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Roux-en-Y gastric bypass leads to a marked improvement of glucose control. The mechanisms are only partly known. Gastrointestinal hormones may play a role. Of these, glucagon-like peptide 1 and peptide YY have been most consistently associated with the beneficial effects of gastric bypass on glucose metabolism and weight. In this paper, a short review of the topic is presented and a suggestion of the improvement of glucose metabolism is made based on the current published work. [ABSTRACT FROM AUTHOR]

Background Involvement of low density lipoprotein (LDL) immune complexes (ICs) in atherogenesis has been proposed. Human FcγRIIa receptor (CD32) plays a crucial role in the phagocytosis of IgG2 ICs and a functional point mutation 131His/Arg diminishes IgG2 binding to the receptor. Study design We examined FcγRIIa-131His/Arg polymorphism, IgG2 antibody titres to oxidized low-density lipoprotein (OxLDL) and Streptococcus pneumoniae cell wall polysaccharide (CWPS) and subclinical atherosclerosis in a large cohort of Finnish subjects ( n = 1041). Results Non-smoking subjects with homozygous 131His/His genotype had more premature atherosclerosis ( P = 0·004) and higher IgG2 to bacterial CWPS ( P = 0·002) compared with other genotypes. Smoking subjects had significantly higher intima-media thickness (IMT) than that of non-smokers ( P < 0·001) and genotype-dependent associations were indistinct. There was no association between FcγRIIa genotype and antibody titres to OxLDL. Conclusions Our data demonstrate that FcγRIIa 131His/Arg polymorphism is associated with subclinical atherosclerosis in non-smoking subjects. Furthermore, FcγRIIa genotype is associated with IgG2 titres to bacterial CWPS, but not to OxLDL. These data propose possible involvement of FcγRIIa receptor in atherogenesis. [ABSTRACT FROM AUTHOR]

Background. Ghrelin, a peptide hormone from stomach, stimulates food intake and decreases fat utilization. Ghrelin binds to growth hormone secretagogue receptor (GHSR). GHSR density has been shown to be upregulated in atherosclerotic lesions, but the relationship between ghrelin concentration and atherosclerosis has not yet been studied. We, therefore, characterized the association between ghrelin concentration and carotid artery intima-media thickness (IMT) in a population-based cohort of 1024 middle-aged (40–60 years) men and women. Methods. Intima-media thickness and the number of atherosclerotic plaques were determined ultrasonographically. Fasting plasma ghrelin concentrations were analysed using RIA-kit (PhoenixPeptide). Results. There was a positive association between mean IMT and ghrelin concentration in the analysis of males before and after adjustments for the traditional risk factors of atherosclerosis [age, systolic blood pressure, LDL cholesterol, body mass index (BMI), and smoking (ancova, P = 0.004 and P = 0.007, respectively)]. However, no such association was found in females ( P = 0.985 and P = 0.915). There was no correlation between ghrelin and CRP concentrations or ghrelin and smoking. Conclusion. Ghrelin concentrations and carotid artery atherosclerosis are positively associated in males even after adjustment for the commonly recognized risk factors of atherosclerosis. Experimental and prospective studies are warranted to elucidate the role of ghrelin in atherosclerosis. [ABSTRACT FROM AUTHOR]

