Minna Soinio

Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus.

Context Previous studies have not assessed the relationship between homocysteine level and coronary heart disease mortality in diabetic patients. Contribution This prospective, 7-year study of 830 middle-aged patients with type 2 diabetes mellitus found that plasma homocysteine level of 15 mol/L or more was independently associated with increased risk for coronary heart disease events, including death. Implications Homocysteine level is an independent risk factor for coronary heart disease in patients with type 2 diabetes mellitus. Caution The study did not assess folate or vitamin B12 intake or whether lowering homocysteine level with folate supplementation would reduce the risk for coronary artery disease. The Editors Moderately elevated plasma homocysteine concentration is associated with an increased risk for cardiovascular events in nondiabetic individuals independent of conventional risk factors, but the results of some prospective studies have been conflicting (1-7). In patients with type 2 diabetes mellitus, who are known to have a 2- to 4-fold increased risk for coronary heart disease (CHD), plasma homocysteine level seems to predict cardiovascular events (8-12). However, few prospective studies in diabetic participants are available, the study cohorts have been rather small, and the studies have shown an independent association only between elevated plasma homocysteine level and all-cause mortality (13-15). Therefore, the role of homocysteine level in predicting CHD in patients with type 2 diabetes is still largely unknown. In this long-term prospective study, we examined whether moderately elevated plasma homocysteine levels predict CHD events during a 7-year follow-up of a large cohort of participants with type 2 diabetes. Methods Baseline Study A detailed description of study participants has been given elsewhere (16). Patients with type 2 diabetes, 45 to 64 years of age, who were born and living in the Turku University Central Hospital district in West Finland and in the Kuopio University Hospital district in East Finland were identified through a national drug reimbursement register. The final sample consisted of 1059 patients with type 2 diabetes. Of these patients, 328 men and 221 women were from West Finland (participation rate, 79%) and 253 men and 257 women were from East Finland (participation rate, 83%). Type 1 diabetes mellitus was excluded in all insulin-treated participants by C-peptide measurements (16). Of the participants, 147 were treated with diet only, 762 were treated with oral medication, and 150 were treated with insulin. In our study, the final study sample consisted of 830 patients with type 2 diabetes (462 men and 368 women) whose plasma homocysteine values were available (Figure 1). Of these, 706 participants did not have myocardial infarction (MI) at baseline. Figure 1. Formation of the sample in the homocysteine study. The baseline examination, performed between 1982 and 1984, included an interview on the history of smoking, alcohol intake, physical activity, use of medication, and history of chest pain suggestive of CHD. The methods have been previously described in detail (16). Chest pain that suggested CHD was recorded by specially trained nurses using the Rose cardiovascular questionnaire (17). Two investigators reviewed all medical records of participants who reported that they had been hospitalized for chest pain; methods were carefully standardized between the reviewers. The World Health Organization criteria for verified definite or possible MI based on chest pain symptoms, electrocardiogram changes, and enzyme determinations were used to define previous MI (18). Electrocardiogram abnormalities were classified according to the Minnesota code (17). Body mass index was calculated (kg/m2), and blood pressure was measured with the person in the sitting position after a 5-minute rest. A participant was defined as having hypertension if systolic blood pressure was 160 mm Hg or more, if the diastolic blood pressure was 95 mm Hg or more, or if the participant was receiving drug treatment for hypertension. All blood specimens were drawn at 8:00 a.m. after a 12-hour fast. Samples were centrifuged within 1 hour and frozen immediately at 20 C. Fasting plasma glucose level was determined by the glucose oxidase method (Boehringer Mannheim, Mannheim, Germany). Glycosylated hemoglobin A1 level was determined by affinity chromatography (Isolab, Akron, Ohio). Serum lipid and lipoprotein cholesterol levels were measured in fresh serum samples. Serum total cholesterol and triglyceride levels were determined enzymatically (Boehringer Mannheim). Serum high-density lipoprotein cholesterol level was determined enzymatically after precipitation of low-density lipoproteins and very-low-density lipoproteins with dextran sulfate MgCl2 (19). Plasma creatinine level was determined by the Jaffe method. The estimated creatinine clearance level was calculated