDA amongst women was associated with a nearly fourfold increased risk of MI [hazard ratio (HR) 3.63, 95% confidence interval (CI) 2.21-5.96) compared to nondiabetic participants, whereas no excess risk was found in men with AIDA (HR 1.30, 95% CI 0.70-2.52). By contrast, type 2 diabetes was associated with an increased MI risk in both men (HR 1.92, 95% CI 1.62-2.26) and women (HR 2.39, 95% CI 1.98-2.89). The metabolic profile was more favourable in patients with AIDA than in those with type 2 diabetes, but glycaemic control was worse. Multivariable models and sensitivity analyses suggest that these results were robust. CONCLUSIONS: Women with AIDA were more likely to develop MI, compared to men with AIDA and both men and women with type 2 diabetes. Further investigations are warranted to confirm this gender difference.

Fructosamine is a risk factor for myocardial infarction and all-cause mortality - Longitudinal experience from the AMORIS cohort.

BACKGROUND AND AIMS: Glycation is linked to microvascular complications of diabetes and also to macrovascular events. Fructosamine is a biomarker of glycation but its associations to macrovascular complications are not well documented. The aim of this study was to evaluate fructosamine as a predictor of myocardial infarction and all-cause mortality in a large population based cohort. METHODS AND RESULTS: Information on glucose and fructosamine was obtained from subjects of the AMORIS cohort (n = 338,443) followed for 19 years on average. Incident cases of myocardial infarction and death from any cause were identified from national patient and cause of death register respectively. The incidence of myocardial infarction (n = 21,526 cases) and all-cause mortality (n = 73,458 deaths) increased at a fructosamine of 2.30 mmol/L or above. For myocardial infarction, the sex-age- fasting- and entry period adjusted hazard ratio in subjects above 2.70 mmol/L vs. reference range subjects was 2.88 (95% CI: 2.70-3.07). The corresponding hazard ratio for all-cause mortality was 2.31 (95% CI: 2.21-2.41). These associations remained basically unchanged after adjustment for total cholesterol, triglycerides, albumin, social class, smoking and hypertension. When additional adjustment for glucose was performed the associations were attenuated but remained. In a sub cohort with simultaneous measurements of fructosamine, HbA1c and fasting glucose respectively similar associations were observed (n = 9746). CONCLUSION: There is a strong association between fructosamine and myocardial infarction and death from any cause when major cardiovascular risk factors are accounted for. In addition, this association could only partly be explained by glucose levels.

Alginate microencapsulation of human islets does not increase susceptibility to acute hypoxia.

Islet transplantation in diabetes is hampered by the need of life-long immunosuppression. Encapsulation provides partial immunoprotection but could possibly limit oxygen supply, a factor that may enhance hypoxia-induced beta cell death in the early posttransplantation period. Here we tested susceptibility of alginate microencapsulated human islets to experimental hypoxia (0.1-0.3% O2 for 8 h, followed by reoxygenation) on viability and functional parameters. Hypoxia reduced viability as measured by MTT by 33.8 ± 3.5% in encapsulated and 42.9 ± 5.2% in nonencapsulated islets (P < 0.2). Nonencapsulated islets released 37.7% (median) more HMGB1 compared to encapsulated islets after hypoxic culture conditions (P < 0.001). Glucose-induced insulin release was marginally affected by hypoxia. Basal oxygen consumption was equally reduced in encapsulated and nonencapsulated islets, by 22.0 ± 6.1% versus 24.8 ± 5.7%. Among 27 tested cytokines/chemokines, hypoxia increased the secretion of IL-6 and IL-8/CXCL8 in both groups of islets, whereas an increase of MCP-1/CCL2 was seen only with nonencapsulated islets. Conclusion. Alginate microencapsulation of human islets does not increase susceptibility to acute hypoxia. This is a positive finding in relation to potential use of encapsulation for islet transplantation.

Alcohol consumption is associated with reduced risk of Type 2 diabetes and autoimmune diabetes in adults: results from the Nord-Trøndelag health study.