Resistin is a hormone secreted by adipocytes and it is also expressed in monocytes. Resistin has been found to increase insulin resistance, a key feature in Type 2 diabetes. The aim of this study was to investigate whether resistin polymorphisms are associated with Type 2 diabetes and its clinical characteristics.We studied the allele and genotype frequencies of the single-nucleotide polymorphisms (SNPs)−420 (C > G),+157 (T > C) and+299 (G> A) in the resistin gene in 258 Finnish Type 2 diabetics and 494 controls.These three markers were in significant linkage disequilibrium with each other. No significant (P < 0.05) differences in the allele or genotype frequencies were observed between the study groups. Subjects with Type 2 diabetes showed a significant association between cerebrovascular disease and the SNPs−420 (P = 0.004) and+299 (P = 0.007), the G-G and A-A genotypes, respectively, had the highest frequencies. SNPs−420 (P = 0.000) and+299 (P = 0.002) in men and SNP+157 in men (P = 0.005) and in women (P = 0.019) showed significant association with higher mean blood glucose. The rare allele homozygotes also had the highest mean blood glucose values. We also observed associations between at least one of the SNPs and fasting blood glucose, glycosylated haemoglobin A1 (GHbA1), low-density lipoprotein (LDL) cholesterol and systolic and diastolic blood pressure. After correction for multiple comparisons, the association between the promoter variant SNP−420 and cerebrovascular disease in both genders and the associations between mean blood glucose and SNP−420 and SNP+299 in men remained significant.The results suggest that resistin may play a role in atherogenesis probably through increasing insulin resistance.Diabet. Med. 22, 583–589 (2005) [ABSTRACT FROM AUTHOR]

Santaniemi M, Ukkola O, Kesäniemi YA (University of Oulu, Oulu, Finland). Tyrosine phosphatase 1B and leptin receptor genes and their interaction in type 2 diabetes. J Intern Med 2004; 256: 48–55. The association between three tyrosine phosphatase 1B (PTP1B) gene polymorphisms and type 2 diabetes was examined by comparing the prevalence rates of these polymorphisms in type 2 diabetic patients and healthy control subjects. Furthermore, the association of the polymorphisms and PTP1B and leptin receptor (LepR) gene­gene interactions with complications of type 2 diabetes were examined in type 2 diabetic patients. We did not find any differences in the genotype distributions or allele frequencies of IVS6 + G82A and Pro387Leu polymorphisms between the type 2 diabetics and controls. There were differences in the genotype frequencies of the Pro303Pro (C981T) ­ polymorphism between the two studied groups (P = 0,018); there were eight T981T subjects in the control population but none amongst the type 2 diabetics. However, there were no differences in the allele frequencies. In addition, significant associations between the IVS6 + G82A polymorphism and body mass index (BMI), albuminuria, glycohaemoglobin A1 (GHBA1) and hypertension in type 2 diabetic patients (P = 0,026–0,031) were observed. Pro387Leu and Pro303Pro did not associate with risk factors or diabetic complications. We also found a gene­gene interaction effect between PTP1B and the LepR gene with the genotype combination IVS6 + A82A and Arg223Arg having the highest BMI compared with the other genotype combinations (P = 0.0043 for trend). The interaction between these two polymorphisms explained 3% of the variation in BMI in diabetic patients when the other covariates were taken into account. We conclude that the PTP1B IVS6 + G82A polymorphism was associated with BMI, albuminuria, GHBA1 and hypertension in type 2 diabetic patients. The 981T/T-genotype of the Pro303Pro- polymorphism might have some protective role against the development of type 2 diabetes. The interaction effects between the PTP1B IVS6 + A82A and LepR Arg223Arg genotypes influenced BMI, explaining 3% of its variation. A synergistic effect of PTP1B and LepR variants on the leptin signalling may be involved. [ABSTRACT FROM AUTHOR]

Abstract Ukkola O, Kesäniemi YA (University of Oulu, Oulu, Finland). Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus. J Intern Med 2003; 254: 391–394. Objectives. The association between the Leu72Met polymorphism of the preproghrelin gene and diabetic complications was examined in patients with type 2 diabetes mellitus. Subjects and methods. A total of 258 patients with type 2 diabetes mellitus and 522 control subjects were screened. Genotypes were determined by polymerase chain reaction technique. The diagnosis of coronary heart disease was based on clinical and ECG criteria. Laboratory analyses were carried out in the hospital laboratory. Results. No differences in the genotype distributions and allele frequencies of the preproghrelin Leu72Met polymorphism were found between type 2 diabetes mellitus patients and controls. The polymorphism was not associated with macro- or micro-angiopathy or hypertension. However, Leu72Met polymorphism was associated with serum creatinine (P = 0.006) and lipoprotein(a) [Lp(a)] levels (P = 0.006) with Leu72Leu subjects showing the highest values. This association was observed only amongst diabetic group. Conclusions. The Leu72Met polymorphism of the preproghrelin gene was not related to cardiovascular disease in type 2 diabetes mellitus patients. Leu72Met polymorphism was, however, associated with serum creatinine and Lp(a) levels in diabetic patients. The mechanism might be associated with a possible change in ghrelin product and its somatotropic effect. [ABSTRACT FROM AUTHOR]

