Changes in cytokine levels during acute hyperinsulinemia in offspring of type 2 diabetic subjects.

OBJECTIVE: To investigate the changes in the levels of cytokines and adhesion molecules in response to acute hyperinsulinemia in the offspring of type 2 diabetic subjects. METHODS: Forty healthy offspring of type 2 diabetic subjects and 19 control offspring of healthy parents were included in the study. Twenty offspring had normal glucose tolerance (NGT) and twenty offspring impaired glucose tolerance (IGT). Insulin sensitivity was determined by the hyperinsulinemic euglycemic clamp and insulin secretion with the intravenous glucose tolerance test. The levels of cytokines and adhesion molecules were measured before and at the end of the clamp. RESULTS: Acute hyperinsulinemia induced by the euglycemic hyperinsulinemic clamp reduced the levels of TNF-alpha, IL-8, IL-10 and IL-18 in healthy controls but not in the offspring of type 2 diabetic subjects having NGT or IGT. In response to insulin, levels of hs-CRP decreased and levels of IL-6 increased significantly in all study groups. The levels of adhesion molecules (ICAM-1, VCAM-1, E-Selectin) remained unchanged in response to hyperinsulinemia. CONCLUSIONS: The suppression of cytokine levels (particularly proinflammatory cytokines) during acute hyperinsulinemia observed in healthy controls was not present in offspring of type 2 diabetic patients. This emphasizes the crucial role of low-grade inflammation in insulin resistance in subjects with high risk of developing diabetes.

Pituitary-adrenal function in patients with acute subarachnoid haemorrhage: a prospective cohort study.

INTRODUCTION: Subarachnoid haemorrhage (SAH) may damage the hypothalamo-pituitary-adrenal gland (HPA) axis and disturb cortisol metabolism. There are no available data that relates to the response of the HPA axis in the acute phase of SAH. We aimed to characterise the behavior of serum adrenocorticotropic hormone (ACTH), total cortisol, stimulated total cortisol and free cortisol concentrations in acute aneurysmal SAH. METHODS: A prospective cohort study was conducted of patients with acute aneurysmal SAH (n = 30) admitted to a tertiary university hospital. Patients admitted for elective aneurysmal surgery (n = 16) served as the control group. An ACTH stimulation test was performed twice during the first week and at three months. The main outcome measure was description of the ACTH-cortisol response by calculating serum free cortisol and measuring total cortisol and ACTH concentrations. A mixed models method was used for testing between the groups, allowing heterogeneity between the groups. RESULTS: Patients with SAH had higher initial serum total cortisol (mean +/- SD; 793 +/- 312 nmol/L) and free cortisol concentrations (83 +/- 55 nmol/L) than control patients (535 +/- 193 nmol/L, p = 0.001 and 33 +/- 18 nmol/L, p < 0.001, respectively). Thereafter, there were no differences in this respect. Serum free and total cortisol concentrations correlated but were unaffected by the severity of SAH. ACTH concentrations were comparable between SAH and control groups. Patients with Hunt-Hess grades IV to V had higher ACTH concentrations at day one (10.7 +/- 7.1 pmol/l/L) and day five (8.2 +/- 7.7 pmol/L) than patients with grade I-III (day one: 3.8 +/- 2.0 pmol/L, p = 0.002; day five: 4.7 +/- 1.8 pmol/L, p = 0.04). CONCLUSIONS: Calculation of serum free cortisol concentration was not helpful in identifying patients with potential hypocortisolism. SAH severity did not affect cortisol concentrations, possibly indicating relative pituitary-adrenal insufficiency in patients with more severe bleeding. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00614887.

Electrocardiographic alterations during hyperinsulinemic hypoglycemia in healthy subjects.

