Kajsa Sjöholm

Bariatric Surgery and Prevention of Type 2 Diabetes in Swedish Obese Subjects

BACKGROUND Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes. METHODS In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination. RESULTS During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P<0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P=0.002 for the interaction) but not by BMI (P=0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications. CONCLUSIONS Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2 diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT01479452.).

Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications.

IMPORTANCE Short-term studies show that bariatric surgery causes remission of diabetes. The long-term outcomes for remission and diabetes-related complications are not known. OBJECTIVES To determine the long-term diabetes remission rates and the cumulative incidence of microvascular and macrovascular diabetes complications after bariatric surgery. DESIGN, SETTING, AND PARTICIPANTS The Swedish Obese Subjects (SOS) is a prospective matched cohort study conducted at 25 surgical departments and 480 primary health care centers in Sweden. Of patients recruited between September 1, 1987, and January 31, 2001, 260 of 2037 control patients and 343 of 2010 surgery patients had type 2 diabetes at baseline. For the current analysis, diabetes status was determined at SOS health examinations until May 22, 2013. Information on diabetes complications was obtained from national health registers until December 31, 2012. Participation rates at the 2-, 10-, and 15-year examinations were 81%, 58%, and 41% in the control group and 90%, 76%, and 47% in the surgery group. For diabetes assessment, the median follow-up time was 10 years (interquartile range [IQR], 2-15) and 10 years (IQR, 10-15) in the control and surgery groups, respectively. For diabetes complications, the median follow-up time was 17.6 years (IQR, 14.2-19.8) and 18.1 years (IQR, 15.2-21.1) in the control and surgery groups, respectively. INTERVENTIONS Adjustable or nonadjustable banding (n = 61), vertical banded gastroplasty (n = 227), or gastric bypass (n = 55) procedures were performed in the surgery group, and usual obesity and diabetes care was provided to the control group. MAIN OUTCOMES AND MEASURES Diabetes remission, relapse, and diabetes complications. Remission was defined as blood glucose <110 mg/dL and no diabetes medication. RESULTS The diabetes remission rate 2 years after surgery was 16.4% (95% CI, 11.7%-22.2%; 34/207) for control patients and 72.3% (95% CI, 66.9%-77.2%; 219/303) for bariatric surgery patients (odds ratio [OR], 13.3; 95% CI, 8.5-20.7; P < .001). At 15 years, the diabetes remission rates decreased to 6.5% (4/62) for control patients and to 30.4% (35/115) for bariatric surgery patients (OR, 6.3; 95% CI, 2.1-18.9; P < .001). With long-term follow-up, the cumulative incidence of microvascular complications was 41.8 per 1000 person-years (95% CI, 35.3-49.5) for control patients and 20.6 per 1000 person-years (95% CI, 17.0-24.9) in the surgery group (hazard ratio [HR], 0.44; 95% CI, 0.34-0.56; P < .001). Macrovascular complications were observed in 44.2 per 1000 person-years (95% CI, 37.5-52.1) in control patients and 31.7 per 1000 person-years (95% CI, 27.0-37.2) for the surgical group (HR, 0.68; 95% CI, 0.54-0.85; P = .001). CONCLUSIONS AND RELEVANCE In this very long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01479452.

Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression

Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6±3.54 pm) and large cells (mean 100.1±3.94 pm). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune‐related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real‐time RT‐PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19‐fold and 22‐fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.—Jernås, M., Palming, J., Sjöholm, K., Jennische, E., Svensson, P.‐A., Gabrielsson, B. G., Levin, M., Sjögren, A., Rudemo, M., Lystig, T. C., Carlsson, B., Carlsson, L. M. S., Lönn, M. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. FASEB J. 20, E832–E839 (2006)

Cardiovascular Events After Bariatric Surgery in Obese Subjects With Type 2 Diabetes

