Reduction of oxidative stress on DNA and RNA in obese patients after Roux-en-Y gastric bypass surgery-An observational cohort study of changes in urinary markers.

Increased oxidative stress in obesity and diabetes is associated with morbidity and mortality risks. Levels of oxidative damage to DNA and RNA can be estimated through measurement of 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) in urine. Both markers have been associated with type 2 diabetes, where especially 8-oxoGuo is prognostic for mortality risk. We hypothesized that Roux-en-Y gastric bypass (RYGB) surgery that has considerable effects on bodyweight, hyperglycemia and mortality, might be working through mechanisms that reduce oxidative stress, thereby reducing levels of the urinary markers. We used liquid chromatography coupled with tandem mass spectrometry to analyze the content of 8-oxodG and 8-oxoGuo in urinary samples from 356 obese patients treated with the RYGB-procedure. Mean age (SD) was 44.2 (9.6) years, BMI was 42.1 (5.6) kg/m2. Ninety-six (27%) of the patients had type 2 diabetes. Excretion levels of each marker before and after surgery were compared as estimates of the total 24-hour excretion, using a model based on glomerular filtration rate (calculated from cystatin C, age, height and weight), plasma- and urinary creatinine. The excretion of 8-oxodG increased in the first months after RYGB. For 8-oxoGuo, a gradual decrease was seen. Two years after RYGB and a mean weight loss of 35 kg, decreased hyperglycemia and insulin resistance, excretion levels of both markers were reduced by approximately 12% (P < 0.001). For both markers, mean excretion levels were about 30% lower in the female subgroup (P < 0.0001). Also, in this subgroup, excretion of 8-oxodG was significantly lower in patients with than without diabetes. We conclude, that oxidative damage to nucleic acids, reflected in the excretion of 8-oxodG and 8-oxoGuo, had decreased significantly two years after RYGB-indicating that reduced oxidative stress could be contributing to the many long-term benefits of RYGB-surgery in obesity and type 2 diabetes.

Oxidatively generated modifications to nucleic acids in vivo: Measurement in urine and plasma.

BACKGROUND: The oxidized guanine nucleosides, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), derived from DNA and RNA, respectively, were used to investigate the importance of oxidative stress to nucleic acids in vivo. High urinary excretion of 8-oxodG is associated with cancer development, whereas high urinary excretion of 8-oxoGuo is associated with mortality in type 2 diabetes. Like creatinine, these small water-soluble molecules are not reabsorbed in the kidney. Therefore, 8-oxo nucleoside/creatinine reciprocal concentration ratios are identical in plasma and urine. The total amount of 8-oxo guanine nucleosides excreted by the kidneys is the product of plasma concentration and glomerular filtration rate. METHODS: With relevant equations and an estimated glomerular filtration rate, the 24-h urinary excretion of 8-oxodG and 8-oxoGuo was calculated in 2679 subjects with type 2 diabetes, displaying good correlation with the measured urinary 8-oxo nucleoside/creatinine ratio: DNA oxidation r = 0.86 and RNA oxidation r = 0.84 (p < 0.05 for both). RESULTS: Survival analyses based on the quartiles of the 8-oxodG/creatinine ratio and the quartiles of calculated 24-h urinary excretion rate of the 2679 subjects gave similar hazard ratio estimates for death due to all causes. This finding was similar for the 8-oxoGuo hazard ratio estimates. CONCLUSIONS: This study shows that oxidatively generated modifications to DNA and RNA in vivo can be measured using 1) a spot urine sample, normalized to urinary creatinine, 2) 24-h urine, or 3) a single plasma sample based on concentrations of 8-oxo nucleoside and creatinine and glomerular filtration rate.

Phosphatidylcholine and its relation to apolipoproteins A-1 and B changes after Roux-en-Y gastric bypass: a cohort study.

