Patient-reported outcomes, weight loss, and remission of type 2 diabetes 3 years after gastric bypass and sleeve gastrectomy (Oseberg); a single-centre, randomised controlled trial.

BACKGROUND: Little is known about the comparative effects of various bariatric procedures on patient-reported outcomes. We aimed to compare 3-year effects of gastric bypass and sleeve gastrectomy on patient-reported outcome measures in patients with obesity and type 2 diabetes. METHODS: The Oseberg trial was a single-centre, parallel-group, randomised trial at Vestfold Hospital Trust, a public tertiary obesity centre in Tønsberg, Norway. Eligible patients were aged 18 years or older with previously verified BMI 35·0 kg/m2 or greater. Diabetes was diagnosed if glycated haemoglobin was at least 6·5% (48 mmol/mol) or by their use of anti-diabetic medications with glycated haemoglobin at least 6·1% (43 mmol/mol). Eligible patients were randomly assigned (1:1) to gastric bypass or sleeve gastrectomy. All patients received identical preoperative and postoperative treatment. Randomisation was done with a computerised random number generator and a block size of ten. Study personnel, patients, and the primary outcome assessor were blinded to allocations for 1 year. The prespecified secondary outcomes reported here were 3-year changes in several clinically important patient-reported outcomes, weight loss, and diabetes remission. Analyses were done in the intention to treat population. This trial is ongoing, closed to recruitment and is registered with ClinicalTrials.gov, NCT01778738. FINDINGS: Between Oct 15, 2012 and Sept 1, 2017, 319 consecutive patients with type 2 diabetes scheduled for bariatric surgery were assessed for eligibility. 101 patients were not eligible (29 did not have type 2 diabetes according to inclusion criteria and 72 other exclusion criteria) and 93 declined to participate. 109 patients were enrolled and randomly assigned to sleeve gastrectomy (n=55) or gastric bypass (n=54). 72 (66%) of 109 patients were female and 37 (34%) were male. 104 (95%) of patients were White. 16 patients were lost to follow up and 93 (85%) patients completed the 3-year follow-up. Three additional patients were contacted by phone for registration of comorbidities Compared with sleeve gastrectomy, gastric bypass was associated with a greater improvement in weight-related quality of life (between group difference 9·4, 95% CI 3·3 to 15·5), less reflux symptoms (0·54, 0·17 to -0·90), greater total bodyweight loss (8% difference, 25% vs 17%), and a higher probability of diabetes remission (67% vs 33%, risk ratio 2·00; 95% CI 1·27 to 3·14). Five patients reported postprandial hypoglycaemia in the third year after gastric bypass versus none after sleeve-gastrectomy (p=0·059). Symptoms of abdominal pain, indigestion, diarrhoea, dumping syndrome, depression, binge eating, and appetitive drive did not differ between groups. INTERPRETATION: At 3 years, gastric bypass was superior to sleeve gastrectomy in patients with type 2 diabetes and obesity regarding weight related quality of life, reflux symptoms, weight loss, and remission of diabetes, while symptoms of abdominal pain, indigestion, diarrhoea, dumping, depression and binge eating did not differ between groups. This new patient-reported knowledge can be used in the shared decision-making process to inform patients about similarities and differences between expected outcomes after the two surgical procedures. FUNDING: Morbid Obesity Centre, Vestfold Hospital Trust. TRANSLATION: For the Norwegian translation of the abstract see Supplementary Materials section.

Changes in dietary intake, food tolerance, hedonic hunger, binge eating problems, and gastrointestinal symptoms after sleeve gastrectomy compared with after gastric bypass; 1-year results from the Oseberg study-a randomized controlled trial.

BACKGROUND: The randomized Oseberg study compared the effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), on the 1-y remission of type 2 diabetes and ß-cell function (primary outcomes). However, little is known about the comparable effects of SG and RYGB on the changes in dietary intakes, eating behavior, and gastrointestinal discomfort. OBJECTIVES: To compare 1-y changes in intakes of macro- and micronutrients, food groups, food tolerance, hedonic hunger, binge eating, and gastrointestinal symptoms after SG and RYGB. METHODS: Among others, prespecified secondary outcomes were dietary intake, food tolerance, hedonic hunger, binge eating, and gastrointestinal symptoms assessed with a food frequency questionnaire, food tolerance questionnaire, Power of food scale, Binge eating scale, and Gastrointestinal symptom rating scale, respectively. RESULTS: A total of 109 patients (66% females), with mean (SD) age 47.7 (9.6) y and body mass index of 42.3 (5.3) kg/m2, were allocated to SG (n = 55) or RYGB (n = 54). The SG group had, compared with the RYGB group, greater 1-y reductions in the intakes of: protein, mean (95% CI) between-group difference, -13 (-24.9, -1.2) g; fiber, -4.9 (-8.2, -1.6) g; magnesium, -77 (-147, -6) mg; potassium, -640 (-1237, -44) mg; and fruits and berries, -65 (-109, -20) g. Further, the intake of yogurt and fermented milk products increased by >2-folds after RYGB but remained unchanged after SG. In addition, hedonic hunger and binge eating problems declined similarly after both surgeries, whereas most gastrointestinal symptoms and food tolerance remained stable at 1 y. CONCLUSIONS: The 1-y changes in dietary intakes of fiber and protein after both surgical procedures, but particularly after SG, were unfavorable with regard to current dietary guidelines. For clinical practice, our findings suggest that health care providers and patients should focus on sufficient intakes of protein, fiber, and vitamin and mineral supplementation after both SG and RYGB. This trial was registered at [clinicaltrials.gov] as [NCT01778738].

