Associations between weight loss history and factors related to type 2 diabetes risk in the Stop Diabetes study.

BACKGROUND: Frequent weight loss attempts are related to maladaptive eating behaviours and higher body mass index (BMI). We studied associations of several type 2 diabetes (T2D) risk factors with weight loss history, defined as the frequency of prior weight loss attempts, among Finnish adults at increased risk for T2D. METHODS: This study (n = 2684, 80% women) is a secondary analysis of the 1-year StopDia lifestyle intervention with digital intervention group, digital intervention + face-to-face counselling group, or control group. The frequency of prior weight loss attempts was categorized into five groups: no attempts/no attempts to lose weight, but trying to keep weight stable/1-2 attempts/3 or more attempts/ continuous attempts. Data on emotional eating and social/emotional nutrition self-efficacy were collected with a digital questionnaire. We assessed baseline differences between categories of weight loss history as well as the intervention effects. RESULTS: Altogether 84% of participants had attempted weight loss. Those with one or more weight loss attempts had higher BMI, larger waist circumference, and more emotional eating compared to 'no attempts' and 'no attempts to lose weight, but trying to keep weight stable' categories. The 'no attempts' category had the highest baseline fasting insulin, whereas it showed the largest decrease in this measure with the intervention. This change in fasting insulin in the 'no attempts' category was significantly different from all the other categories. Emotional nutrition self-efficacy slightly improved in the 'no attempts' category, which was significantly different from its concomitant decrease in the categories '1-2 attempts' and '3 or more attempts'. The intervention group assignment did not affect the results. CONCLUSIONS: Multiple attempts to lose weight may unfavourably affect T2D risk factors as well as lifestyle intervention outcomes. More research is needed on how weight loss frequency could affect T2D risk factors and how to design lifestyle interventions for individuals with frequent previous weight loss attempts.

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. METHODS: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). RESULTS: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. CONCLUSION: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

Alterations in fatty acid metabolism in response to obesity surgery combined with dietary counseling.

BACKGROUND: The effects of obesity surgery on serum and adipose tissue fatty acid (FA) profile and FA metabolism may modify the risk of obesity-related diseases. METHODS: We measured serum (n=122) and adipose tissue (n=24) FA composition and adipose tissue mRNA expression of genes regulating FA metabolism (n=100) in participants of the Kuopio Obesity Surgery Study (KOBS, age 47.2±8.7 years, BMI 44.6±6.0, 40 men, 82 women) before and one year after obesity surgery. As part of the surgery protocol, all the subjects were instructed to add sources of unsaturated fatty acids, such as rapeseed oil and fatty fish, into their diet. The results were compared with changes in serum FA composition in 122 subjects from the Finnish Diabetes Prevention study (DPS) (age 54.3±7.1 years, BMI 32.2±4.6, 28 men, 94 women). RESULTS: The proportion of saturated FAs decreased and the proportion of n-3 and n-6 FAs increased in serum triglycerides after obesity surgery (all P<0.002). Weight loss predicted changes in quantitative amounts of saturated FAs, monounsaturated FAs, n-3 and n-6 FAs in triglycerides (P<0.002 for all). Moreover, the changes in adipose tissue FAs reflected the changes in serum FAs, and some of the changes were associated with mRNA expression of elongases and desaturases in adipose tissue (all P<0.05). In line with this the estimated activity of elongase (18:1 n-7/16:1 n-7) increased significantly after obesity surgery in all lipid fractions (all P<4 × 10-7) and the increase in the estimated activity of D5D in triglycerides was associated with higher weight loss (r=0.415, P<2 × 10-6). Changes in serum FA profile were similar after obesity surgery and lifestyle intervention, except for the change in the absolute amounts of n-3 FAs between the two studies (P=0.044). CONCLUSIONS: Beneficial changes in serum and adipose tissue FAs after obesity surgery could be associated with changes in endogenous metabolism and diet.

Obstructive sleep apnea: the effect of bariatric surgery after 12 months. A prospective multicenter trial.

