Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: An IMI-DIRECT study.

AIM: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (ß = 0.36, 95% CI 0.13-0.58), Subgroup 3 (ß = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (ß = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

Effect of metformin on plasma metabolite profile in the Copenhagen Insulin and Metformin Therapy (CIMT) trial.

AIM: Metformin is the first-line treatment for Type 2 diabetes. However, not all people benefit from this drug. Our aim was to investigate the effects of metformin on the plasma metabolome and whether the pretreatment metabolite profile can predict HbA1c outcome. METHODS: Post hoc analysis of the Copenhagen Insulin and Metformin Therapy (CIMT) trial, a multicentre study from May 2008 to December 2012, was carried out. We used a non-target method to analyse 87 plasma metabolites in participants with Type 2 diabetes (n = 370) who were randomized in a 1 : 1 ratio to 18 months of metformin or placebo treatment. Metabolites were measured by liquid chromatography-mass spectrometry at baseline and at 18-month follow-up and the data were analysed using a linear mixed-effect model. RESULTS: At baseline, participants who were on metformin before the trial (n = 312) had higher levels of leucine/isoleucine and five lysophosphatidylethanolamines (LPEs), and lower levels of carnitine and valine compared with metformin-naïve participants (n = 58). At follow-up, participants randomized to metformin (n = 188) had elevated levels of leucine/isoleucine and reduced carnitine, tyrosine and valine compared with placebo (n = 182). At baseline, participants on metformin treatment with the highest levels of carnitine C10:1 and leucine/isoleucine had the lowest HbA1c (P-interaction = 0.02 and 0.03, respectively). This association was not significant with HbA1c at follow-up. CONCLUSIONS: Metformin treatment is associated with decreased levels of valine, tyrosine and carnitine, and increased levels of leucine/isoleucine. None of the identified metabolites can predict the HbA1c -lowering effect of metformin. Further studies of the association between metformin, carnitine and leucine/isoleucine are warranted.

Metabolite profiling of obese individuals before and after a one year weight loss program.

OBJECTIVE: We and others have previously characterized changes in circulating metabolite levels following diet-induced weight loss. Our aim was to investigate whether baseline metabolite levels and weight-loss-induced changes in these are predictive of or associated with changes in body mass index (BMI) and metabolic risk traits. METHODS: Serum metabolites were analyzed with gas and liquid chromatography/mass spectrometry in 91 obese individuals at baseline and after participating in a 1 year non-surgical weight loss program.ResultsA total of 137 metabolites were identified and semi-quantified at baseline (BMI 42.7±5.8, mean±s.d.) and at follow-up (BMI 36.3±6.6). Weight-loss-induced modification was observed for levels of 57 metabolites in individuals with ⩾10% weight loss. Lower baseline levels of xylitol was predictive of a greater decrease in BMI (ß=0.06, P<0.01) and ⩾10% weight loss (odds ratio (OR)=0.2, confidence interval (CI)=0.07-0.7, P=0.01). Decreases in levels of isoleucine, leucine, valine and tyrosine were associated with decrease in BMI (ß>0.1, P<0.05) and ⩾10% weight loss (isoleucine: OR=0.08, CI=0.01-0.3, leucine: OR=0.1, CI=0.01-0.6, valine: OR=0.1, CI=0.02-0.5, tyrosine: OR=0.1, CI=0.03-0.6, P<0.02). CONCLUSIONS: Diet-induced weight loss leads to mainly reduced levels of metabolites that are elevated in obese insulin resistant individuals. We identified multiple new associations with metabolic risk factors and validated several previous findings related to weight loss-mediated metabolite changes. Levels of specific metabolites, such as xylitol, may be predictive of the response to non-surgical weight loss already at baseline.

Cost-effectiveness of sensor-augmented pump therapy versus standard insulin pump therapy in patients with type 1 diabetes in Denmark.