by using the following formula described by Cockcroft and Gault (20): creatinine clearance (mL/s) = (1 60) [(140 y) kg K] serum creatinine, where K is a constant factor (that is, 1.23 for men and 1.05 for women), y is age, and kg is body weight. These values were then corrected for body surface area. Plasma homocysteine level was analyzed from baseline samples in 1999 to 2000 by using fluorescence polarization immunoassay technique (IMx Homocysteine assay, Abbott Laboratories, Abbott Park, Illinois). Follow-up Study In 1990, a questionnaire about hospitalization for acute chest pain was sent to every surviving participant of the original study cohort. One of the investigators reviewed medical records of all participants who died between the baseline examination and 31 December 1989 or who reported in the questionnaire that they had been hospitalized because of chest pain between the baseline examination and 31 December 1989. The modified World Health Organization criteria for definite or possible MI were used similarly as in the baseline study. In the final classification of the causes of death, hospital records and autopsy records were used, if available. Copies of death certificates of those participants who had died were obtained from the Central Statistical Office of Finland. To ensure that the data collection was complete, a computerized hospital discharge register was used to check for hospitalizations of all participants in the baseline study. In cases of diagnoses suggesting MI, medical records were also checked. The Joint Commission on Ethics of the Turku University, Turku University Central Hospital, and University of Kuopio approved the study. Informed written consent was obtained from all participants. Statistical Analyses All statistical analyses were performed by using SPSS for Windows, version 10.0 (SPSS, Inc., Chicago, Illnois). Data of continuous variables are expressed as means (SD). Differences between groups were assessed by the Student t-test for independent samples. Plasma homocysteine and triglyceride levels were analyzed after logarithmic transformation because of their skewed distribution. A plasma homocysteine level of 15 mol/L, corresponding to the 90th percentile of the distribution, was the cutoff point for a mildly elevated level in statistical analyses because higher values are considered to indicate moderate hyperhomocysteinemia, according to a statement by the American Heart Association (21). The chi-square test was used to compare categorical variables with variables divided in quartiles. Univariate and multivariate Cox regression analyses were performed to investigate the association between CHD risk factors and the time to CHD events. Role of the Funding Sources The funding sources had no role in the design, data collection, analysis, or interpretation of the study or in the decision to submit the manuscript for publication. Results Table 1 presents plasma homocysteine levels and background data of the study sample in relation to CHD mortality during the 7-year follow-up. In both men and women, the mean plasma homocysteine concentration was statistically significantly higher in those who died of CHD than in those who did not. Serum creatinine level was statistically significantly higher and calculated creatinine clearance was statistically significantly lower in men who had a fatal CHD event than in those who did not, but these differences were not seen in women. The mean (SD) plasma homocysteine concentration was significantly higher in men (11.4 4.8 mol/L vs. 10.2 4.8 mol/L) and women (10.1 3.4 mol/L vs. 9.4 3.9 mol/L) who had a fatal or nonfatal MI compared with those who did not (P = 0.004 and P = 0.036, respectively). Table 1. Plasma Homocysteine Concentration, Cardiovascular Risk Factors, and Other Clinical Characteristics of Men and Women with Type 2 Diabetes at Baseline in Relation to Coronary Heart Disease Mortality When we divided plasma homocysteine level into quartiles (cutoff points of 7.7 mol/L, 9.3 mol/L, 11.7 mol/L, in both sexes combined), CHD mortality rates were 11.9%, 9.9%, 16.5%, and 20.4% and CHD mortality or nonfatal MI rates were 19.0%, 17.8%, 27.2%, and 31.3% in the lowest, second, third, and highest quartiles, respectively (overall, P = 0.011 and P = 0.002, respectively). We then compared the incidence of CHD events in patients with type 2 diabetes whose plasma homocysteine levels were 15 mol/L or more and those whose plasma homocysteine levels were below 15 mol/L (Figure 2). With respect to CHD mortality, as well as CHD death or nonfatal MI, the CHD event rate was statistically significantly higher in participants with plasma homocysteine levels of 15 mol/L or more. Results were unchanged if we excluded participants who already had MI at baseline (n = 124). Figure 2. Coronary heart disease ( CHD ) events by baseline plasma homocysteine concentration in men and women with type 2 diabetes. top MI bottom The following differences were found in the baseline characteristics of patie