BACKGROUND: Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder, particularly in bariatric patients. It is known to be tightly linked with metabolic abnormalities and cardiovascular morbidity. Obesity is the most noteworthy individual risk factor for OSA. The aim of this study was to investigate the effect of a laparoscopic Roux-en-Y gastric bypass (LRYGB) on OSA one year after surgery. METHODS: In this prospective multicenter study standard overnight cardiorespiratory recording was conducted 12 months after bariatric surgery in 132 patients who had OSA in the baseline recording prior to the operation. The main outcome measures were changes in the prevalence of OSA and apnea-hypopnea index (AHI). In addition, the changes in anthropometric and demographic measurements including weight, body mass index (BMI), and waist and neck circumference were evaluated. A sleep symptom questionnaire was administered at baseline and at 12 months. RESULTS: The prevalence of OSA decreased from 71% at baseline to 44% at 12 months after surgery (p < 0.001). OSA was cured in 45% and cured or improved in 78% of the patients, but moderate or severe OSA still persisted in 20% of the patients after the operation. De novo OSA occurred in eight percent of the patients, and total AHI decreased from 27.8 events/h to 9.9 events/h (p < 0.001). CONCLUSIONS: LRYGB is effective in treating OSA. However, the findings demonstrate that a postoperative cardiorespiratory recording is needed in order to identify the patients with persistent moderate to severe OSA after the operation. CLINICAL TRIAL REGISTRATION: ClinalTrials.gov; No.: NCT01080404; URL: www.clinicaltrials.gov.

Prevalence of Obstructive Sleep Apnoea Among Patients Admitted for Bariatric Surgery. A Prospective Multicentre Trial.

BACKGROUND: Obesity has become one of the greatest public health concerns worldwide and is known to be the most important risk factor for obstructive sleep apnoea (OSA). Prevalence of OSA has increased over the last two decades, but it is estimated that the majority of cases still remain undiagnosed. The aim of this study was to investigate the prevalence of OSA in Finnish bariatric surgery candidates. METHODS: In this prospective multicentre study, standard overnight cardiorespiratory recording was conducted in 197 consecutive patients from three different hospitals. A sleep questionnaire was also administered. Anthropometric and demographic measurements included age, weight, body mass index (BMI) and waist and neck circumference. RESULTS: Altogether, 71 % of the patients were diagnosed with OSA. The prevalence was higher in males (90 %) than in females (60 %) (p < 0.001). In OSA patients' group, the mean neck and waist circumference was larger (p < 0.001) and the body weight higher (p < 0.01) than in non-OSA group. When separating patients by gender, a significant difference remained only concerning neck circumference in female patients. CONCLUSIONS: OSA is very common among bariatric surgery patients, especially in men. Considering this and the increased long-term morbidity and mortality generally related to OSA, a routine screening for OSA seems indicated in bariatric patients, particularly men.

Association of plasma fatty acid composition with plasma irisin levels in normal weight and overweight/obese children.

BACKGROUND: Irisin has been suggested to protect against overweight. There are no previous data on the association of plasma fatty acid (FA) composition with plasma irisin. OBJECTIVES: We studied the association of FA composition with plasma irisin in normal weight and overweight/obese children. METHODS: This cross-sectional study included pre-pubertal children (388 normal weight children and 55 overweight/obese children); 6-9 years of age, taking part in the Physical Activity and Nutrition in Children Study. After an overnight fast, we measured plasma FA composition by gas chromatography and plasma irisin levels by enzyme-linked immunosorbent assay. RESULTS: Higher proportion of total monounsaturated fatty acids in plasma cholesteryl esters (CEs) (ß = 0.139, P = 0.003) and phospholipids (PLs) (ß = 0.147, P = 0.002) and lower proportion of total polyunsaturated fatty acids in plasma CE (ß = -0.130, P = 0.006) and PL (ß = -0.165, P < 0.001) were associated with higher plasma irisin level in the whole study group. The association of plasma FA composition with plasma irisin level was stronger among overweight/obese children compared to normal weight children. Higher proportion of γ-linolenic acid (ß = 0.324, P = 0.017) and lower proportion of linoleic acid (ß = -0.397, P = 0.005) in plasma CE were related to higher plasma irisin level among overweight/obese children, indicating the direct association of estimated D6D activity in plasma CE (ß = 0.343, P = 0.011) with plasma irisin. Furthermore, higher proportion of oleic acid in plasma CE (ß = 0.345, P = 0.012) and PL (ß = 0.292, P = 0.033) and higher proportion of adrenic acid (ß = 0.366, P = 0.008) and docosapentaenoic acid (ß = 0.351, P = 0.010) in plasma PL were associated with higher plasma irisin level among overweight/obese children. CONCLUSION: Metabolically unfavourable plasma FA profile was associated with higher plasma irisin level especially in overweight/obese children, suggesting that excess body fat might modulate these relationships.