AIMS: We investigated the influence of different aspects of alcohol consumption on the risk of Type 2 diabetes and autoimmune diabetes in adults. METHODS: We used data from the Nord-Trøndelag Health Survey (HUNT) study, in which all adults aged ≥ 20 years from Nord-Trondelag County were invited to participate in three surveys in 1984-1986, 1995-1997 and 2006-2008. Patients with diabetes were identified using self-reports, and participants with onset age ≥ 35 years were classified as having Type 2 diabetes if they were negative for anti-glutamic acid decarboxylase (n = 1841) and as having autoimmune diabetes if they were positive for anti-glutamic acid decarboxylase (n = 140). Hazard ratios of amount and frequency of alcohol use, alcoholic beverage choice, and binge drinking and alcohol use disorders were estimated. RESULTS: Moderate alcohol consumption (adjusted for confounders) was associated with a reduced risk of Type 2 diabetes in men, but not in women (hazard ratio for men 10-15 g/day 0.48, 95% CI 0.28-0.77; hazard ratio for women ≥ 10 g/day 0.81, 95% CI 0.33-1.96). The reduced risk was primarily linked to consumption of wine [hazard ratio 0.93, 95% CI 0.87-0.99 (per g/day)]. No increased risk was seen in participants reporting binge drinking or in problem drinkers. The results were also compatible with a reduced risk of autoimmune diabetes associated with alcohol consumption [hazard ratio 0.70, 95% CI 0.45-1.08 (frequent consumption) and hazard ratio 0.36, 95% CI 0.13-0.97 (2-7 g/day)]. CONCLUSIONS: Moderate alcohol consumption associates with reduced risk of both Type 2 diabetes and autoimmune diabetes. A protective effect of alcohol intake may be limited to men. High alcohol consumption does not seem to carry an increased risk of diabetes.

Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway.

AIMS: The aetiology of latent autoimmune diabetes in adults (LADA), assessed by autoimmune markers, is insufficiently clarified. We cross-sectionally investigated the prevalence and prospectively the prediabetic and postdiabetic presence of antibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 and zinc transporter 8 in LADA and in type 1 diabetes. METHODS: We included 208 'classic' type 1, 161 LADA and 302 type 2 diabetic cases from the second (HUNT2: 1995­1997) and third (HUNT3: 2006­2008) Nord-Trøndelag health surveys. Prospective data were available for 59 type 1, 44 LADA and 302 type 2 diabetic cases followed from HUNT2 to HUNT3. From HUNT3, 24 type 1 diabetic and 31 LADA incident cases were available. RESULTS: Cross-sectionally, 90% of LADA cases were positive for only one antibody (10% multiple-antibodypositive). Prospectively, 59% of GADA-positive LADA patients in HUNT2 were no longer positive in HUNT3. LADA patients who became negative possessed less frequently risk HLA haplotypes and were phenotypically more akin to those with type 2 diabetes than to those who stayed positive. Still, those losing positivity differed from those with type 2 diabetes by lower C-peptide levels (p = 0.009). Of incident LADA cases in HUNT3, 64% were already antibody-positive in HUNT2, i.e. before diabetes diagnosis. These incident LADA cases were phenotypically more akin to type 1 diabetes than were those who did not display positivity in HUNT2. CONCLUSION/INTERPRETATION: The pattern of antibodies, the postdiabetic loss or persistence as well as the prediabetic absence or presence of antibodies influence LADA phenotypes. Time-dependent presence or absence of antibodies adds new modalities to the heterogeneity of LADA.

No effect by the common gene variant rs10830963 of the melatonin receptor 1B on the association between sleep disturbances and type 2 diabetes: results from the Nord-Trøndelag Health Study.

AIMS/HYPOTHESIS: Genetic variation in the melatonin receptor 1B (MTNR1B) is associated with type 2 diabetes. Melatonin contributes to the regulation of sleep, and sleep problems are a documented risk factor for type 2 diabetes. The aim of this study was to investigate whether the MTNR1B gene variant rs10830963 is associated with sleep problems and whether this variant contributes to the association between sleep disturbances and type 2 diabetes. METHODS: This was a case-control study nested within the population-based Nord-Trøndelag Health Study, including 1,322 prevalent cases of type 2 diabetes and 1,447 controls. In addition, prospective data were available for 838 incident cases and 1,133 controls. Genotyping was done by TaqMan single-nucleotide polymorphism allelic discrimination analysis. ORs and 95% CIs were calculated using logistic regression models. RESULTS: Our findings confirm an association between sleep disturbances and type 2 diabetes (OR 1.69, 95% CI 1.22-2.33, p = 0.0016) and between the risk allele of rs10830963 and type 2 diabetes (OR 1.12, 95% CI 1.00-1.27, p = 0.0579). There was a tendency for an association between the risk allele and prevalence of sleep problems (specifically early awakening). However, the risk allele did not influence the association of sleep problems with diabetes, which was unaltered after adjustment for the MTNR1B risk allele (OR 1.69, 95% CI 1.23-2.34, p = 0.0014). Results based on prospective data were similar, although non-significant. CONCLUSIONS/INTERPRETATION: Our findings do not support participation of the MTNR1B gene variant rs10830963 in the well documented association between sleep disturbances and type 2 diabetes.