AIMS: The use of continuous subcutaneous insulin infusion (CSII) in type 1 diabetes (T1D) has increased in recent years. Sensor-augmented pump therapy (SAP) with low glucose suspend (LGS) (allowing temporary suspension of insulin delivery if blood glucose level falls below a pre-defined threshold level) provides additional benefits over CSII alone, but is associated with higher acquisition costs. Therefore, a cost-effectiveness analysis of SAP+LGS versus CSII in patients with T1D was performed. METHODS: Analyses were performed using the CORE Diabetes Model in two different patient cohorts in Denmark, one with hyperglycemia at baseline and one with increased risk for hypoglycemic events. Clinical input data were sourced from published literature. The analysis was performed over a lifetime time horizon from a societal perspective. Future costs and clinical outcomes were discounted at 3% per annum. RESULTS: In patients who were hyperglycemic at baseline the use of SAP+LGS versus CSII resulted in improved quality-adjusted life expectancy (12.44 versus 10.99 quality-adjusted life years [QALYs]) but higher mean lifetime costs (DKK 2,027,316 versus DKK 1,801,293) leading to an incremental cost-effectiveness ratio (ICER) of DKK 156,082 per QALY gained. For patients at increased risk for hypoglycemic events the ICER for SAP+LGS versus CSII was DKK 89,868 per QALY gained. CONCLUSIONS: The ICER for SAP+LGS versus CSII falls below commonly cited willingness-to-pay thresholds. Therefore, in Denmark, the use of SAP+LGS is likely to be considered cost-effective relative to CSII for patients with T1D who are either hyperglycemic, despite CSII use, or who experience frequent severe hypoglycemic events.

High and low vitamin D level is associated with cardiovascular autonomic neuropathy in people with Type 1 and Type 2 diabetes.

AIM: To investigate the possible association between vitamin D deficiency and cardiovascular autonomic neuropathy in people with diabetes. METHODS: A total of 113 people with Type 1 or Type 2 diabetes [mean (interquartile range) diabetes duration 22.0 (12-31) years, mean (sd) age 56.2 (13.0) years, 58% men] underwent vitamin D (D2 and D3) assessment, and were screened for cardiovascular autonomic neuropathy using three cardiovascular reflex tests [heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva manoeuvre] and assessment of 5-min resting heart rate and heart rate variability indices. RESULTS: We found an inverse U-shaped association between serum vitamin D level and E/I ratio, 30/15 ratio and three heart rate variability indices (P < 0.05). Vitamin D level was non-linearly associated with cardiovascular autonomic neuropathy diagnosis (P < 0.05 adjusted for age and sex). Linear regression models showed that an increase in vitamin D level from 25 to 50 nmol/l was associated with an increase of 3.9% (95% CI 0.1;7.9) in E/I ratio and 4.8% (95% CI 4.7;9.3) in 30/15 ratio. Conversely, an increase from 125 to 150 nmol/l in vitamin D level was associated with a decrease of 2.6% (95% CI -5.8;0.1) and 4.1% (95% CI -5.8;-0.5) in the respective outcome measures. CONCLUSIONS: High and low vitamin D levels were associated with cardiovascular autonomic neuropathy in people with diabetes. Future studies should explore this association and the efficacy of treating dysvitaminosis D to prevent cardiovascular autonomic neuropathy.

Potential positive impact of group-based diabetes dialogue meetings on diabetes distress and glucose control in people with type 1 diabetes.