Markers of cholesterol metabolism as biomarkers in predicting diabetes in the Finnish Diabetes Prevention Study.

BACKGROUND AND AIMS: We examined the effect of serum markers of cholesterol synthesis and absorption on the incidence of type 2 diabetes (T2D) in the randomized Finnish Diabetes Prevention Study (DPS). We also explored a possible interaction of ABCG8 rs4299376 on sterol levels and lifestyle intervention. METHODS AND RESULTS: We conducted a prospective cohort study including overweight, middle-aged people with impaired glucose tolerance at baseline who participated in the randomized DPS. The primary outcome of the DPS was the diagnosis of T2D based on repeated oral glucose tolerance tests (OGTTs). After active intervention (median of four years, 1994-2001), non-T2D participants were further followed until T2D diagnosis, dropout or the end of 2009. Of these, 340 participants who had ß-sitosterol, campesterol, lathosterol and desmosterol measured by gas chromatography-mass spectrometry during the active four-year follow-up and who were not using cholesterol lowering medications were analysed. Surrogate indexes of insulin sensitivity (IS) and secretion were calculated from an OGTT. In adjusted models, plant sterols during the four-year follow-up were associated with lower T2D incidence during the extended eight-year follow-up (HR for 1-SD change in ß-sitosterol and campesterol: 0.76 [0.63-0.92], and 0.81 [0.67-0.99], respectively). Lathosterol levels were associated with higher T2D incidence (HR: 1.35 [1.13-1.62]). These associations, though, were not independent of IS. There was an interaction between rs4299376 and study group on ß-sitosterol (p = 0.001) and campesterol (p = 0.004) levels during the follow-up. CONCLUSIONS: Markers of low absorption and high synthesis of cholesterol were associated with the risk of developing T2D, mostly ascribed to IS.

Associations of I148M variant in PNPLA3 gene with plasma ALT levels during 2-year follow-up in normal weight and overweight children: the PANIC Study.

OBJECTIVES: PNPLA3 I148M polymorphism (rs738409) has been strongly associated with liver fat content and plasma alanine aminotransferase (ALT) levels in obese adults and children, but little is known about these relationships in normal weight individuals. We studied the associations and interactions of overweight and the PNPLA3 I148M polymorphism with plasma ALT levels during 2-year follow-up in children. METHODS: Subjects were a population sample of 481 Caucasian children aged 6-8 years examined at baseline and 419 children re-examined after 2-year follow-up. Altogether, 58 (12%) of 481 children at baseline and 71 (17%) of 419 children after 2-year follow-up were overweight. We assessed plasma ALT levels and other cardiometabolic risk factors and genotyped the PNPLA3 I148M polymorphism. RESULTS: Being overweight and carrying PNPLA3 148M allele were associated with increased ALT levels at baseline (P = 0.002; P = 0.033) and after 2-year follow-up (P < 0.001; P = 0.001). Being overweight (P < 0.001) and carrying PNPLA3 148M allele (P = 0.001) were also associated with increase in ALT levels during 2-year follow-up. PNPLA3 148M allele carriers had increased ALT levels at baseline (P = 0.024 for interaction) and after 2-year follow-up (P = 0.002 for interaction) as well as a larger increase in ALT levels during 2-year follow-up (P = 0.002 for interaction) if they were overweight but not if they were normal weight. Further adjustment for clinical puberty, dietary factors, physical activity or sedentary behaviour had little or no effect on these associations. CONCLUSION: PNPLA3 148M allele carriers had higher plasma ALT levels and larger increase in ALT levels during follow-up than non-carriers only among overweight children.