OBJECTIVE Obese individuals with type 2 diabetes have an increased risk of cardiovascular disease. The effect of bariatric surgery on cardiovascular events in obese individuals with type 2 diabetes remains to be determined. The Swedish Obese Subjects (SOS) study is a prospective, controlled intervention study that examines the effects of bariatric surgery on hard end points. The aim of the present study was to examine the effect of bariatric surgery on cardiovascular events in the SOS study participants with type 2 diabetes. RESEARCH DESIGN AND METHODS All SOS study participants with type 2 diabetes at baseline were included in the analyses (n = 345 in the surgery group and n = 262 in the control group). Mean follow-up was 13.3 years (interquartile range 10.2–16.4) for all cardiovascular events. RESULTS Bariatric surgery was associated with a reduced myocardial infarction incidence (38 events among the 345 subjects in the surgery group vs. 43 events among the 262 subjects in the control group; log-rank P = 0.017; adjusted hazard ratio [HR] 0.56 [95% CI 0.34–0.93]; P = 0.025). No effect of bariatric surgery was observed on stroke incidence (34 events among the 345 subjects in the surgery group vs. 24 events among the 262 subjects in the control group; log-rank P = 0.852; adjusted HR 0.73 [0.41–1.30]; P = 0.29). The effect of surgery in reducing myocardial infarction incidence was stronger in individuals with higher serum total cholesterol and triglycerides at baseline (interaction P value = 0.02 for both traits). BMI (interaction P value = 0.12) was not related to the surgery outcome. CONCLUSIONS Bariatric surgery reduces the incidence of myocardial infarction in obese individuals with type 2 diabetes. Preoperative BMI should be integrated with metabolic parameters to maximize the benefits of bariatric surgery.

PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals

BACKGROUND Obesity is a risk factor for cancer, including hepatocellular carcinoma. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) genetic variant has been associated with hepatocellular carcinoma (HCC) in individuals with chronic alcohol abuse or hepatic viral infection. In the present study we examined the association between the PNPLA3 I148M genetic variant and hepatocellular carcinoma in obese individuals from the Swedish Obese Subjects cohort (n = 4047). METHODS We performed a matched, prospective, controlled, interventional trial, investigating the effect of bariatric surgery (surgery group) compared to conventional treatment (control group) for obesity. RESULTS A total of 9 events were observed in the 15-year median follow up (5 in the control group and 4 in the surgery group). A significantly higher incidence of hepatocellular carcinoma in PNPLA3 148M allele carriers was found in obese individuals in the control group (log-rank P-value = 0.001), but not in the surgery group (log-rank P-value = 0.783). Consistently, an increased risk (for each PNPLA3 148M allele, hazard ratio: 5.9; 95% confidence interval 1.5-23.8; P-value = 0.013) of developing hepatocellular carcinoma was observed only in the control group. CONCLUSION The current study is the first prospective report showing the association of the PNPLA3 I148M genetic variant and hepatocellular carcinoma in severely obese individuals.

Gene expression in human brown adipose tissue

Brown adipose tissue (BAT) has profound effects on body weight and metabolism in rodents. Recent reports show that human adults have significant amounts of BAT. Our aim was to study the gene expression profile of human BAT. Biopsies of adipose tissue with brown-red color and subcutaneous white adipose tissue (WAT) were obtained from 24 patients undergoing surgery in the thyroid region. Intrascapular BAT and epididymal WAT biopsies were obtained from 10 mice. Expression was analyzed by DNA microarray, real-time PCR and immunohistochemistry. Using the expression of the brown adipocyte-specific gene uncoupling protein 1 (UCP1) as a marker, approximately half of the human brown-red adipose tissue biopsies taken in the thyroid region contained BAT, and the presence of cells with brown adipocyte morphology was also verified by histology. Microarray analysis of 9 paired human BAT and WAT samples showed that 17 genes had at least a 4-fold higher expression in BAT compared to WAT and five of them (CKMT1, KCNK3, COBL, HMGCS2, TGM2) were verified using real-time PCR (P<0.05 for all). In addition, immunohistochemistry showed that the UCP1, KCNK3 and CKMT1 proteins are expressed in brown adipocytes. Except for UCP1 and KCNK3, the genes overexpressed in human BAT were not overexpressed in mouse BAT compared to mouse WAT. Our analysis identified genes that are differentially expressed in human BAT compared to WAT. The results also show that there are species-specific differences in BAT gene expression and this emphasizes the need for further molecular characterization of human BAT to clarify the mechanisms involved in regulated heat production in humans.