BACKGROUND: We evaluated the arrhythmogenic potential of hypoglycemia by studying electrocardiographic (ECG) changes in response to hyperinsulinemic hypoglycemia and associated sympathoadrenal counterregulatory responses in healthy subjects. METHODS: The study population consisted of 18 subjects, aged 30-40 years. Five-minute ECG recordings and blood samplings were performed at baseline and during the euglycemic and hypoglycemic hyperinsulinemic clamp studies. PR, QT, and QTc intervals of electrocardiogram and ECG morphology were assessed from signal-averaged ECG. RESULTS: Although cardiac beat interval remained unchanged, PR interval decreased (P < 0.01) and QTc interval (P < 0.001) increased in response to hyperinsulinemic hypoglycemia. Concomitant morphological alterations consisted of slight increases in R-wave amplitude and area (P < 0.01 for both), significant decreases in T-wave amplitude and area (P < 0.001 for both), and moderate ST depression (P < 0.001). Counterregulatory norepinephrine response correlated with amplification of the R wave (r =-0.620, P < 0.05) and epinephrine response correlated with flattening of the T wave (r =-0.508, P < 0.05). CONCLUSIONS: Hyperinsulinemic hypoglycemia with consequent sympathetic humoral activation is associated with several ECG alterations in atrioventricular conduction, ventricular depolarization, and ventricular repolarization. Such alterations in cardiac electrical function may be of importance in provoking severe arrhythmias and "dead-in-bed" syndrome in diabetic patients with unrecognized hypoglycemic episodes.

Markers of endothelial dysfunction and low-grade inflammation are associated in the offspring of type 2 diabetic subjects.

The offspring of type 2 diabetic patients are at elevated risk for type 2 diabetes and cardiovascular disease. The aim of our study was to characterize the role of various biomarkers of endothelial activation in a cohort of offspring of type 2 diabetic subjects and to assess the association of adhesion molecules with inflammatory markers and metabolic parameters. Cytokine and adhesion molecule levels were measured in 19 healthy subjects and in 129 offspring of patients with type 2 diabetes (109 with normal glucose tolerance and 20 with impaired glucose tolerance). Insulin sensitivity was determined with the hyperinsulinemic-euglycemic clamp, insulin secretion with the intravenous glucose tolerance test, and abdominal fat distribution with computed tomography. The levels of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-Selectin and vascular adhesion protein-1 were not increased in offspring of type 2 diabetic subjects, but they correlated with inflammatory markers (C-reactive protein, tumor necrosis-alpha, interleukin-6, interleukin-1 beta, interleukin-1 receptor antagonist, interleukin-8, interleukin-10 and interleukin-18). In conclusion, the levels of adhesion molecules were not elevated in the prediabetic state. Inflammatory markers and adhesion molecules were correlated suggesting that low-grade inflammation may precede the elevation of levels of adhesion molecules.

Changes in inflammatory cytokines are related to impaired glucose tolerance in offspring of type 2 diabetic subjects.

OBJECTIVE: We sought to determine whether levels of inflammatory markers and different cytokines are abnormal in nondiabetic offspring of type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: Cytokine levels were measured in 19 healthy control subjects and 129 offspring of patients with type 2 diabetes (109 with normal glucose tolerance [NGT] and 20 with impaired glucose tolerance [IGT]). Insulin sensitivity was determined with the hyperinsulinemic-euglycemic clamp, insulin secretion with the intravenous glucose tolerance test, and abdominal fat distribution with computed tomography. RESULTS: Levels of C-reactive protein and inflammatory cytokines were elevated in nondiabetic offspring of type 2 diabetic subjects. Interleukin (IL)-1beta was increased in the NGT group and decreased in the IGT group. In contrast, levels of IL-1 receptor antagonist (IL-1Ra) were increased in both groups. IL-1beta and -Ra levels correlated inversely (P < 0.05) with rates of whole-body glucose uptake and IL-1beta positively with visceral fat mass (P < 0.05) in normoglycemic offspring. CONCLUSIONS: Nondiabetic offspring of type 2 diabetic subjects have changes in the levels of inflammatory cytokines. The level of IL-1Ra seems to be the most sensitive marker of cytokine response in the pre-diabetic state.

Visceral obesity is associated with high levels of serum squalene.