Genetic risk score does not predict the outcome of obesity surgery.

BACKGROUND: We evaluated the benefit of using combined genetic risk score (GRS) of known single nucleotide polymorphisms (SNPs) for body mass index (BMI) and waist/hip ratio (WHR) in the prediction of weight loss and weight regain after obesity surgery. METHODS: A total of 163 consecutive morbidly obese individuals undergoing Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in a single bariatric center in Finland were recruited. Fasting blood samples were drawn after 12 h of fasting before and 1 year after bariatric operation. Data for weight regain and medication were collected with a questionnaire after 3.1 ± 2.7 years (mean ± SD) follow-up. Nonalcoholic steatohepatitis (NASH) was diagnosed with liver histology. Twenty BMI- and 13 WHR-related SNPs were genotyped. Linear regression was used to identify factors predicting weight loss and weight regain. RESULTS: Lower baseline BMI predicted greater decline in BMI (p = 0.0005) and excess weight loss (EWL) (p = 0.009). In the multiple linear regression analysis age and BMI, explained the variance of EWL during the first year while GRS, sex, fasting plasma glucose, serum insulin and NASH diagnosis did not have any effect. None of the baseline clinical variables explained BMI regain. The combined GRS did not associate with weight or BMI at baseline, with 1-year changes or with weight regain between 1 year and an average of 3.1 years follow-up. CONCLUSIONS: In our study, we found that the genotype risk score does not predict weight loss after obesity surgery while lower baseline BMI predicted the greater weight loss.

Glomerular filtration rate and parathyroid hormone are associated with 1,25-dihydroxyvitamin D in men without chronic kidney disease.

BACKGROUND AND AIM: Vitamin D, estimated glomerular filtration rate (eGFR) and parathyroid hormone (PTH) are related to cardiovascular disease risk. We examined the associations between the levels of 25-hydroxyvitamin D (25-D) and 1,25-dihydroxyvitamin D (1,25-D) and both eGFR and PTH. DESIGN AND SETTING: Cross-sectional population-based study in Kuopio, Eastern Finland. SUBJECTS: A total of 909 men without known chronic kidney disease (CKD) and not receiving antidiabetic medication, aged from 45 to 73 years, were included in the study. Main outcome measures. Fasting levels of 25-D, 1,25-D, creatinine and PTH were measured, and an oral glucose tolerance test (OGTT) was performed. RESULTS: High levels of 25-D were associated with low levels of eGFR and PTH (ß = -0.17, P = 9 × 10(-7) and ß = -0.28, P = 6 × 10(-17) , respectively, adjusted for age, body mass index and levels of calcium, phosphorus and glucose in a 2-h OGTT, and also for either eGFR or PTH). By contrast, high 1,25-D levels were associated with high levels of eGFR and PTH (ß = 0.17, P = 2 × 10(-6) and ß = 0.19, P = 5 × 10(-8) , respectively, adjusted as mentioned earlier and additionally for 25-D). Eighteen per cent of men in the highest 25-D quartile were in the lowest 1,25-D quartile and also had a lower eGFR than men with high levels of both 25-D and 1,25-D (P = 4 × 10(-5) ). Finally, 15% of men in the lowest 25-D quartile were in the highest 1,25-D quartile and also had higher PTH levels than men with low levels of both 25-D and 1,25-D (P = 2 × 10(-3) ). CONCLUSION: Our findings suggest that both eGFR and PTH are significantly associated with vitamin D metabolism in men without known CKD.