Impaired insulin action is important in the pathophysiology of multiple metabolic abnormalities such as obesity and type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is considered a negative regulator of insulin signalling. This is best evidenced by studies on knockout mice showing that lack of PTP1B is associated with increased insulin sensitivity as well as resistance to obesity and in vitro studies whilst studies in animals and humans have given contradictory results. However, several studies support the notion that insulin signalling can be enhanced by the inhibition of PTP1B providing an attractive target for therapy against type 2 diabetes and obesity. In addition, recent genetic studies support the association between PTP1B with insulin resistance. The development of PTP1B inhibitors has already begun although it has become clear that is not easy to find both a selective, safe and effective PTP1B inhibitor. The objective of this paper is to review the current evidence of PTP1B in the pathophysiology of obesity, type 2 diabetes and cancer as well as in the treatment of these disorders. [ABSTRACT FROM AUTHOR]

Objectives: The role of the lipoprotein lipase (LPL) gene Hind III, S447X, Bam HI and Pvu II polymorphisms on body composition and lipid and lipoprotein changes in response to long-term overfeeding was studied.Subjects: Twelve pairs of male monozygotic twins ate a 4.2 MJ day-1 energy surplus, 6 days a week, during a period of 100 days.Results: Overfeeding induced a decrease in high-density lipoprotein 2 cholesterol (HDL2-C) and HDL2-C to HDL3-C ratio in the H2H2 (n = 12) subjects of the LPL Hind III polymorphism. In contrast, the H1H1/H1H2 (n = 12) subjects experienced increases both in the HDL2-C and HDL2-C to HDL3-C ratio (P = 0.009 and 0.007, respectively, for differences in percentage changes between H2H2 and H1H1/H1H2). In addition, the H2H2 genotype was associated with higher levels of very-low-density lipoprotein triglyceride (VLDL-TG) (P < 0.03) and VLDL-C (P < 0.05) before and after overfeeding and higher HDL-TG levels (P < 0.003) after overfeeding. Postheparin lipoprotein lipase (PH-LPL) activity tended to increase in H1H1/H1H2 and decrease in H2H2 subjects. The H2H2 subjects had lower total HDL-C than those with the genotype H1H1/H1H2 4 months and 5 years after overfeeding (P = 0.04 and 0.10, respectively). The plasma lipid differences were similar amongst subjects with the S447S (n = 4) genotype of the S447X and H2H2 genotype of the Hind III polymorphisms. Body composition changes in response to overfeeding were not different between the Hind III genotypes. LPL Pvu II and Hind III polymorphisms were associated weakly with body weight gain (P = 0.015-0.039) but strongly with adipose tissue LPL activity (P < 0.01) after the caloric surplus.Conclusions: We conclude that the H2H2 subjects of the LPL gene Hind III polymorphism experience a decrease in the concentration of antiaterogenic lipoproteins when they are exposed to long-term positive energy balance. This may have been partly caused by a diminished catabolism of TG-rich particles in H2H2 subjects. LPL Pvu II and Bam HI polymorphisms were associated with body weight gain and adipose tissue LPL activity. Genetic variation at the LPL locus could thus be one of the factors responsible for the inter-individual differences observed in plasma lipid and lipoprotein responses to chronic positive energy balance. It must be kept in mind that the sample size for this study was small. Nonetheless, it provides useful information on the genes and pathways that should be further explored. [ABSTRACT FROM AUTHOR]