Hyperthyroidism Increases Brown Fat Metabolism in Humans

CONTEXT Thyroid hormones are important regulators of brown adipose tissue (BAT) development and function. In rodents, BAT metabolism is up-regulated by thyroid hormones. OBJECTIVE The purpose of this article was to investigate the impact of hyperthyroidism on BAT metabolism in humans. DESIGN This was a follow-up study using positron emission tomography imaging. MAIN OUTCOME MEASURES Glucose uptake (GU) and perfusion of BAT, white adipose tissue, skeletal muscle, and thyroid gland were measured using [18F]2-fluoro-2-deoxy-D-glucose and [15O]H2O and positron emission tomography in 10 patients with overt hyperthyroidism and in 8 healthy participants. Five of the hyperthyroid patients were restudied after restoration of euthyroidism. Supraclavicular BAT was quantified with magnetic resonance imaging or computed tomography and energy expenditure (EE) with indirect calorimetry. RESULTS Compared with healthy participants, hyperthyroid participants had 3-fold higher BAT GU (2.7±2.3 vs 0.9±0.1 μmol/100 g/min, P=.0013), 90% higher skeletal muscle GU (P<.005), 45% higher EE (P<.005), and a 70% higher lipid oxidation rate (P=.001). These changes were reversible after restoration of euthyroidism. During hyperthyroidism, serum free T4 and free T3 were strongly associated with EE and lipid oxidation rates (P<.001). TSH correlated inversely with BAT and skeletal muscle glucose metabolism (P<.001). Hyperthyroidism had no effect on BAT perfusion, whereas it stimulated skeletal muscle perfusion (P=.04). Thyroid gland GU did not differ between hyperthyroid and euthyroid study subjects. CONCLUSIONS Hyperthyroidism increases GU in BAT independently of BAT perfusion. Hyperthyroid patients are characterized by increased skeletal muscle metabolism and lipid oxidation rates.

Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients

BACKGROUND & AIMS Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity. METHODS Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery. RESULTS Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects. CONCLUSIONS This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non-diabetic patients for the same weight reduction.

Obesity is associated with white matter atrophy: A combined diffusion tensor imaging and voxel‐based morphometric study

Little is known about the mechanisms by which obesity influences brain structure. In this study, the obesity‐related changes in brain white and gray matter integrity were examined.

Effect of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Roux-en-Y Gastric Bypass on Weight Loss at 5 Years Among Patients With Morbid Obesity: The SLEEVEPASS Randomized Clinical Trial