OBJECTIVE: To evaluate the effect of group-based diabetes dialogue meetings (DDMs) on diabetes distress, perceived competence and glycaemic control. METHODS: Patients with type 1 diabetes (T1D) were invited to DDMs with peers and healthcare professionals. The impact of participation was evaluated by change in diabetes distress measured by Problem Areas in Diabetes (PAID), diabetes competence measured by Perceived Competence in Diabetes (PCD), change in HbA1c before and one year after the DDMs. RESULTS: 120 patients with T1D participated in at least one DDM: 75% female, mean age 50 years (range 21-76), mean diabetes duration 23 years (range 0-64); 39% of all participants had a baseline PAID score≥33, indicating high levels of distress. After one year, both PAID (from 30.4±16.6 to 27.4±17.1; n=81, p=0.03), and mean HbA1c (61.6±10.2 to 58.8±9.9; n=120, p<0.0001) had improved significantly. PCD showed no change. Meanwhile, the benefit from participating was rated high with a median of four out of five and the major gain being the possibility to share experiences with peers. CONCLUSION: Group-based DDMs were highly appreciated by participants and associated with significant improvements in diabetes distress and HbA1c. PRACTICE IMPLICATIONS: DDMs target a large group of patients using few staff resources.

Vitamin D insufficiency over 5 years is associated with increased fracture risk-an observational cohort study of elderly women.

UNLABELLED: This study of elderly Swedish women investigated the association between chronic vitamin D insufficiency and osteoporotic fractures occurring between ages 80-90. The incidence and risk of hip and major osteoporotic fractures was significantly higher in elderly women with low vitamin D levels maintained over 5 years. INTRODUCTION: Vitamin D insufficiency among the elderly is common; however, relatively little is known about the effects of long-term hypovitaminosis D on fracture. We investigated sequential assessment of serum 25(OH)D at age 75 and 80 to determine if continuously low 25(OH)D levels are associated with increased 10-year fracture incidence. METHODS: One thousand forty-four Swedish women from the population-based OPRA cohort, all 75 years old, attended at baseline (BL); 715 attended at 5 years. S-25(OH)D was available in 987 and 640, respectively and categorized as: <50 (Low), 50-75 (Intermediate), and >75 nmol/L (High). Incident fracture data was collected with maximum follow-up to 90 years of age. RESULTS: Hip fracture incidence between age 80-85 was higher in women who had low 25(OH)D at both baseline and 5 years (22.2 % (Low) vs. 6.6 % (High); p = 0.003). Between age 80-90, hip fracture incidence was more than double that of women in the high category (27.9 vs. 12.3 %; p = 0.006). Within 5-years, 50 % of women in the continuously low group compared to 34 % in the continuously high 25(OH)D group had an osteoporotic fracture (p = 0.004) while 10-year incidence was higher compared to the intermediate (p = 0.020) but not the high category (p = 0.053). The 10-year relative risk of hip fracture was almost three times higher and osteoporotic fracture risk almost doubled for women in the lowest 25(OH)D category compared to the high category (HR 2.7 and 1.7; p = 0.003 and 0.023, respectively). CONCLUSION: In these elderly women, 25(OH)D insufficiency over 5-years was associated with increased 10-year risk of hip and major osteoporotic fractures.

Six-minute walk test before and after a weight reduction program in obese subjects.

UNLABELLED: OBEJCTIVE: Weight loss and physical activity have shown favorable effects on risks associated with obesity. It is therefore of interest to evaluate exercise capacity and related co-morbidities in obese patients. DESIGN AND METHODS: We present data from obese subjects evaluated by the 6-minute walk test (6MWT) before and after a 7.3 (6.1-8.2) month weight reduction program. RESULTS: 251 subjects completed the test at baseline (BMI 40.6 [36.9-44.6] kg/m(2) ) and 129 (51.4%) repeated the test after intervention (BMI 35.6 [31.2-38.5] kg/m(2) ). The six minute walking distance (6MWD) at baseline (535 [480-580] m) and at follow up (599 [522-640] m) correlated to several cardiovascular risk markers. Age, weight, height, resting heart rate, smoking status, fP-glucose and use of ß-blockers explained 43 % of the variance in predicted 6MWD at baseline. The effect of smoking status, fP-glucose, ß-blockers, and resting heart rate lost significance at follow up. Presence of diabetes and the metabolic syndrome had a negative influence on 6MWD but did not affect the impact of intervention based on percentage increase in walking distance. Gender had no impact on 6MWD. Reported pain during the test was common but decreased after intervention (57.0% vs. 28.7%, P < 0.001). CONCLUSIONS: The 6MWT may be used to evaluate intervention success beyond kilogram weight loss in obese subjects. We present formulas to predict 6MWD and the effect of weight loss on walking distance in clinical practice. Pain is a common problem which has to be considered when giving advice on exercise as a part of weight loss intervention.