Abstract. Ukkola O, Erkkilä PH, Savolainen MJ, Kesäniemi YA (University of Oulu, Oulu, Finland). Lack of association between polymorphisms of catalase, copper–zinc superoxide dismutase (SOD), extracellular SOD and endothelial nitric oxide synthase genes and macroangiopathy in patients with type 2 diabetes mellitus. J Intern Med 2001; 249: 451–459. Objectives. The association between the polymorphisms of three different antioxidative enzyme – catalase, copper–zinc superoxide dismutase (Cu/ Zn-SOD) and extracellular superoxide dismutase (EC-SOD) – genes and macroangiopathy was examined in patients with type 2 diabetes mellitus. The prevalence of the missense Glu298Asp variant of the endothelial nitric oxide synthase (eNOS) gene and its association with macroangiopathy were also determined. Design. Cross-sectional study. Setting. District around Oulu University Hospital, North Finland. Subjects and methods. A total of 239 patients with type 2 diabetes mellitus and 245 control subjects were screened. Genotypes were determined by polymerase chain reaction (PCR) technique. The diagnosis of coronary heart disease (CHD) was based on clinical and ECG criteria. The prevalences of cerebrovascular (CVD) and peripheral vascular diseases (PVD) were assessed on the basis of clinical criteria. Laboratory analyses were carried out in the hospital laboratory. Results. No differences in the genotype distributions and allele frequencies of the antioxidative enzymes were found between type 2 diabetes mellitus patients and controls. The eNOS genotypes and allele frequencies were also similar in the diabetic patients and controls being close to that reported earlier in the British population. None of the polymorphisms were associated with macro- or microangiopathy or hypertension. However, male diabetic patients with eNOS Asp298Asp genotype had higher plasma very-low density lipoprotein (VLDL) cholesterol and VLDL-triglyceride concentrations than those with the genotypes Glu298Glu or Glu298Asp (P < 0.01 for trend). Conclusions. The polymorphism of catalase, Cu/Zn SOD and EC-SOD genes were not related to cardiovascular disease in type 2 diabetes mellitus patients. The eNOS Glu298Asp variant was associated with plasma VLDL-containing lipoproteins but not with macroangiopathy in diabetic male patients. The findings do not support the notion that the polymorphisms of the key antioxidative enzymes could be amongst the factors that explain the high prevalence of macroangiopathy in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Objectives: The role of the leptin receptor (LEPR) gene Gln223Arg polymorphism on the metabolic and body composition changes in response to overfeeding was studied.Subjects: Twelve pairs of male monozygotic twins ate a 4.2 MJ day-1 energy surplus, 6 days week-1, during a period of 100 days.Results: Overfeeding induced a significantly greater increase in glucose (P = 0.001 for percentage change) and insulin (P = 0.038) areas under the curve during oral glucose tolerance tests (OGTTs) in the GlnGln (n = 10) than in the GlnArg/ArgArg (n = 14) subjects. In addition, the GlnGln genotype was associated with a greater increase in plasma levels of leptin (P = 0.037) and total triglycerides (P = 0.003), as well as a greater decrease in high-density lipoprotein cholesterol (P = 0.010), than for the combined GlnArg/ArgArg genotypes. Body composition changes were not different between the genotypes.Conclusions: We conclude that the GlnGln subjects of the LEPR gene polymorphism are more susceptible to metabolic abnormalities when they are exposed to long-term positive energy balance. These findings provide new information on the genetic basis of individual differences in response to chronically elevated food intake. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of polymorphisms in codon 16 (Arg16Gly) and codon 27 (Gln27Glu) of the beta2-adrenergic receptor gene (ADRB2) on anthropometric, endocrine, metabolic and haemodynamic variables.Design: A cross-sectional study.Subjects: A subgroup of 284 Swedish men from a population sample of 1040 at the age of 51 years.Main Outcome Measures: Genotype examination of ADRB2 polymorphisms in codon 16 and codon 27 with polymerase chain reaction and restriction fragment length polymorphism. Anthropometric measurements included body mass index, waist-to-hip ratio and abdominal sagittal diameter. Endocrine measurements included blood levels of testosterone, insulin-like growth factor I, and leptin plus salivary cortisol. Overnight fasting values of serum insulin, blood glucose, triglycerides, total, low and high density lipoprotein cholesterol, as well as blood pressure and resting heart rate, were also determined.Results: Polymorphisms were frequent in both codon 16 and codon 27. The Arg16Gly genotype showed significant relationships to elevated central distribution of body fat and to systolic blood pressure, whilst the Glu27Glu genotype was associated with elevated leptin and triglyceride levels but not to other measurements, including obesity variables.Conclusions: We conclude that only a few cardiovascular risk factors are associated with DNA sequence variation in the ADRB2 in Swedish men. [ABSTRACT FROM AUTHOR]