Importance Laparoscopic sleeve gastrectomy for treatment of morbid obesity has increased substantially despite the lack of long-term results compared with laparoscopic Roux-en-Y gastric bypass. Objective To determine whether laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass are equivalent for weight loss at 5 years in patients with morbid obesity. Design, Setting, and Participants The Sleeve vs Bypass (SLEEVEPASS) multicenter, multisurgeon, open-label, randomized clinical equivalence trial was conducted from March 2008 until June 2010 in Finland. The trial enrolled 240 morbidly obese patients aged 18 to 60 years, who were randomly assigned to sleeve gastrectomy or gastric bypass with a 5-year follow-up period (last follow-up, October 14, 2015). Interventions Laparoscopic sleeve gastrectomy (n = 121) or laparoscopic Roux-en-Y gastric bypass (n = 119). Main Outcomes and Measures The primary end point was weight loss evaluated by percentage excess weight loss. Prespecified equivalence margins for the clinical significance of weight loss differences between gastric bypass and sleeve gastrectomy were −9% to +9% excess weight loss. Secondary end points included resolution of comorbidities, improvement of quality of life (QOL), all adverse events (overall morbidity), and mortality. Results Among 240 patients randomized (mean age, 48 [SD, 9] years; mean baseline body mass index, 45.9, [SD, 6.0]; 69.6% women), 80.4% completed the 5-year follow-up. At baseline, 42.1% had type 2 diabetes, 34.6% dyslipidemia, and 70.8% hypertension. The estimated mean percentage excess weight loss at 5 years was 49% (95% CI, 45%-52%) after sleeve gastrectomy and 57% (95% CI, 53%-61%) after gastric bypass (difference, 8.2 percentage units [95% CI, 3.2%-13.2%], higher in the gastric bypass group) and did not meet criteria for equivalence. Complete or partial remission of type 2 diabetes was seen in 37% (n = 15/41) after sleeve gastrectomy and in 45% (n = 18/40) after gastric bypass (P > .99). Medication for dyslipidemia was discontinued in 47% (n = 14/30) after sleeve gastrectomy and 60% (n = 24/40) after gastric bypass (P = .15) and for hypertension in 29% (n = 20/68) and 51% (n = 37/73) (P = .02), respectively. There was no statistically significant difference in QOL between groups (P = .85) and no treatment-related mortality. At 5 years the overall morbidity rate was 19% (n = 23) for sleeve gastrectomy and 26% (n = 31) for gastric bypass (P = .19). Conclusions and Relevance Among patients with morbid obesity, use of laparoscopic sleeve gastrectomy compared with use of laparoscopic Roux-en-Y gastric bypass did not meet criteria for equivalence in terms of percentage excess weight loss at 5 years. Although gastric bypass compared with sleeve gastrectomy was associated with greater percentage excess weight loss at 5 years, the difference was not statistically significant, based on the prespecified equivalence margins. Trial Registration clinicaltrials.gov Identifier: NCT00793143

The Effects of Bariatric Surgery on Pancreatic Lipid Metabolism and Blood Flow

CONTEXT Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis. OBJECTIVE The objective of this study was to investigate the effects of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control. DESIGN This was a longitudinal study. SETTING The study was conducted in a clinical research center. PARTICIPANTS This study included 27 morbidly obese and 15 healthy control subjects. INTERVENTIONS Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid and radiowater ([(15)O]H2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux-en-Y gastric bypass or sleeve gastrectomy). MAIN OUTCOME MEASURES Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of β-cell function, glucose tolerance, and insulin sensitivity. RESULTS Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and β-cell function. CONCLUSIONS Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes.

Weight Loss After Bariatric Surgery Reverses Insulin-Induced Increases in Brain Glucose Metabolism of the Morbidly Obese

Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not different between groups. However, the hyperinsulinemic clamp increased brain glucose metabolism in a widespread manner in the obese but not control subjects, and brain glucose metabolism was significantly higher during clamp in obese than in control subjects. After follow-up, 6 months postoperatively, the increase in glucose metabolism was no longer observed, and this attenuation was coupled with improved peripheral insulin sensitivity after weight loss. We conclude that obesity is associated with increased insulin-stimulated glucose metabolism in the brain and that this abnormality can be reversed by bariatric surgery.

Changes in bone metabolism after bariatric surgery by gastric bypass or sleeve gastrectomy.

Bariatric surgery results in rapid weight loss and beneficial metabolic effects, but may have negative effects on the skeleton. The objective of this prospective study was to evaluate changes in bone metabolism in response to bariatric surgery with two surgical techniques. 46 morbidly obese subjects (mean 44.9years, BMI 42.1) with (n=19) or without (n=27) type 2 diabetes (T2DM) at baseline underwent either Roux-en-Y gastric bypass (RYGB, n=21) or sleeve gastrectomy (SG, n=25). Bone turnover markers (CTX, PINP, TRAcP5b, TotalOC and ucOC) were measured before and six months after surgery. Volumetric bone mineral density (vBMD) at lumbar spine and vertebral bone marrow (VBM) fat were measured in 21 subjects (7 RYGB and 14 SG) with three-dimensional quantitative computer tomography and 1H MR spectroscopy, respectively. 25 non-obese subjects were recruited as controls (mean 45.8years, BMI 23.0) and assessed at a single cross-sectional visit. Obese subjects had significantly lower bone turnover at baseline when compared to non-obese controls. Bone metabolic markers markedly increased post-operatively (p<0.0001 for all). The activation of bone remodeling was significantly higher after RYGB than after SG and was particularly observed in patients, whose type 2 diabetes was in remission after weight loss. There was no change in volumetric BMD or marrow fat at lumbar spine six months after surgery in our sample. In conclusion, severe obesity decreases bone remodeling, which is activated after bariatric surgery. The increase in bone turnover after surgery is affected by the choice of surgical technique and by the post-surgery remission of T2DM.