Activation of PKC-epsilon counteracts maturation and apoptosis of HL-60 myeloid leukemic cells in response to TNF family members.

Protein kinase C (PKC)-epsilon, a component of the serine/threonine PKC family, has been shown to influence the survival and differentiation pathways of normal hematopoietic cells. Here, we have modulated the activity of PKC-epsilon with specific small molecule activator or inhibitor peptides. PKC-epsilon inhibitor and activator peptides showed modest effects on HL-60 maturation when added alone, but PKC-epsilon activator peptide significantly counteracted the pro-maturative activity of tumor necrosis factor (TNF)-alpha towards the monocytic/macrophagic lineage, as evaluated in terms of CD14 surface expression and morphological analyses. Moreover, while PKC-epsilon inhibitor peptide showed a reproducible increase of TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis, PKC-epsilon activator peptide potently counteracted the pro-apoptotic activity of TRAIL. Taken together, the anti-maturative and anti-apoptotic activities of PKC-epsilon envision a potentially important proleukemic role of this PKC family member.

Beneficial effects of K-ATP channel openers in diabetes: an update on mechanisms and clinical experiences.

Stresses associated with the diabetic state participate in the demise of beta-cells and therapies that eliminate or reduce such stresses are much needed. K-ATP channel openers, of which diazoxide is the most studied, are potentially useful because experimental studies show that they can counteract chronic over-stimulation of beta-cells and protect against toxic conditions, including relative hypoxia. Several mechanisms may underlie the beneficial effects of diazoxide; these may include both indirect (counteracting over-stimulation) and direct mitochondrial effects. Side effects of diazoxide have limited its use in human trials. We have tested lower doses than previously of diazoxide and thereby largely eliminated side effects. In this setting, we demonstrate positive effects on beta-cell function in type 2 diabetic patients who were simultaneously treated with bedtime insulin. However, such effects were absent in insulin-naïve patients. In newly diagnosed type 1 diabetic patients, a 6-month intervention with diazoxide failed to result in better preservation of beta-cell function. K-ATP channel openers have a potential to improve beta-cell function in subgroups of type 2 diabetes patients. Analogues of diazoxide with more potency in relation to side effects would heighten the possibilities for K-ATP channel openers to be of therapeutic use in type 1 diabetes.

Urinary albumin excretion in latent autoimmune diabetes in adults (LADA) is more similar to type 2 than type 1 diabetes: results of the Nord-Trøndelag Health Study 1995-1997.

AIM: As it is unclear, whether or not, urinary albumin excretion (UAE) differs between patients classified as latent autoimmune diabetes in adults (LADA) and other forms of diabetes, our study aimed to investigate the distribution of the albumin-to-creatinine ratio (ACR) in LADA compared with those in the "classical" types 1 (T1D) and 2 (T2D) diabetes. METHODS: We used data from the Nord-Trøndelag Health Study (HUNT) (n=64,931) of 1995-1997. ACR (mg/mmol) was measured in three urine samples from all diabetic patients (n=1525) and from 5% of the non-diabetic study population (n=2104). We calculated the geometric means and 95% confidence intervals (CI) using a general linear model. RESULTS: The unadjusted mean ACR in LADA was similar to that in T2D (1.45, CI: 1.23-1.71 vs 1.41, CI: 1.33-1.49, respectively) but was significantly higher than those in T1D (0.99, CI: 0.83-1.19; P=0.002) and non-diabetics (0.72, CI: 0.69-0.74; P<0.001). These results remained similar even after multiple adjustments. CONCLUSION: In this cross-sectional study, the ACR in LADA and in T2D were similar and higher than in T1D. This similarity between LADA and T2D makes it unlikely that the autoimmune processes that operate in LADA promote albuminuria.

Impact of metabolic abnormalities for beta cell function: clinical significance and underlying mechanisms.

It is firmly established that poor metabolic control in diabetes inhibits beta cell function. Chronic hyperglycaemia is probably the most important factor, exerting both primary negative effects (by glucose per se and/or metabolites) and secondary ones (by beta cell exhaustion). Dyslipidemia in diabetes aggravates the glucose effects both by inducing insulin resistance and by direct effects on beta cells. Much experimental and some clinical evidence indicates that therapies that promote "beta cell rest" such as early and intensive insulin treatment and K-ATP channel blockers can be beneficial.

Activation of PKC-ε counteracts maturation and apoptosis of HL-60 myeloid leukemic cells in response to TNF family members.