Association of indices of liver and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 diabetes in 6,733 non-diabetic Finnish men.

AIMS/HYPOTHESIS: Of the confirmed type 2 diabetes susceptibility loci only a few are known to affect insulin sensitivity. We examined the association of indices of hepatic and adipocyte insulin resistance (IR) with 19 confirmed type 2 diabetes risk loci in a large population-based study. METHODS: Non-diabetic participants (n = 8,460, age 57.3 ± 7.0 years, BMI 26.8 ± 3.8 kg/m(2); mean ± SD) from a population-based cohort underwent an OGTT. Of them, 6,733 non-diabetic men were genotyped for single nucleotide polymorphisms (SNPs) in or near PPARG2 (also known as PPARG), KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, MTNR1B and SNP rs7480010. We investigated hepatic IR with a new index of liver IR. The adipocyte IR index was defined as a product of fasting NEFA and plasma insulin levels. RESULTS: Type 2 diabetes risk SNPs in or near KCNJ11 and HHEX were significantly (p < 0.0013), and those in or near CDKN2B, NOTCH2 and MTNR1B were nominally (p < 0.05), associated with decreased liver IR index. The Pro12 allele of PPARG2 was significantly associated with a high adipocyte IR index and nominally associated with high liver IR. CONCLUSIONS/INTERPRETATION: The Pro12 allele of PPARG2 seems to impair insulin's antilipolytic effect, leading to high NEFA release in the fasting state and IR. In addition, the type 2 diabetes risk alleles of KCNJ11 and HHEX, which are known to impair insulin secretion, were associated with increased hepatic insulin sensitivity.

Diverse associations of 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D with dyslipidaemias.

BACKGROUND AND AIM: Previous studies have suggested a link between circulating levels of 25-hydroxyvitamin D (25-D) and dyslipidaemias. However, it is not known whether 25-D and the active hormone 1,25-dihydroxyvitamin D (1,25-D) have similar associations with dyslipidaemias. Therefore, we studied the associations between both 25-D and 1,25-D and total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides in a population-based study. DESIGN: Cross-sectional population-based study. SETTING: Kuopio, Eastern Finland. SUBJECTS: A total of 909 men, aged from 45 to 70 years, who were not receiving antidiabetic medication were enrolled. MAIN OUTCOME MEASURES: Fasting serum samples were obtained for measurement of 25-D, 1,25-D and lipid levels. An oral glucose tolerance test was performed, and insulin sensitivity was evaluated using the Matsuda insulin sensitivity index (Matsuda ISI). RESULTS: We found a significant inverse association between 25-D and total-C, LDL-C and triglycerides (ß = -0.15, -0.13 and -0.17, respectively, P < 0.001), but no association between 25-D and HDL-C was observed. By contrast, 1,25-D was associated with HDL-C (ß = 0.18, P < 0.001), whereas no relationship was found between 1,25-D and LDL-C or triglycerides. The associations remained significant after the exclusion of subjects receiving statin treatment and after adjustment for age, waist circumference, body mass index, alcohol consumption, smoking, renal function, glucose tolerance and Matsuda ISI. CONCLUSION: Low levels of active vitamin D (1,25-D) are associated with low HDL-C levels, whereas low levels of the storage form 25-D are associated with high levels of total-C, LDL-C and triglycerides. Our findings may provide new insights into the understanding of the link between vitamin D deficiency and cardiovascular disease.

High circulating levels of RBP4 and mRNA levels of aP2, PGC-1alpha and UCP-2 predict improvement in insulin sensitivity following pioglitazone treatment of drug-naïve type 2 diabetic subjects.