Willingness to pay for diabetes drug therapy in type 2 diabetes patients: based on LEAD clinical programme results.

OBJECTIVE: The purpose of this study was to investigate the preferences of people with diabetes for liraglutide vs other glucose lowering drugs, based on outcomes of clinical trials. METHODS: Willingness to pay (WTP) for diabetes drug treatment was assessed by combining results from a recent WTP study with analysis of results from the Liraglutide Effect and Action in Diabetes (LEAD) programme. The LEAD programme included six randomised clinical trials with 3967 participants analysing efficacy and safety of liraglutide 1.2 mg (LEAD 1-6 trials), rosiglitazone (LEAD 1 trial), glimepiride (LEAD 2-3 trials), insulin glargine (LEAD 5 trial), and exenatide (LEAD 6 trial). The WTP survey used discrete choice experimental (DCE) methodology to evaluate the convenience and clinical effects of glucose lowering treatments. RESULTS: People with type 2 diabetes were prepared to pay an extra €2.64/day for liraglutide compared with rosiglitazone, an extra €1.94/day compared with glimepiride, an extra €3.36/day compared with insulin glargine, and an extra €0.81/day compared with exenatide. Weight loss was the largest component of WTP for liraglutide compared with rosiglitazone, glimepiride, and insulin glargine. Differences in the administration of the two drugs was the largest component of WTP for liraglutide (once daily anytime) compared with exenatide (twice daily with meals). A limitation of the study was that it was based on six clinical trials where liraglutide was the test drug, but each trial had a different comparator, therefore the clinical effects of liraglutide were much better documented than the comparators. CONCLUSIONS: WTP analyses of the clinical results from the LEAD programme suggested that participants with type 2 diabetes were willing to pay appreciably more for liraglutide than other glucose lowering treatments. This was driven by the relative advantage of weight loss compared with rosiglitazone, glimepiride, and insulin glargine, and administration frequency compared with exenatide.

Willingness-to-pay for benefits associated with basal insulin treatment of type 2 diabetes.

Data from a 20-week trial comparing insulin detemir and neutral protamine Hagedorn (NPH) insulin in insulin-naïve people with type 2 diabetes were analyzed using willingness-to-pay (WTP) data, a proxy for patient preference. The advantages of insulin detemir relative to NPH insulin with respect to a lower hypoglycemia rate and less weight gain were associated with a value of €27.87 per month.

Willingness to pay for health improvements associated with anti-diabetes treatments for people with type 2 diabetes.

OBJECTIVES: This study aimed to investigate the most important consequences of diabetes medication, as measured by the patients' willingness to pay (WTP). RESEARCH DESIGN AND METHODS: People in Sweden were recruited using existing nationwide e-mail panels if they were adults (>or=18 years) with type 2 diabetes and were receiving pharmacological anti-diabetes treatment(s). Data were collected electronically and results were analysed using a standard statistical model designed for choice games (conditional logit). Six characteristics relating to treatment of diabetes were examined: weight (gain or loss), mean glycated haemoglobin level (HbA(1c)), hypoglycaemic events, nausea, need for injections (with or independently of meals), and blood glucose testing. RESULTS: A total of 461 people with type 2 diabetes (291 males; 170 females) completed an internet questionnaire and were eligible for inclusion. Participants placed high value on weight loss and nausea avoidance; they would pay 176 Swedish Krona (SEK)/euro15.61 per month to lose 1 kg, and would pay SEK 560 (euro49.67) per month to avoid nausea completely. Patients wanting to reduce the number of hypoglycaemic events from three per month to none were willing to pay SEK 419 (euro37.17) per month. Patients valued a 1 percentage point reduction in HbA(1c) at SEK 414 (euro36.72) per month. Participants preferred taking tablets to injections and required a compensation of SEK 376 (euro33.35) to accept one injection/day. Injections independent of meals were preferred to injections with meals (WTP: SEK 140/euro12.42 per month). Potential limitations of this study are that the preferences expressed may not match preferences in real-life situations, and bias through the use of electronic questionnaire, which restricted participation to those with access to, and experience with, the internet. CONCLUSION: People with type 2 diabetes were willing to pay a considerable amount of money each month to lose weight, reduce or avoid hypoglycaemic events and reduce HbA(1C).