Effect of Bariatric Surgery on Adipose Tissue Glucose Metabolism in Different Depots in Patients With or Without Type 2 Diabetes

OBJECTIVE We investigated fat distribution and tissue-specific insulin-stimulated glucose uptake (GU) in seven fat compartments (visceral and subcutaneous) and skeletal muscle in morbidly obese patients with (T2D) and without (ND) type 2 diabetes before and 6 months after bariatric surgery. RESEARCH DESIGN AND METHODS A total of 23 obese patients (BMI 43.0 ± 3.6 kg/m2; 9 T2D and 14 ND) were recruited from a larger, randomized multicenter SLEEVEPASS study. MRI (for fat distribution) and [18F]-fluorodeoxyglucose PET (for GU) studies were performed for the obese patients before and 6 months postsurgery; 10 lean subjects served as control subjects and were studied once. RESULTS At baseline, visceral fat GU was 30 ± 7% of muscle GU in control subjects and 57 ± 5% in obese patients. Visceral and deep subcutaneous fat were more abundant (despite same total fat mass) and less insulin sensitive in T2D than ND; in both, GU was impaired compared with control subjects. Postsurgery, visceral fat mass decreased (∼40%) more than subcutaneous fat (7%). Tissue-specific GU was improved, but not normalized, at all sites in T2D and ND alike. The contribution of visceral fat to whole-body GU was greater in T2D than ND but decreased similarly with surgery. Subcutaneous fat made a fourfold greater contribution to whole-body GU in obese versus lean subjects (15% vs. 4%) both before and after surgery. CONCLUSIONS Bariatric surgery leads to sustained weight loss and improves tissue-specific glucose metabolism in morbidly obese patients. We conclude that 1) enhanced visceral fat accumulation is a feature of T2D, 2) severe obesity compromises muscle insulin sensitivity more than fat insulin sensitivity, and 3) fat mass expansion is a sink for plasma glucose.

Pancreatic Metabolism, Blood Flow, and β-Cell Function in Obese Humans

CONTEXT Glucolipotoxicity is believed to induce pancreatic β-cell dysfunction in obesity. Previously, it has not been possible to study pancreatic metabolism and blood flow in humans. OBJECTIVE The objective of the study was to investigate whether pancreatic metabolism and blood flow are altered in obesity using positron emission tomography (PET). In the preclinical part, the method was validated in animals. DESIGN This was a cross-sectional study. SETTING The study was conducted in a clinical research center. PARTICIPANTS Human studies consisted of 52 morbidly obese and 25 healthy age-matched control subjects. Validation experiments were done with rodents and pigs. INTERVENTIONS PET and magnetic resonance imaging studies using a glucose analog ([(18)F]fluoro-2-deoxy-d-glucose), a palmitate analog [14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid], and radiowater ([(15)O]H2O) were performed. In animals, a comparison between ex vivo and in vivo data was performed. MAIN OUTCOME MEASURES Pancreatic glucose/fatty acid (FA) uptake, fat accumulation, and blood flow parameters of β-cell function were measured. RESULTS PET proved to be a feasible method to measure pancreatic metabolism. Compared with healthy participants, obese participants had elevated pancreatic FA uptake (P < .0001), more fat accumulation (P = .0001), lowered glucose uptake both during fasting and euglycemic hyperinsulinemia, and blunted blood flow (P < .01) in the pancreas. Blood flow, FA uptake, and fat accumulation were negatively associated with multiple markers of β-cell function. CONCLUSIONS Obesity leads to changes in pancreatic energy metabolism with a substrate shift from glucose to FAs. In morbidly obese humans, impaired pancreatic blood flow may contribute to β-cell dysfunction and in the pathogenesis of type 2 diabetes.