Editorial. Discusses the role of ghrelin peptide on glucose and insulin metabolism. Interaction between ghrelin and insulin; Effects of ghrelin on adiposity; Insulin secretion.

Abstract. Rosmond R, Ukkola O, Chagnon M, Bouchard C & Björntorp P (Department of Heart and Lung Diseases, Göteborg University, Sweden; Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA; Department of Internal Medicine, University of Oulu, Oulu, Finland). Polymorphisms of the β2-adrenergic receptor gene (ADRB2) in relation to cardiovascular risk factors in men. J Intern Med 2000; 248: 239–244. Objective. To investigate the effect of polymorphisms in codon 16 (Arg16Gly) and codon 27 (Gln27Glu) of the β2-adrenergic receptor gene (ADRB2) on anthropometric, endocrine, metabolic and haemodynamic variables. Design. A cross-sectional study. Subjects. A subgroup of 284 Swedish men from a population sample of 1040 at the age of 51 years. Main outcome measures. Genotype examination of ADRB2 polymorphisms in codon 16 and codon 27 with polymerase chain reaction and restriction fragment length polymorphism. Anthropometric measurements included body mass index, waist-to-hip ratio and abdominal sagittal diameter. Endocrine measurements included blood levels of testosterone, insulin-like growth factor I, and leptin plus salivary cortisol. Overnight fasting values of serum insulin, blood glucose, triglycerides, total, low and high density lipoprotein cholesterol, as well as blood pressure and resting heart rate, were also determined. Results. Polymorphisms were frequent in both codon 16 and codon 27. The Arg16Gly genotype showed significant relationships to elevated central distribution of body fat and to systolic blood pressure, whilst the Glu27Glu genotype was associated with elevated leptin and triglyceride levels but not to other measurements, including obesity variables. Conclusions. We conclude that only a few cardiovascular risk factors are associated with DNA sequence variation in the ADRB2 in Swedish men. [ABSTRACT FROM AUTHOR]

Background: Regardless of progress in treatment of coronary artery disease (CAD), there is still a significant residual risk of death in patients with CAD, highlighting the need for additional risk stratification markers. Our previous study provided evidence for a novel blood pressure-regulating mechanism involving 4β-hydroxycholesterol (4βHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4βHC as a prognostic factor in CAD., Methods and Results: The ARTEMIS (Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection) cohort consists of 1946 patients with CAD. Men and women were analyzed separately in quartiles according to plasma 4βHC. Basic characteristics, medications, ECG, and echocardiography parameters as well as mortality rate were analyzed. At baseline, subjects with a beneficial cardiovascular profile, as assessed with traditional markers such as body mass index, exercise capacity, prevalence of diabetes, and use of antihypertensives, had the highest plasma 4βHC concentrations. However, in men, high plasma 4βHC was associated with all-cause death, cardiac death, and especially sudden cardiac death (SCD) in a median follow-up of 8.8 years. Univariate and comprehensively adjusted hazard ratios for SCD in the highest quartile were 3.76 (95% CI, 1.6-8.7; P =0.002) and 4.18 (95% CI, 1.5-11.4; P =0.005), respectively. In contrast, the association of cardiac death and SCD in women showed the lowest risk in the highest 4βHC quartile., Conclusions: High plasma 4βHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4βHC as a novel sex-specific risk marker of cardiac death and especially SCD in chronic CAD., Registration Information: clinicaltrials.gov. Identifier NCT01426685.