Alcohol consumption and alcohol problems after bariatric surgery in the swedish obese subjects study

Increased sensitivity to alcohol after gastric bypass has been described. The aim of this study was to investigate whether bariatric surgery is associated with alcohol problems.

ALK7 expression is specific for adipose tissue, reduced in obesity and correlates to factors implicated in metabolic disease

Human adipose tissue is a major site of expression of inhibin beta B (INHBB) which homodimerizes to form the novel adipokine activin B. Our aim was to determine if molecules needed for a local action of activin B are expressed in adipose tissue. Microarray analysis showed that adipose tissue expressed activin type I and II receptors and that the expression of activin receptor-like kinase 7 (ALK7) was adipose tissue specific. In obesity discordant siblings from the SOS Sib Pair study, adipose tissue ALK7 expression was higher in lean (n = 90) compared to obese (n = 90) subjects (p = 4 × 10−31). Adipose tissue ALK7 expression correlated with several measures of body fat, carbohydrate metabolism and lipids. In addition, ALK7 and INHBB expression correlated but only in lean subjects and in subjects with normal glucose tolerance. We conclude that activin B may have local effects in adipose tissue and thereby influence obesity and its comorbidities.

C/EBP{alpha} in adipose tissue regulates genes in lipid and glucose metabolism and a genetic variation in C/EBP{alpha} is associated with serum levels of triglycerides.

CONTEXT CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor involved in adipogenesis and hepatic glucose and lipid metabolism. OBJECTIVE The aim of the study was to test the hypothesis that adipose tissue C/EBPalpha regulates genes in lipid and glucose metabolism and to test for an association between a polymorphism in C/EBPalpha and metabolic parameters. DESIGN AND METHODS Adipose tissue C/EBPalpha mRNA expression was analyzed at four time points in obese subjects with (n = 12) and without (n = 12) the metabolic syndrome during caloric restriction (450 kcal/d for 16 wk) using DNA microarray and real-time PCR. Adenoviral overexpression of C/EBPalpha was used to identify genes regulated by C/EBPalpha in 3T3-L1 cells. Association between a genetic variation in C/EBPalpha (rs12691) and metabolic parameters was tested in the Swedish Obese Subjects (SOS) study (n = 528) and replicated in Finnish individuals from the Botnia type 2 diabetes study (n = 4,866). RESULTS During caloric restriction, adipose tissue C/EBPalpha mRNA levels were reduced in subjects with the metabolic syndrome (P = 0.024) and correlated to metabolic parameters. In 3T3-L1 cells, C/EBPalpha regulated the expression of adiponectin; hexokinase 2; lipoprotein lipase; diacylglycerol O-acyltransferase 1 and 2; ATP-binding cassette, sub-family D, member 2; acyl-coenzyme A synthetase long-chain family member 1; CD36; and hydroxysteroid 11-beta dehydrogenase 1. Furthermore, the expression of the human homologs, except adiponectin, correlated to C/EBPalpha mRNA levels in human adipose tissue. The AA genotype of rs12691 was associated with higher serum triglyceride levels in the SOS study (P = 0.022), and this association was replicated in the Botnia study (P = 0.041). CONCLUSIONS Adipose tissue C/EBPalpha regulates several genes in glucose and lipid metabolism, and a genetic variation in C/EBPalpha is associated with triglycerides in two independent populations.

The incidence of albuminuria after bariatric surgery and usual care in swedish obese subjects (SOS): a prospective controlled intervention trial

Background:Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria.Subjects:The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37–60 years and BMI⩾34 in men and BMI⩾38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30 mg per 24 h) over up to 15 years.Results:During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30–0.47; P<0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine.Conclusions:Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.