OBJECTIVE: To investigate the impact of visceral obesity on cholesterol metabolism in normoglycemic offspring of patients with type 2 diabetes. RESEARCH METHODS AND PROCEDURES: The proportion of intra-abdominal fat (IAF) was measured by abdominal computer tomography, and serum cholesterol synthesis and absorption markers were determined by gas-liquid chromatography in 109 normoglycemic offspring of patients with type 2 diabetes. Insulin action was measured with the hyperinsulinemic euglycemic clamp. The gene encoding squalene synthase (farnesyl-diphosphate farnesyltransferase 1) was screened with the single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Cholesterol synthesis markers correlated positively with IAF (r = 0.213 to 0.309, p < or = 0.027) and negatively with the rates of insulin-stimulated whole-body glucose uptake (r = -0.372 to -0.248, p < or = 0.010). However, serum squalene, the first measured precursor of cholesterol synthesis, showed a positive correlation with IAF (r = 0.309, p = 0.001) without any association with subcutaneous fat or insulin sensitivity. Variation in the farnesyl-diphosphate farnesyltransferase 1 gene did not explain elevated serum squalene levels in viscerally obese subjects. From the cholesterol absorption markers, cholestanol was associated negatively with IAF and positively with whole-body glucose uptake (p < 0.05). DISCUSSION: High serum squalene levels are associated with visceral obesity but not with subcutaneous obesity. Whether this finding is causally connected to visceral obesity remains to be established.

Subtle hyperproinsulinaemia characterises the defective insulin secretory capacity in offspring of glutamic acid decarboxylase antibody-positive patients with latent autoimmune diabetes mellitus in adults.

OBJECTIVE: We set out to assess whether hyperproinsulinaemia is an early finding in latent autoimmune diabetes in adults (LADA). RESEARCH DESIGN AND METHODS: We measured plasma proinsulin and C-peptide responses during a 2-h oral glucose tolerance test (OGTT) and in the hyperglycaemic clamp in 21 normoglycaemic offspring of LADA patients testing positive for glutamic acid decarboxylase antibodies (GADA) or islet cell antibodies (ICA), and in 17 healthy control subjects without a family history of diabetes. RESULTS: The study groups had comparable areas under the curves of blood glucose, plasma proinsulin, C-peptide and proinsulin/C-peptide in the OGTT. However, the offspring of LADA patients had higher proinsulin/C-peptide in the hyperglycaemic clamp (P < 0.01 versus the control group). The offspring of GADA-positive LADA patients (n = 9) had higher proinsulin and proinsulin/C-peptide than did the control group in the OGTT (P < 0.05 for both comparisons) and in the hyperglycaemic clamp (P < 0.001 and P < 0.05 respectively). They also had higher proinsulin than the offspring of ICA-positive LADA patients (n = 12) (P < 0.001) in the hyperglycaemic clamp. The offspring of ICA-positive LADA patients did not clearly show hyperproinsulinaemia during the tests, but they had lower maximal glucose-stimulated insulin secretory capacity than the control group (P < 0.05) and the offspring of GADA-positive LADA patients (P < 0.05) in the hyperglycaemic clamp. CONCLUSIONS: These results suggested that insulin secretion in the offspring of GADA-positive LADA patients is characterised by subtle defects in the processing of insulin precursors. Furthermore, various proinsulin responses among the offspring of LADA patients with different autoimmune markers provided further evidence that LADA is a heterogeneous disorder.

Association of adiponectin level and variants in the adiponectin gene with glucose metabolism, energy expenditure, and cytokines in offspring of type 2 diabetic patients.