CONTEXT: High levels of circulating retinol-binding protein 4 (RBP4) and baseline expression of adipogenic genes correlate with subsequent improvement in insulin sensitivity following Thiazolidinedione (TZD) treatment. OBJECTIVE: The aim was to identify baseline characteristics and early changes related to TZD treatment that could predict a good treatment response. DESIGN: Subjects were examined with oral glucose tolerance test, intravenous glucose tolerance test, hyperinsulinaemic euglycaemic clamp, body composition and standard blood sampling at baseline and after 4 and 12 weeks treatment. Subcutaneous adipose tissue biopsies were taken from the abdominal region at baseline, after 3 days and 4 weeks treatment to examine the gene expression profile. SETTING: Research laboratory in a University hospital. PARTICIPANTS: Ten newly diagnosed and previously untreated type 2 diabetic subjects were treated with pioglitazone for 3 months. MAIN OUTCOME MEASURES: Baseline characteristics and early changes related to TZD treatment that could predict the response after 3 months. RESULTS: Pioglitazone improved insulin sensitivity after 4 weeks combined with lower glucose and insulin levels without any change in BMI. It was accompanied by lower circulating resistin and plasminogen activator inhibitor-1 levels rapidly increased levels of circulating total and high molecular weight adiponectin as well as adiponectin and adipocyte fatty acid-binding protein (aP2) mRNA expression in the adipose tissue. High levels of circulating RBP4 at baseline and adipose tissue expression of aP2, proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1alpha) and uncoupling protein 2 (UCP-2) predicted a good treatment response measured as improvement in insulin-stimulated whole-body glucose uptake after 3 months. CONCLUSIONS: Circulating levels of RBP4 as an index of insulin sensitivity and mRNA levels of adipogenic genes correlate with the subsequent improvement in insulin sensitivity following TZD treatment.

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes.

AIMS/HYPOTHESIS: The mechanisms by which the calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes. SUBJECTS AND METHODS: Insulin secretion was determined by an IVGTT, insulin action by the hyperinsulinaemic-euglycaemic clamp and abdominal fat distribution by computed tomography in 158 non-diabetic offspring (age 34.9+/-6.3 years [mean+/-SD], BMI 26.2+/-4.9 kg/m(2)) of type 2 diabetic patients. RESULTS: SNP-43 (p=0.009 over the three genotypes, adjusted for age, sex, BMI and family relationship) and haplotypes carrying the A allele of SNP-43 were associated with intra-abdominal fat area. The A allele of SNP-43 was associated with intra-abdominal fat area in men (p=0.014) but not in women. SNP-44, InDel-19 and SNP-63 were not associated with intra-abdominal fat area or insulin action. Furthermore, we demonstrated in a separate sample of middle-aged men (n=234) who had a history of type 2 diabetes in first-degree relatives that the A allele of SNP-43 was associated with a large waist circumference, and high insulin levels in an OGTT. CONCLUSIONS/INTERPRETATION: SNP-43 of CAPN10 may contribute to the risk of diabetes by regulating abdominal obesity in subjects with high risk of type 2 diabetes.

High amount of visceral fat mass is associated with multiple metabolic changes in offspring of type 2 diabetic patients.

OBJECTIVE: To investigate the relative contribution of total body fat mass (TFM) and intra-abdominal fat mass (IAFM) to metabolic consequences of obesity in offspring of type 2 diabetic parents. DESIGN: Cross-sectional study of 129 nondiabetic offspring of diabetic parents (59 men, 70 women, age 35.7 +/- 6.3 y, body mass index 26.2 +/- 4.6 kg/m2). Study subjects were grouped according to TFM (assessed with bioelectrical impedance) and IAFM (assessed with CT). Insulin sensitivity was assessed with the euglycemic hyperinsulinemic clamp, insulin secretion with the intravenous glucose tolerance test and energy expenditure with indirect calorimetry. Furthermore, C-reactive protein (CRP) and adiponectin levels were measured. RESULTS: Insulin resistance, low rates of oxidative and nonoxidative glucose disposal, high rates of lipid oxidation and reduced energy expenditure during hyperinsulinemia were associated with high IAFM, independently of TFM. Adiponectin level was reduced and CRP level increased in subjects with high IAFM. CONCLUSIONS: The metabolic changes relating to obesity are largely attributable to high IAFM, and are present even in normal weight subjects with high IAFM.

Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes.

AIMS/HYPOTHESIS: Decreased expression of the peroxisomal proliferator activated receptor gamma coactivator 1 alpha gene (PPARGC1A) is found in patients with type 2 diabetes, and variants in this gene have been linked with type 2 diabetes. Therefore, we investigated the effects of single nucleotide polymorphisms in PPARGC1A on body composition and glucose tolerance and on insulin sensitivity and secretion. METHODS: Non-diabetic offspring (n=156, age 34.9+/-0.5 years [mean+/-SEM], BMI 26.2+/-0.4 kg/m2) underwent an OGTT and an IVGTT and the hyperinsulinaemic-euglycaemic clamp. The promoter and coding regions of PPARGC1A were sequenced. RESULTS: Two haplotype blocks in PPARGC1A were observed, one in the promoter region (G-1774A, A-1679G, T-1422C, A-1278G, C-543A) and one in the coding region and 3' regions (Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, Thr612Met, G+2381A). The coding region haplotype carrying the rare allele in codons 482 and 528 was associated with elevated glucose levels in an OGTT (p=0.024, adjusted for age, sex and BMI) and a haplotype carrying the rare alleles in codons 394 and 475 was associated with low BMI (p=0.033), high rates of whole-body glucose uptake (p=0.045) and low glucose levels in the OGTT (p=0.037). CONCLUSIONS/INTERPRETATION: We conclude that PPARGC1A is likely to contribute to the risk of diabetes in offspring of patients with type 2 diabetes.

Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to Type 2 diabetes. The Finnish Diabetes Prevention Study.

AIMS/HYPOTHESIS: Type 2 diabetes is a complex disorder with strong heritability. The aim of our study was to investigate whether common polymorphisms in the genes regulating the early insulin signalling pathway (insulin; A-23T, insulin-like growth factor 1 receptor [IGF-1R]; GAG1013GAA, plasma cell membrane glycoprotein 1 [PC-1]; K121Q, insulin receptor substrate [IRS-1]; G972R, insulin receptor substrate 2 [IRS-2]; G1057D and phosphatidylinositol 3-kinase p85 alpha [PI3K]; M326I) affect the weight change and development of Type 2 diabetes in the Finnish Diabetes Prevention Study. METHODS: We screened for the polymorphisms in 490 overweight subjects with impaired glucose tolerance whose DNA was available from the Finnish Diabetes Prevention Study. These subjects were randomly allocated into a control group and an intervention group characterised by intensive, individualised diet and exercise. RESULTS: In carriers of the GAA1013GAA genotype of IGF-1R, the R972 allele of IRS-1 and the D1057D genotype of IRS-2, lifestyle intervention did not lead to significant differences in weight loss between the intervention and control groups, implying a role of these risk genotypes in the regulation of body weight. We observed a statistically significant difference in the conversion rate from IGT to diabetes between the genotypes of the IGF-1R gene (GAG1013GAG: 18.6%, GAG1013GAA: 10.4%, GAA1013GAA: 19.5%, p=0.033). Common polymorphisms in the insulin, PC-1 and PI3K genes did not regulate weight change or conversion to diabetes. CONCLUSIONS/INTERPRETATION: The common polymorphisms of the IGF-1R, IRS-1 and IRS-2 genes may modify the weight change response to a lifestyle intervention but not the conversion from IGT to Type 2 diabetes, whereas IGF-1R may also regulate the risk of developing Type 2 diabetes.

A major gene effect on fasting insulin and insulin sensitivity in familial combined hyperlipidemia.