A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans.

AIMS/HYPOTHESIS: It has recently been suggested that the rs738409 G allele in PNPLA3, which encodes adiponutrin, is strongly associated with increased liver fat content in three different ethnic groups. The aims of the present study were as follows: (1) to try to replicate these findings in European individuals with quantitative measures of hepatic fat content; (2) to study whether the polymorphism influences hepatic and adipose tissue insulin sensitivity; and (3) to investigate whether PNPLA3 expression is altered in the human fatty liver. METHODS: We genotyped 291 Finnish individuals in whom liver fat had been measured using proton magnetic resonance spectroscopy. Hepatic PNPLA3 expression was measured in 32 participants. Hepatic and adipose tissue insulin sensitivities were measured using a euglycaemic-hyperinsulinaemic (insulin infusion 0.3 mU kg(-1) min(-1)) clamp technique combined with infusion of [3-(3)H]glucose in 109 participants. RESULTS: The rs738409 G allele in PNPLA3 was associated with increased quantitative measures of liver fat content (p = 0.011) and serum aspartate aminotransferase concentrations (p = 0.002) independently of age, sex and BMI. Fasting serum insulin and hepatic and adipose tissue insulin sensitivity were related to liver fat content independently of genotype status. PNPLA3 mRNA expression in the liver was positively related to obesity (r = 0.62, p < 0.0001) and to liver fat content (r = 0.58, p = 0.025) in participants who were not morbidly obese (BMI < 40 kg/m(2)). CONCLUSIONS/INTERPRETATION: A common variant in PNPLA3 increases the risk of hepatic steatosis in humans.

Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents.

BACKGROUND: The global prevalence of obesity and overweight is increasing rapidly among adults as well as among children and adolescents. Recent genome-wide association studies have provided strong support for association between variants in the FTO gene and obesity. We sequenced regions of the FTO gene to identify novel variants that are associated with obesity and related metabolic traits. RESULTS: We screened exons 3 and 4 including exon-intron boundaries in FTO in 48 obese children and adolescents and identified three novel single nucleotide polymorphism in the fourth intronic region, (c.896+37A>G, c.896+117C>G and c.896+223A>G). We further genotyped c.896+223A>G in 962 subjects, 450 well-characterized obese children and adolescents and 512 adolescents with normal weight. Evidence for differences in genotype frequencies were not detected for the c.896+223A>G variant between extremely obese children and adolescents and normal weight adolescents (P=0.406, OR=1.154 (0.768-1.736)). Obese subjects with the GG genotype, however, had 30% increased fasting serum insulin levels (P=0.017) and increased degree of insulin resistance (P=0.025). There were in addition no differences in body mass index (BMI) or BMI standard deviation score (SDS) levels among the obese subjects according to genotype and the associations with insulin levels and insulin resistance remained significant when adjusting for BMI SDS. CONCLUSION: These findings suggest that this novel variant in FTO is affecting metabolic phenotypes such as insulin resistance, which are not mediated through differences in BMI levels.