OBJECTIVE: Adiponectin is an adipose-specific secretory protein abundantly present in the circulation. The role of adiponectin in the control of energy expenditure and substrate utilization has not yet been established. DESIGN: We performed detailed metabolic studies in a large cohort (n = 158) of offspring of patients with type 2 diabetes (T2DM) to determine the association of adiponectin level with glucose and lipid oxidation, energy expenditure, insulin sensitivity, and visceral obesity by applying the euglycemic clamp technique and indirect calorimetry. RESULTS: The adiponectin level was lower in offspring of T2DM patients than in control subjects. When the data were analyzed by adiponectin tertiles, an elevated adiponectin level was associated with high total, oxidative, and nonoxidative glucose disposal and high energy expenditure during hyperinsulinemia; low levels of free fatty acids and low rates of lipid oxidation during hyperinsulinemia; as well as low levels of inflammatory cytokines; and a low amount of intraabdominal fat evaluated by computed tomography. No association of single nucleotide polymorphism 45 or single nucleotide polymorphism 276 with adiponectin level was found. CONCLUSIONS: We conclude that adiponectin has multiple effects on glucose, lipid and free fatty acid metabolism, and cytokines in offspring of T2DM subjects.

Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines, and adhesion molecules in subjects with metabolic syndrome.

BACKGROUND: Detailed metabolic defects in glucose and energy metabolism and abnormalities in a variety of cardiovascular risk factors are largely unknown in subjects with the metabolic syndrome. METHODS AND RESULTS: We characterized the metabolic syndrome in 119 nondiabetic offspring of diabetic probands. Cardiovascular risk factors, including cytokines and adhesion molecules, were measured. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp and indirect calorimetry; intra-abdominal fat and subcutaneous fat were assessed by CT; and maximal oxygen consumption was measured with a bicycle ergometer test. By applying factor analysis, we identified a single factor, the metabolic syndrome factor, from the following variables: 2-hour glucose, fasting insulin, body mass index, waist, HDL cholesterol, triglycerides, and mean blood pressure. Subjects with the highest factor score were defined as having the metabolic syndrome. During hyperinsulinemia, the highest factor score was associated with decreased rates of glucose oxidation and nonoxidative glucose disposal, high rates of lipid oxidation, low energy expenditure, and impaired suppression of free fatty acids during hyperinsulinemia. Furthermore, the metabolic syndrome was associated with a high amount of visceral fat, hypoadiponectinemia, a low maximum oxygen uptake, and high levels of C-reactive protein, proinflammatory cytokines, and adhesion molecules. CONCLUSIONS: The metabolic syndrome is characterized by an excess of intra-abdominal fat, hypoadiponectinemia, insulin resistance in skeletal muscle and adipose tissue, multiple defects in glucose and energy metabolism, and elevated levels of cytokines and adhesion molecules.

The Val103Ile polymorphism of melanocortin-4 receptor regulates energy expenditure and weight gain.

OBJECTIVE: The melanocortin-4 receptor (MC4R) regulates energy intake. On the basis of animal studies, it may also regulate energy expenditure. RESEARCH METHODS AND PROCEDURES: The effect of the Val103Ile polymorphism of the MC4R gene on energy metabolism was studied in 229 middle-aged nondiabetic subjects (Group 1, age 51.2 +/- 9.8 years, BMI 26.8 +/- 4.5 kg/m2) and on weight gain in 1013 elderly subjects (Group 2, age 69.9 +/- 2.9 years, BMI 27.4 +/- 4.1 kg/m2) during a 3.5-year follow-up study. In Group 1, insulin sensitivity, energy expenditure, and substrate oxidation were measured with the hyperinsulinemic euglycemic clamp combined with indirect calorimetry. RESULTS: In Group 1, the Val103Ile genotype was associated with high rates of energy expenditure (63.42 +/- 13.40 in eight subjects with the Val103Ile genotype vs. 59.86 +/- 7.33 J/kg per minute in 221 subjects with the Val103Val genotype, p = 0.007), high rates of glucose oxidation (8.90 +/- 6.15 vs. 6.07 +/- 4.38 micromol/kg per minute, p = 0.020), and low levels of free fatty acids (0.45 +/- 0.18 vs. 0.56 +/- 0.23 mM, p = 0.029) in the fasting state, and with high rates of glucose oxidation during the clamp (18.88 +/- 4.63 vs. 17.60 +/- 3.24 micromol/kg per minute, p = 0.031). In Group 2, the 103Ile allele was associated with an increase in weight gain during the follow-up (0.78 +/- 3.98 vs. -0.82 +/- 3.98 kg, p = 0.038). DISCUSSION: The Val103Ile polymorphism of the MC4R gene is associated with energy expenditure in humans. Furthermore, it may associate with glucose oxidation, free fatty acid levels, and weight gain.