Protein kinase C (PKC)-ε, a component of the serine/threo-nine PKC family, has been shown to influence the survival and differentiation pathways of normal hematopoietic cells. Here, we have modulated the activity of PKC-ε with specific small molecule activator or inhibitor peptides. PKC-ε inhibitor and activator peptides showed modest effects on HL-60 maturation when added alone, but PKC-ε activator peptide significantly counteracted the pro-maturative activity of tumor necrosis factor (TNF)-α towards the monocytic/macrophagic lineage, as evaluated in terms of CD14 surface expression and morphological analyses. Moreover, while PKC-ε inhibitor peptide showed a reproducible increase of TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis, PKC-ε activator peptide potently counteracted the pro-apoptotic activity of TRAIL. Taken together, the anti-maturative and anti-apoptotic activities of PKC-ε envision a potentially important proleukemic role of this PKC family member.

Effects of insulin vs. glibenclamide in recently diagnosed patients with type 2 diabetes: a 4-year follow-up.

AIM: To compare effects of early insulin vs. glibenclamide treatment on beta-cell function, metabolic control and quality of life (QL) in recently diagnosed patients with type 2 diabetes. METHODS: Forty-nine patients with type 2 diabetes diagnosed 0-2 years before inclusion were randomized to two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide at six diabetic clinics in Sweden. C-peptide-glucagon tests were performed yearly after 3 days of withdrawal of treatment. RESULTS: Thirty-four patients completed 4 years of study. Daily dose of insulin was increased from 20.4 +/- 1.8 U at year 1 to 26.1 +/- 2.9 U at year 4 (p = 0.005). Glibenclamide dosage increased from 2.7 +/- 0.4 mg at year 1 to 4.5 +/- 0.8 mg at year 4 (p = 0.02). Weight increased more in insulin than in glibenclamide treated (+4.4 +/- 0.8 vs. +0.3 +/- 1.0 kg, p < 0.005). Following short-term withdrawal of treatment, the C-peptide responses to glucagon were significantly higher in the insulin vs. glibenclamide group at years 1 (p < 0.01) and 2 (p < 0.02). HbA1c improved identical during the first year but thereafter deteriorated in the glibenclamide group (p < 0.005 for difference at year 4). Ratios of proinsulin to insulin were higher during treatment in glibenclamide- vs. insulin-treated patients after year 2. QL after 4 years as measured by the MOS 36-item Short-Form Health Survey (SF-36) form was not significantly altered. CONCLUSIONS: In a 4-year perspective, beta-cell function deteriorated in both groups. However, deterioration occurred faster in the glibenclamide group, indicating that alleviating demands on secretion by insulin treatment is beneficial.

Effects of marine n-3 fatty acid supplementation on lipoprotein subclasses measured by nuclear magnetic resonance in subjects with type II diabetes.

OBJECTIVE: To measure effects of fish oil supplements on lipoprotein subclasses by nuclear magnetic resonance (NMR) in subjects with type II diabetes and relate them to insulin sensitivity. DESIGN: Two-armed, parallel, placebo-controlled, randomized. SUBJECTS: Normotriglyceridemic subjects with type II diabetes without insulin treatment were given either fish oil (n=12, median intake 5.9 g/day total n-3 fatty acids (FA) (1.8 g 20:5n-3, 3.0 g 22:6n-3)) or corn oil (n=14, 8.5 g/day 18:2n-6 FA). METHODS: Size and concentration of lipoproteins subclasses were measured by NMR, insulin sensitivity by hyperinsulinemic, isoglycemic clamps. RESULTS: After 9 weeks, there were differences between those treated with fish and corn oil with respect to very low-density lipoprotein (VLDL) size (median -15 vs +0.6%, P=0.001), particle concentrations of large VLDL (-99 vs -4.1%, P=0.041) and small high-density lipoprotein (HDL) (-12 vs +10%, P=0.051). Compared with corn oil fish oil tended to increase HDL size and small low-density lipoprotein (LDL) concentration (P=0.063 and 0.068, respectively, for differences between groups). There was no effect on oxidized LDL. Insulin sensitivity (glucose utilization) decreased in the fish oil group compared with the corn oil group (P=0.049). The decrease in insulin sensitivity did not correlate with the effects on lipoprotein subclasses. CONCLUSIONS: A high intake of n-3 FA exerts effects on several lipoprotein subclasses without obvious influence from changes in insulin sensitivity.

Socio-economic position at three points in life in association with type 2 diabetes and impaired glucose tolerance in middle-aged Swedish men and women.