The hormone-sensitive lipase C-60G promoter polymorphism is associated with increased waist circumference in normal-weight subjects.

OBJECTIVE: Hormone-sensitive lipase (HSL) is a key enzyme in the mobilization of fatty acids from triglyceride stores in adipocytes. The aim of the present study was to investigate the role of the HSL gene promoter variant C-60G, a polymorphism which previously has been associated with reduced promoter activity in vitro, in obesity and type 2 diabetes. DESIGN: We genotyped two materials consisting of obese subjects and non-obese controls, one material with offspring-parents trios, where the offspring was abdominally obese and one material with trios, where the offspring had type 2 diabetes or impaired glucose homeostasis. HSL promoter containing the HSL C-60G G-allele was generated and tested against a construct with the C-allele in HeLa cells and primary rat adipocytes. HSL mRNA levels were quantified in subcutaneous and visceral fat from 33 obese subjects. RESULTS: We found that the common C-allele was associated with increased waist circumference and WHR in lean controls, but there was no difference in genotype frequency between obese and non-obese subjects. There was a significant increased transmission of C-alleles to the abdominally obese offspring but no increased transmission of C-alleles was observed to offspring with impaired glucose homeostasis. The G-allele showed reduced transcription in HeLa cells and primary rat adipocytes. HSL mRNA levels were significantly higher in subcutaneous compared to visceral fat from obese subjects. CONCLUSION: The HSL C-60G polymorphism is associated with increased waist circumference in non-obese subjects.

Increased risk of obesity associated with the variant allele of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men.

AIMS/HYPOTHESIS: The variant allele of the Gly482Ser polymorphism in peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PPARGC1A or PGC1alpha), a critical determinant of skeletal muscle metabolism, has been associated with obesity and type 2 diabetes. Previous studies indicate that these risks depend on sex and environmental triggers such as age. The aim of the present study was to investigate the possible interactions between genotype and age and physical activity on risk of obesity. METHODS: We genotyped PPARGC1A Gly482Ser, in a population-based study comprising 899 women and 902 men aged between 30 and 75 years in Vara, Sweden. RESULTS: Genotyping revealed that 56% of the males and 57% of the females carried the PPARGC1A 482Ser variant allele. Elderly males (>or=50 years) carrying 482Ser had an increased risk of obesity compared with subjects who were homozygous for the wild-type allele (odds ratio [OR]=1.99, 95% CI 1.14-3.47, p=0.015). The risk was restricted to males with a low leisure-time physical activity level, and was significantly weaker (OR=0.44, 95% CI 0.22-0.87, p=0.018) for the homozygous 482Gly carriers among this subgroup. No association with obesity was found in elderly males with a high level of physical activity, in younger males, or in females of any age group or level of physical activity. CONCLUSIONS/INTERPRETATION: Our findings confirm that sex and age should be considered when investigating the influence of the PPARGC1A Gly482Ser polymorphism on metabolic disease. The risk of obesity associated with 482Ser is evident only in physically inactive elderly male subjects. Whenever possible, the level of physical activity should be addressed in future studies on disease risk associated with PPARGC1A Gly482Ser.

Obesity and cardiovascular risk factors in type 2 diabetes: results from the Swedish National Diabetes Register.