The effect of the -308A allele of the TNF-alpha gene on insulin action is dependent on obesity.

OBJECTIVE: Promoter polymorphisms of the tumor necrosis factor alpha (TNF-alpha) gene are associated with insulin sensitivity and BMI. We investigated whether the effect of the G-308A polymorphism of the TNF-alpha gene on insulin action depends on BMI. RESEARCH METHODS AND PROCEDURES: The effects of the G-308A polymorphism on the rates of glucose and lipid oxidation and free fatty acid (FFA) levels were studied using the hyperinsulinemic euglycemic clamp combined with indirect calorimetry in 129 healthy subjects. RESULTS: The -308A allele of the TNF-alpha gene was associated with high rates of glucose oxidation (p = 0.008 adjusted for age, gender, and BMI) and lipid synthesis (p = 0.037) and suppression of FFA levels (p = 0.023) during hyperinsulinemia. In normal weight subjects (BMI < 26 kg/m(2)), the -308 allele was associated with high rates of glucose oxidation (p = 0.036) during the clamp but not with high rates of lipid synthesis (p = 0.896) or FFA suppression (p = 0.464). In overweight subjects (BMI >or= 26 kg/m(2)), high rates of lipid synthesis and FFA suppression (p = 0.010 and p = 0.042, respectively) but not the rates of glucose oxidation during the clamp (p = 0.193) were associated with the -308A allele. DISCUSSION: The -308A allele of the promoter of the TNF-alpha gene is associated with high rates of glucose oxidation in normal weight subjects and with effective lipid storage in overweight subjects. These findings suggest an interaction of the polymorphism with obesity.

The Leu7Pro polymorphism of the neuropeptide Y gene regulates free fatty acid metabolism.

The Leu7Pro polymorphism in the signal peptide of the preproneuropeptide Y (NPY) has been associated with dyslipidemias and free fatty acid (FFA) levels during exercise. The association of this polymorphism with insulin sensitivity has not been studied. In this study, the Leu7Pro polymorphism was determined in 2 groups of nondiabetic middle-aged subjects (n = 266 and n = 295). Insulin sensitivity was measured with the hyperinsulinemic euglycemic clamp (n = 266) or with an intravenous glucose tolerance test (IVGTT, n = 295). First-phase insulin secretion was determined as insulin area under the curve (AUC) during the first 10 minutes of the IVGTT. FFAs were measured both in the fasting state and during the hyperinsulinemic clamp. The Leu7Pro polymorphism of the NPY gene was not associated with the rates of whole body glucose uptake, insulin sensitivity index, insulin secretion during the IVGTT, or insulin AUC during the oral glucose tolerance test. However, the Pro7 allele was associated with low FFA levels both in the fasting state (P =.043) and during the hyperinsulinemic clamp (P =.003). In conclusion, the Leu7Pro polymorphism of the NPY gene associates with alterations in FFA metabolism but does not have an impact on insulin sensitivity, insulin secretion, or glucose metabolism.

Effects of euglycaemic and hypoglycaemic hyperinsulinaemia on sympathetic and parasympathetic regulation of haemodynamics in healthy subjects.