The most common inherited dyslipidemia, familial combined hyperlipidemia (FCHL), is associated with insulin resistance. Whether insulin sensitivity in these families is inherited is not known. Therefore, we investigated the inheritance of insulin sensitivity in 352 nondiabetic family members from 37 families with FCHL, 105 of whom had undergone testing using the hyperinsulinemic-euglycemic clamp technique for the measurement of insulin sensitivity. First, complex segregation analysis of fasting insulin levels (both unadjusted and age-, age(2)-, and BMI-adjusted) was used for modeling of the variance in fasting insulin levels. In these analyses, Mendelian codominant inheritance (P = 0.320 for unadjusted and P = 0.295 for adjusted insulin values) was not rejected over the most general model and fit the data significantly better than the sporadic model (P < 0.001). Polygenic and environmental models were rejected (P < 0.001). The Mendelian codominant model explained 44 and 45% of the variance in unadjusted and adjusted fasting insulin levels, respectively. The proposed genotypes of this locus, based on segregation analysis, were associated with directly measured insulin sensitivity in 105 FCHL family members who underwent the hyperinsulinemic-euglycemic clamp (P < 0.001). These results provide evidence for a major gene regulating insulin sensitivity in FCHL families. Possible pleiotropic effects of this insulin sensitivity locus on dyslipidemias in FCHL remain to be elucidated.

Association of angiotensin converting enzyme and plasminogen activator inhibitor-1 promoter gene polymorphisms with features of the insulin resistance syndrome in patients with premature coronary heart disease.

Polymorphisms of the angiotensin-converting enzyme (ACE) (insertion/deletion (I/D) in intron 16) and of the plasminogen activator inhibitor-1 (PAI-1) (promoter 4G/5G) genes have been linked with coronary heart disease (CHD) and/or myocardial infarction (MI). We studied the association of polymorphisms in these genes with CHD with linkage and association analyses in 118 families with premature and severe CHD and in 110 healthy controls. In linkage analysis there was no evidence for a linkage of the ACE or PAI-1 loci with CHD. However, in quantitative linkage analysis the ACE locus was linked with fasting glucose (P=0. 047) and fasting free fatty acid levels (P=0.029). In association analysis the ACE genotype frequencies of probands with CHD did not differ from those of healthy controls. Normoglycemic probands with MI and with the ACE polymorphism DD genotype had characteristics of the insulin resistance syndrome. They had higher levels of 1-h glucose (P=0.008) and 2-h free fatty acids (P=0.011) in an oral glucose tolerance test and higher levels of total (P=0.005) and very-low-density lipoprotein triglycerides (P=0.006) than probands with the ID or the II genotypes. The PAI-1 gene polymorphism was not associated with any of the variables of glucose or lipid metabolism. In conclusion, the ACE and PAI-1 gene polymorphisms are not linked with early-onset CHD. However, the ACE gene polymorphism is associated with features of the insulin resistance syndrome.

The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance.

BACKGROUND: Insulin resistance in the most common familial dyslipidemia, familial combined hyperlipidemia (FCHL), could be due to variations in the hormone sensitive lipase (HSL) gene. MATERIALS AND METHODS: The coding region of the HSL gene was screened with the single strand conformation polymorphism analysis in probands of 27 FCHL families with 228 members. In addition, the C-60G promoter substitution of the HSL gene was determined by the restriction fragment length polymorphism analysis in these subjects. RESULTS: No variants in the coding region of the HSL gene were found and the allele frequencies of the C-60G promoter substitution and the silent variant (G3138A) in the 3' untranslated region did not differ between 110 control subjects and 27 probands with FCHL. However, in control women the C-60G substitution was associated with high body mass index [30.6 +/- 0.9 kg m(-2) (mean +/- SD) in subjects with the C/G genotype and 24.8 +/- 4.6 in subjects with the C/C genotype, P = 0.012], and in control men with high rates of insulin-stimulated whole body glucose uptake (70.1 +/- 14.7 vs. 56.7 +/- 14.2 micromol kg(-1) min(-1), P = 0.014). In 228 FCHL family members this substitution was associated with high low-density lipoprotein cholesterol levels in men (4.51 +/- 1.12 vs. 5.17 +/- 1.28 mmol L(-1), P = 0.049), but not in women. CONCLUSIONS: The HSL gene is not a major gene for FCHL. However, the - 60G allele of this gene may affect body weight, insulin sensitivity and serum cholesterol levels.