BACKGROUND: Phosphatidylcholine (PC), the most abundant of the phospholipids, has several metabolic functions in organs such as the liver and the intestine, important structural- and signaling functions in biological membranes, and might have a role in the effects of Roux-en-Y gastric bypass (RYGB), an operation known to ameliorate metabolic diseases, including type 2 diabetes. We hypothesized that serum PC, as a reflection of phospholipid metabolism, changes after RYGB, and that changes are related to weight loss and possibly to changes in glucose metabolism (reflected in the HbA1c-level) as well as to changes in serum Apo A1, Apo B and Apo B/Apo A1 ratio. METHODS: In a cohort of 220 RYGB patients, we studied changes in serum PC after RYGB in relation to serum Apo A1 and Apo B, the main apolipoproteins in HDL- and LDL/VLDL-particles, respectively, up to 2 years following RYGB-surgery. RESULTS: Serum PC reached its lowest levels 3 months postoperatively to later rebound to preoperative levels 24 months after RYGB. No difference was seen between patients with or without type 2 diabetes. Serum Apo A1 showed a similar pattern whereas serum Apo B concentrations stayed low after the initial decrease after RYGB. As a result, the Apo B / Apo A1 ratio constantly decreased during follow-up. There was a strong positive correlation between PC and Apo A1, and between PC and Apo B, but none between Apo A1 and Apo B. After RYGB surgery, both PC and Apo A1, but not Apo B, correlated positively to weight loss. In relation to total cholesterol, the molar ratio between serum PC and plasma cholesterol increased steadily after RYGB. CONCLUSIONS: We conclude that changes in PC and apolipoproteins after RYGB are highly dynamic, reflecting a large plasticity and capability of accommodating lipid metabolism including PC-, cholesterol- and apolipoprotein metabolism imposed by RYGB surgery, independent of glucose tolerance. We suggest that after RYGB and major weight loss, PC and Apo A1 might have a special role in the altered metabolism of lipoproteins.

A Novel Mutation of the Calcium-Sensing Receptor Gene Causing Familial Hypocalciuric Hypercalcemia Complicates Medical Followup after Roux-en-Y Gastric Bypass: A Case Report and a Summary of Mutations Found in the Same Hospital Laboratory.

Heterozygous inactivating mutations in the calcium-sensing receptor (CaSR) gene are known to cause familial hypocalciuric hypercalcemia (FHH), usually a benign form of hypercalcemia without symptoms of a disrupted calcium homeostasis. FHH can be mistaken for the more common primary hyperparathyroidism (PHPT), for which surgical treatment may be needed. We describe a case of a 36-year-old woman with hypercalcemia and elevated PTH, initially suspected of having PHPT. Sequencing of the CaSR-gene revealed a mutation in nucleotide 437, changing the amino acid in position 146 from Glycine to Aspartate. The mutation was previously undescribed in the literature, but a very low calcium:creatinine clearance ratio supported the diagnosis FHH. A few years later, the patient's two daughters were tested and the association between mutation and hypercalcemia could be confirmed. The patient was gastric bypass-operated and therefore, due to malabsorption and increased risk of fracture, was in need of adequate calcium supplementation. The chronically elevated calcium levels challenged medical followup, as calcium sufficiency could not be monitored in a traditional manner. Eventually the patient developed elevated alkaline phosphatase, a further increased PTH and a decreased DXA T-score indicating calcium deficiency and bone resorption. As a supplement, all CaSR-mutations found at our hospital, 2005-2018.

Changes in Serum Sphingomyelin After Roux-en-Y Gastric Bypass Surgery Are Related to Diabetes Status.