The effects of hypoglycaemia during hyperinsulinaemia, occurring under various pathophysiological conditions, on the cardiovascular regulatory system and vasculature are largely unknown. The aim of the present study was to investigate regulatory and haemodynamic responses to acute hyperinsulinaemia and consequent hypoglycaemia in 18 healthy subjects. Blood sampling and 5 min ECG and blood pressure recordings were performed at baseline and during the euglycaemic and hypoglycaemic phases of a hyperinsulinaemic clamp. Heart rate variability (HRV) and blood pressure variability (BPV) were assessed by using power spectral analysis, and baroreflex sensitivity (BRS) was assessed using the cross-spectral method. Stroke volume was assessed from the non-invasive blood pressure signal by the arterial pulse contour method. Euglycaemic hyperinsulinaemia did not change plasma catecholamine concentrations, HRV, BPV, BRS, heart rate, blood pressure, stroke volume, cardiac output or peripheral resistance. However, hyperinsulinaemic hypoglycaemia resulted in an 11.7-fold increase in the plasma adrenaline concentration (from 0.19+/-0.03 to 1.68+/-0.32 nmol/l; P <0.001), and a modest 1.3-fold increase in the plasma noradrenaline concentration (from 1.74+/-0.22 to 2.02+/-0.19 nmol/l; P <0.05) compared with baseline. Furthermore, we observed significant decreases in diastolic blood pressure (from 68+/-3 to 60+/-3 mmHg; P <0.05) and peripheral resistance (from 24.1+/-1.2 to 18.5+/-1.1 mmHg.min(-1) x l(-1); P <0.01). Stroke volume and cardiac output increased markedly from the euglycaemic to the hypoglycaemic period only ( P <0.01 for both). Hypoglycaemia did not influence HRV, BPV or BRS. Our findings indicate that hyperinsulinaemic hypoglycaemia is characterized by a significant increase in the plasma adrenaline concentration and by decreases in peripheral resistance and blood pressure. Counter-regulation during hyperinsulinaemic hypoglycaemia involves selective adrenomedullary sympathetic activation, and does not influence cardiac parasympathetic regulation or baroreflex control of heart rate.

A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1.

BACKGROUND: ATP-sensitive potassium (KATP) channels are major regulators of glucose-induced insulin secretion in pancreatic beta cells. We have described a dominant heterozygous mutation--E1506K--in the sulfonylurea receptor 1 (SUR1) gene (ABCC8) in a Finnish family, which leads to congenital hyperinsulinaemia due to reduction of K(ATP)-channel activity. We aimed to characterise glucose metabolism in adults heterozygous for the E1506K mutation. METHODS: Glucose tolerance was assessed by an oral glucose tolerance test, insulin secretion by the intravenous glucose tolerance test and hyperglycaemic clamp, and insulin sensitivity by hyperinsulinaemic euglycaemic clamp in 11 people heterozygous for the E1506K mutation and 19 controls. FINDINGS: Four people who were heterozygous for the SUR1 E1506K mutation had diabetes, five had impaired glucose tolerance, one had impaired fasting glucose, and one had normal glucose tolerance. Although glucose-induced, first-phase insulin secretion was normal in children younger than 10 years of age who were heterozygous for the SUR1 E1506K mutation (n=2; 66 and 334 pmol/L), it fell rapidly after puberty (n=3; 12-32 pmol/L), and was almost completely lost in adulthood (n=11; 12-32 pmol/L). Furthermore, these heterozygous people had a substantial reduction in maximum glucose-stimulated insulin secretion during hyperglycemic clamp (carriers without diabetes 422 pmol/L; carriers with diabetes 97 pmol/L). By contrast, insulin sensitivity (M/I value) was normal in carriers of the E1506K mutation who did not have diabetes and was reduced by 15% in those who were heterozygous with diabetes (0.07 in those without diabetes and 0.05 in those with the disorder; not significantly different from controls). INTERPRETATION: Heterozygous E1506K substitution in the SUR1 gene causes congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes in middle-age. This variant represents a new subtype of autosomal dominant diabetes.

The K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with dyslipidemia.