OBJECTIVES: To compare obese with normal and overweight type 2 diabetic patients regarding body mass index (BMI) and cardiovascular risk factors, and to analyse changes in weight versus risk factors. DESIGN AND SETTING: A cross-sectional study of 44 042 type 2 patients, and a 6-year prospective study of 4468 type 2 patients. RESULTS: Obese patients (BMI > or = 30 kg m(-2)), 37% of all patients, had high frequencies of hypertension (88%), hyperlipidaemia (81%) and microalbuminuria (29%). Only 11% had blood pressure <130/80 mmHg. Their ratio of triglycerides to HDL cholesterol was considerably elevated, whilst the mean total and LDL cholesterol were similar as in normal weight subjects. Obese patients had elevated odds ratios for hypertension, hyperlipidaemia and microalbuminuria: 2.1, 1.8 and 1.4 in the cross-sectional study, similarly confirmed in the prospective 6-year study. BMI was an independent predictor of these risk factors (P < 0.001), although only slightly associated with HbA1c and not with total or LDL cholesterol. A change in BMI during the prospective study was related to a change in HbA1c in patients treated with diet and oral hypoglycaemic agents (OHAs) but not with insulin. In all patients, an increase in BMI was related to the development of hypertension, and a change in BMI to change in blood pressure, also mostly confirmed when treated with diet, OHAs or insulin. CONCLUSIONS: The high frequencies of risk factors in obese type 2 patients implies an increased risk of cardiovascular disease and the need for therapeutic measures. The paradox that hypoglycaemic treatment accompanied by weight gain may increase cardiovascular risk factors seems to be verified here concerning hypertension but not concerning microalbuminuria.

A polymorphism in the adiponectin gene influences adiponectin expression levels in visceral fat in obese subjects.

OBJECTIVE: Reduced serum adiponectin levels have been found in obesity and type 2 diabetes and variations in the adiponectin gene (APM1) have been associated with type 2 diabetes and features of the metabolic syndrome in different populations. STUDY DESIGN: Here, we investigated the expression of APM1 in adipose tissue and studied the relationship between variation in APM1 expression, the APM1 G276T polymorphism, the common PPARG Pro12Ala polymorphism and clinical features of 36 morbidly obese (body mass index (BMI) 41.5 +/- 4.9 kg/m2) nondiabetic subjects. RESULTS: APM1 mRNA expression in visceral fat was correlated with serum adiponectin levels (r = 0.54, P = 0.012). In visceral, but not in subcutaneous, adipose tissue APM1 mRNA level was 38% higher among carriers of the APM1 G276T T allele (G/T and T/T) than among carriers of the G/G genotype (0.91 +/- 0.06 for G/T and T/T carriers vs 0.66 +/- 0.09 for G/G carriers, P = 0.013). Carriers of the T allele also had significantly higher body fat percent compared to G/G carriers (65 +/- 6 vs 56 +/- 10%, P = 0.011). CONCLUSION: Our results indicate that genetic variation in APM1 influences the expression of the gene in visceral adipose tissue and suggest a potential role for such variation in regulation of body fat accumulation in obese subjects.

Role of the FOXC2 -512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome.

OBJECTIVE: Overexpression of the human transcription factor FOXC2 gene (FOXC2) protects against insulin resistance in mice and a common FOXC2 polymorphism (-512C>T) has been suggested to be associated with insulin resistance in humans. Here, we addressed the potential role for FOXC2 as a candidate gene for type 2 diabetes and associated phenotypes. MATERIALS AND METHODS: A case-control study was performed in 390 type 2 diabetic patients and 307 control subjects. The number of patients was increased to a total of 768 subjects for further study of phenotypic differences relating to the dysmetabolic syndrome relative to genetic variation. The FOXC2 -512C>T polymorphism was genotyped by a restriction fragment length polymorphism PCR assay. RESULTS: FOXC2 -512C>T allele and genotype distribution did not differ between patients with type 2 diabetes and control subjects, but the C/C genotype was associated with increased body mass index (BMI, kg/m2) (Pa=0.03) among type 2 diabetic patients. The FOXC2 -512C>T polymorphism was a significant independent predictor of BMI (P=0.001) in a multiple regression model including age, gender and affection status. We found no significant association with type 2 diabetes-related metabolic parameters but that the C-allele (P=0.01) and C/C and C/T genotypes (P=0.03) were significantly over-represented in type 2 diabetic males with a concomitant diagnosis of dysmetabolic syndrome. CONCLUSION: We conclude that FOXC2 is associated with obesity and metabolic deterioration but does not contribute to an increased risk for type 2 diabetes.