BACKGROUND: It has been suggested that low socio-economic position (SEP) during childhood and adolescence predicts risk of adult type 2 diabetes. We investigated the associations between type 2 diabetes and childhood SEP (fathers' occupational position), participants' education and adult SEP (participants' occupational position). To determine possible independent associations between early SEP (fathers' occupational position and participants' education) and disease, we adjusted for adult SEP and factors present in adult life associated with type 2 diabetes. METHODS: This cross-sectional study comprised 3128 men and 4821 women aged 35-56 years. All subjects have gone through a health examination and answered a questionnaire on lifestyle factors. At the health centre, an oral glucose tolerance test was administered and identified 55 men and 52 women with previously undiagnosed type 2 diabetes. Relative risks (RRs) with 95% CIs were calculated in multiple logistic regression analyses. RESULTS: The age-adjusted RRs of type 2 diabetes if having a father with middle occupational position were 2.3 [Confidence interval (CI:1.0-5.1) for women and, 2.0 (CI:0.7-5.6) for men]. Moreover, low education was associated with type 2 diabetes in women, RR = 2.5 (CI:1.2-4.9). Low occupational position in adulthood was associated with type 2 diabetes in women, RR = 2.7 (CI:1.3-5.9) and men, RR = 2.9 (CI:1.5-5.7). The associations between early SEP and type 2 diabetes disappeared after adjustment for adult SEP and factors associated with type 2 diabetes. CONCLUSION: The association between type 2 diabetes and low SEP during childhood and adolescence in middle-aged Swedish subjects disappeared after adjustment for adult SEP and adult risk factors of diabetes.

Twelve weeks' treatment with diazoxide without insulin supplementation in Type 2 diabetes is feasible but does not improve insulin secretion.

AIMS: Treatment with K-ATP channel openers, such as diazoxide, can have beneficial effects on insulin secretion in both Type 1 and Type 2 diabetes. However, the precise conditions for obtaining beneficial effects without untoward events have not been determined. We tested the hypothesis that intermittent administration of diazoxide at bedtime for 12 weeks could produce beneficial effects in the absence of side-effects in Type 2 diabetic patients who were not taking insulin. METHODS: After an 8-week run-in period, during which treatment with repaglinide and metformin was optimized, we randomized 26 patients to either diazoxide, 100 mg at bedtime, or placebo. RESULTS: Side-effects were absent or minimal. HbA(1c) did not change. However day-time glucose concentrations by home glucose monitoring were approximately 1.5 mmol/l higher with diazoxide vs. placebo. Stimulation tests (C-peptide-glucagon and breakfast) did not indicate improved pancreatic B-cell function, except by posthoc analysis, in a subgroup of younger age. CONCLUSION: Compared with previous results with diazoxide together with bedtime insulin, the present results are less favourable and indicate that concomitant insulin treatment is needed during intervention with K-ATP channel openers.

Age, overweight and physical inactivity increase the risk of latent autoimmune diabetes in adults: results from the Nord-Trøndelag health study.

AIMS/HYPOTHESIS: Latent autoimmune diabetes (LADA) is a common form of diabetes, yet the risk factors are poorly characterised. The aim of this study was to investigate the influence of age, overweight and physical activity on the risk of LADA. METHODS: We analysed age, overweight and physical inactivity and the incidence of LADA in 38,800 men and women, observed between 1984 and 1986 and 1995 and 1997 as part of the Nord-Trøndelag Health Survey. We also compared such factors with incident cases of type 2 (n = 738) and 'classic' type 1 diabetes (n = 18). Patients classified as LADA (n = 81) had antibodies against GAD and were insulin independent at diagnosis. RESULTS: The proportion of those who were older, overweight and inactive before diagnosis was almost identical in LADA and type 2 diabetes patients. BMI >or=30 kg/m(2) was strongly associated with LADA incidence (relative risk [RR] = 15.0, 95% CI 7.51-29.97). The association was similar for type 2 diabetes (RR = 15.37, 95% CI 12.07-19.57) but not for type 1 diabetes. Similarly, age (>or=60 years) was an important risk factor for LADA (RR = 5.62, 95% CI 2.36-13.4) as well as for type 2 diabetes (RR = 6.78, 95% CI 5.07-9.06) in contrast to type 1 diabetes. Physical inactivity was associated with an increased risk of both LADA and type 2 diabetes. CONCLUSIONS/INTERPRETATION: This study suggests that increased age, overweight and physical inactivity are as strong risk factors for LADA as for type 2 diabetes. These findings suggest a role for insulin resistance in the pathogenesis of LADA.