OBJECTIVE: To investigate the relationship of the K121Q polymorphism of the plasma cell glycoprotein 1 (PC-1) gene with insulin resistance, insulin secretion, and lipids and lipoproteins. RESEARCH DESIGN AND METHODS: Altogether, 110 normoglycemic subjects (group I) underwent a hyperinsulinemic-euglycemic clamp for evaluation of insulin sensitivity. The first-phase insulin secretion was determined by the intravenous glucose tolerance test (IVGTT) in a separate sample of 295 normoglycemic subjects (group II). RESULTS: The 121Q allele (genotypes K121Q and Q121Q) compared with the K121K genotype was related to higher fasting insulin levels (group I: 69.6 +/- 45.6 vs. 51.9 +/- 28.4 pmol/l [mean +/- SD], P = 0.050; group II: 66.6 +/- 38.8 vs. 53.8 +/- 26.6 pmol/l, P = 0.009). In group I, subjects carrying the 121Q allele compared with subjects with the K121K genotype had lower rates of whole-body glucose uptake (51.17 +/- 12.07 vs. 60.12 +/- 14.86 micro mol x kg(-1) x min(-1), P = 0.012) and nonoxidative glucose disposal (33.71 +/- 10.51 vs. 41.51 +/- 13.36 micro mol x kg(-1) x min(-1), P = 0.015) during the clamp. In group II, there was no significant difference between the 121Q allele carriers and subjects with the K121K genotype in total first-phase insulin secretion during the first 10 min of the IVGTT (2,973 +/- 2,224 vs. 2,520 +/- 1,492 pmol. l(-1). min(-1), P = 0.415). No association of the K121Q polymorphism with serum lipids and lipoproteins was found. CONCLUSIONS: In healthy normoglycemic Finnish subjects, the K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with impaired insulin secretion or dyslipidemia.

The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity.

Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in many tissues. IL-6 null mice show low energy expenditure, but the effect of the variants of the IL-6 gene on energy expenditure has not been previously studied in humans. Therefore, we investigated the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure, measured by indirect calorimetry in healthy Finnish subjects (n = 124). We also measured insulin sensitivity by the hyperinsulinemic-euglycemic clamp. Subjects with the C-174C genotype of the IL-6 gene had significantly lower energy expenditure than subjects with the G-174C or G-174G genotypes both in fasting (CC 13.68 +/- 1.98, CG 14.73 +/- 1.57, GG 14.81 +/- 2.01 kcal x kg(-1) x min(-1); P = 0.012) and during the euglycemic-hyperinsulinemic clamp (CC 15.24 +/- 2.05, CG 16.62 +/- 2.06, GG 16.66 +/- 2.50 kcal x kg(-1) x min(-1); P = 0.007). Moreover, subjects homozygous for the C allele had lower rates of whole-body glucose uptake than carriers of the G allele (CC 50.95 +/- 13.91, CG 59.40 +/- 14.17, GG 59.21 +/- 15.93 micro mol x kg(-1) x min(-1); P = 0.016). The rates of both oxidative (P = 0.013) and nonoxidative (P = 0.016) glucose disposal were significantly affected by the IL-6 promoter polymorphism. In conclusion, the C-174C promoter polymorphism of the IL-6 gene influences energy expenditure and insulin sensitivity in healthy normoglycemic subjects. Whether this polymorphism is a risk factor for obesity or type 2 diabetes can be estimated only in prospective population-based studies.

Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study.

Metformin, an insulin-sensitizing drug, has been shown to improve ovarian function and glucose metabolism in obese women with polycystic ovary syndrome (PCOS), but its effects and possible benefits in nonobese PCOS subjects are not well known. Seventeen nonobese (body mass index < 25 kg/m(2)) women with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months; n = 8) or ethinyl estradiol (EE, 35 microg)-cyproterone acetate (CA, 2 mg) oral contraceptive pills (EE-CA; n = 9). Waist to hip ratio; serum concentrations of sex steroids, glucose, and insulin during a 75-g oral glucose tolerance test; early phase insulin and C-peptide secretion; and insulin sensitivity using a euglycemic hyperinsulinemic clamp were assessed at baseline and at 3 and 6 months of treatment. Metformin did not have any effect on glucose tolerance or insulin sensitivity, but fasting insulin concentrations decreased from 44.4 +/- 5.1 (SE) to 29.8 +/- 4.3 pmol/liter (P = 0.03), the waist to hip ratio decreased from 0.78 +/- 0.01 to 0.75 +/- 0.01 (P = 0.01), and hepatic insulin clearance increased during the treatment. Furthermore, metformin decreased serum testosterone levels from 2.7 +/- 0.3 to 2.0 +/- 0.2 nmol/liter (P = 0.01) and improved menstrual cyclicity. EE-CA did not have any significant effect on glucose tolerance, serum insulin levels, or insulin sensitivity, but it increased slightly the body mass index (P = 0.09) and significantly serum leptin concentrations (P < 0.001) and decreased serum testosterone levels from 2.1 +/- 0.2 to 1.4 +/- 0.2 nmol/liter (P = 0.03). In conclusion, EE-CA seems to be an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin and glucose metabolism also have to be taken into consideration in nonobese subjects. Metformin improved hyperandrogenism, hyperinsulinemia, and menstrual cyclicity, most likely through its positive effect on insulin clearance and abdominal adiposity. Thus, similarly to obese PCOS women, nonobese PCOS subjects with anovulation may also benefit from metformin treatment.