Metabolic surgery is superior to lifestyle intervention in reducing weight and lowering glycemia and recently suggested as treatment for type 2 diabetes mellitus. Especially Roux-en-Y gastric bypass (RYGB) has been focus for much research, but still the mechanisms of action are only partly elucidated. We suggest that several mechanisms might be mediated by sphingolipids like sphingomyelin. We measured serum sphingomyelin before and up to 2 years after RYGB surgery in 220 patients, divided before surgery in one non-diabetic subgroup and two diabetic subgroups, one of which contained patients obtaining remission of type 2 diabetes after RYGB, while patients in the other still had diabetes after RYGB. Pre- and postoperative sphingomyelin levels were compared within and between groups. Sphingomyelin levels were lower in diabetic patients than in non-diabetic patients before surgery. Following RYGB, mean sphingomyelin concentration fell significantly in the non-diabetic subgroup and the preoperative difference between patients with and without diabetes disappeared. Changes in diabetic subgroups were not significant. Relative to bodyweight, an increase in sphingomyelin was seen in all subgroups, irrespective of diabetes status. We conclude that RYGB has a strong influence on sphingomyelin metabolism, as seen reflected in changed serum levels. Most significantly, no differences between the two diabetic subgroups were detected after surgery, which might suggest that patients in both groups still are in a "diabetic state" using the non-diabetic subgroup as a reference.

Comparison of two immunoassay systems for hCGß and PAPP-A in prenatal screening for trisomy 21, 18, and 13 in the first trimester.

OBJECTIVES: The biochemical serum markers free ß-human chorionic gonadotropin (hCGß) and pregnancy associated plasma protein A (PAPP-A), used in screening for trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) during the first trimester, can be measured on different laboratory instruments e.g. Kryptor (Brahms) and Cobas (Roche). We compared the performance of these two analytical instruments when used for first trimester combined testing. DESIGN AND METHODS: Serum samples from 944 singleton pregnant women attending for first trimester combined testing were routinely assayed for hCGß and PAPP-A on Kryptor, and re-analyzed on Cobas. In addition, serum samples from 70 pregnant women carrying a fetus affected by T21, T18 or T13, were re-assayed on Cobas. RESULTS: For the screening population, the hCGß and PAPP-A results in multiples of the median (MoM) from Kryptor and Cobas were significantly lower on Cobas when compared to Kryptor. The number of pregnant women with a risk above 1:300 for T21 was 48 for both Cobas and Kryptor, although a few patients only had a high risk with one of the methods. Overall, the screen positive rate was 5.1% for both instruments. In the trisomy groups the calculated risks for T21, T18, and T13 agreed well between Cobas and Kryptor. CONCLUSIONS: The screen positive rate for T21 (5.1%) did not differ between the two analytical platforms in our screening population, although PAPP-A measurements form Cobas were significantly lower than those from Kryptor. The calculated risks for the pregnancies affected by trisomies using hCGß MoM and PAPP-A MoM from Kryptor agreed well with those from Cobas.

Gastric bypass surgery reveals independency of obesity and diabetes melitus type 2.

BACKGROUND: Roux-en-Y gastric bypass surgery is widely applied to ameliorate morbid obesity, including diabetes in people with type 2 diabetes. The latter vanish a few days after surgery for many, but not in all patients before any weight reduction has occurred. The explanation for this change in metabolic status is poorly understood, but the observation may suggest that the fate obesity and diabetes is only partly linked after surgery. METHODS: The trajectories of weight reduction measured as reduced body mass index (BMI) in 741obese subjects with and without diabetes were evaluated. Evaluation was performed on three groups: 1) subjects that were non-diabetic before and after surgery; 2) subjects that were diabetics before surgery but non-diabetics after surgery; and 3) subjects that were diabetics before surgery and remained diabetics after surgery. The diabetic state was established at HbA1c above 48 mmol/mol. RESULTS: The trajectories differ significantly between groups and any sub-populations of groups, the latter identified by the distance between individual trajectories using a k-means procedure. The results suggest that different domains in the enormous genetic network governing basic metabolism are perturbed in obesity and diabetes, and in fact some of the patients are affected by two distinct diseases: obesity and diabetes mellitus type 2. CONCLUSION: Although RYGB "normalized" many glycaemic parameters in some of the diabetic subjects apparently converting to a non-diabetics state, other diabetic subjects stay diabetic in the context of the new gut anatomy after surgery. Thus, the obesity part of the glycaemic derangement may have been ameliorated, but some defects of the diabetic state had not.