Promoter polymorphisms -359T/C and -303A/G of the catalytic subunit p110beta gene of human phosphatidylinositol 3-kinase are not associated with insulin secretion or insulin sensitivity in finnish subjects.

OBJECTIVE: Phosphatidylinositol (PI) 3-kinase activity is required for insulin-stimulated translocation of GLUT4 transporters and glucose uptake and utilization. Therefore, genes encoding the subunits of PI 3-kinase are promising candidate genes for insulin resistance and type 2 diabetes. We recently cloned the catalytic subunit p110beta gene of human PI 3-kinase and reported two nucleotide polymorphisms, -359T/C and -303A/G, in the promoter region of this gene. In this study, we determined the effects of these polymorphisms on insulin secretion and insulin sensitivity. RESEARCH DESIGN AND METHODS: We studied two separate groups of Finnish nondiabetic subjects. Insulin secretion was evaluated by intravenous glucose tolerance test and insulin sensitivity by hyperinsulinemic-euglycemic clamp. RESULTS: Our results showed that the -359T/C and -303A/G polymorphisms did not have a significant effect on fasting plasma insulin levels, insulin secretion, or insulin sensitivity. CONCLUSIONS: It is unlikely that the promoter polymorphisms -359T/C and -303A/G of the catalytic subunit p110beta gene of human PI 3-kinase have a major impact on insulin secretion, insulin sensitivity, or the risk of type 2 diabetes in Finnish subjects.

Mutations in the cardiac myosin-binding protein C gene are the predominant cause of familial hypertrophic cardiomyopathy in eastern Finland.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in genes encoding sarcomere proteins. This study screened all patients with HCM from the Kuopio University Hospital region in eastern Finland for variants in the cardiac myosin-binding protein C gene ( MYBPC3). All 35 exons of MYBPC3 were screened by the single-strand conformation polymorphism method in 37 unrelated patients with HCM. In MYBPC3 we identified seven novel (Gln1061X, IVS5-2A-->C, IVS14-13G-->A, Ex25DeltaLys, Pro147Leu, Ser236Gly, and Arg1138His) and two previously reported (Arg326Gln, Val896Met) variants, all of which are predicted to affect the structure of the encoded protein. Four of the nine variants, a nonsense mutation Gln1061X, a splice acceptor mutation (IVS5-2A-->C), a novel substitution in intron 14 (IVS14-13G-->A), and a novel 3-bp deletion in exon 25 (Ex25DeltaLys) were concluded to be disease-causing mutations because they cosegregated with the HCM phenotype or were absent in more than 200 normal chromosomes, or both. The mutation Gln1061X was found most frequently, being present in 6 families (23 subjects) while the other three mutations were found in single families each. Haplotype analysis indicated a likely founder effect among the families carrying the Gln1061X mutation. We found four novel mutations in MYBPC3, accounting for approx. 38% of familial and 24% of all cases of HCM. In our previous and unpublished studies no more frequent cause of HCM has been found in genetic analyses of other eight sarcomeric proteins. Consequently MYBPC3 is the predominant gene for HCM in eastern Finland. In addition, several amino acid substitutions in MYBPC3 suspected to be not associated with HCM were identified, indicating that some of the missense variants found in MYBPC3 are possibly not disease-causing mutations.