Distinct T cell subsets in adipose tissue are associated with obesity.

Adipose tissue inflammation is a driving factor for the development of obesity-associated metabolic disturbances, and a role of adipose tissue T cells in initiating the pro-inflammatory signaling is emerging. However, data on human adipose tissue T cells in obesity are limited, reflected by the lack of phenotypic markers to define tissue-resident T cell subsets. In this study, we performed a deep characterization of T cells in blood and adipose tissue depots using multicolor flow cytometry and RNA sequencing. We identified distinct subsets of T cells associated with obesity expressing the activation markers, CD26 and CCR5, and obesity-specific genes that are potentially engaged in activating pro-inflammatory pathway, including ceramide signaling, autophagy, and IL-6 signaling. These findings increase our knowledge on the heterogeneity of T cells in adipose tissue and on subsets that may play a role in obesity-related pathogenesis.

Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity.

Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (-0.39 [95% CI: -0.82, -0.09]) and 40% (-0.09 fmol/µg protein [95% CI: -0.18, -0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific.

Correlations between 4ß-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range.

PURPOSE: Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4ß-hydroxycholesterol (4ßOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4ßOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. METHODS: The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4ßOHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. RESULTS: 4ßOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (ρ = 0.15, p = 0.53). 4ßOHC concentrations correlated weakly with midazolam absolute bioavailability (ρ = - 0.23, p = 0.027) and apparent oral clearance (ρ = 0.28, p = 0.008), but not with systemic clearance (ρ = - 0.03, p = 0.81). CONCLUSION: These findings suggest that 4ßOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4ßOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs. TRIAL REGISTRATION: Clinical. TRIALS: gov identifier: NCT02386917.

Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity.

AIM: Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5-hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. METHODS: This trial included patients with severe obesity preparing for RYGB (n = 40) or diet-induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations. RESULTS: Mean ± SD weight loss from baseline was similar in the RYGB-group (13 ± 2.4%) and the diet group (10.5 ± 3.9%) at week 9, but differed at year 2 (RYGB -30 ± 6.9%, diet -3.1 ± 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3-9), but not in the diet-group (between-group difference -0.30 [-0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. CONCLUSION: Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed.

Effect of Aerobic Exercise Intensity on Energy Expenditure and Weight Loss in Severe Obesity-A Randomized Controlled Trial.

OBJECTIVE: This study aimed to compare the effects of two aerobic exercise programs of different intensities on energy expenditure. METHODS: This was a single-center randomized controlled trial of patients with severe obesity allocated to a 24-week moderate-intensity continuous training (MICT) program or a combined MICT with high-intensity interval training (HIIT/MICT) program. The primary outcome was energy expenditure during exercise (EEDE). Secondary outcomes included resting metabolic rate, cardiorespiratory fitness, and body composition. RESULTS: A total of 82 (56% females) patients were screened, and 71 (55% females) patients were allocated to HIIT/MICT (n = 37) or MICT (n = 34). Per-protocol analysis showed that EEDE increased by 10% (95% CI: 3%-17%) in the HIIT/MICT group (n = 16) and 7.5% (95% CI: 4%-10%) in the MICT group (n = 24), with no differences between groups. In the 8- to 16- week per-protocol analysis, the HIIT/MICT group had a significantly larger increase in EEDE compared with the MICT group. Resting metabolic rate remained unchanged in both groups. HIIT/MICT and MICT were associated with significant weight loss of 5 kg and 2 kg, respectively. CONCLUSIONS: Patients completing a 24-week combined HIIT/MICT program did not achieve a higher EEDE compared with those who completed a 24-week MICT program. The HIIT/MICT group experienced, on average, a 3-kg-larger weight loss than the MICT group.

Associations between cardiorespiratory fitness and weight loss in patients with severe obesity undergoing an intensive lifestyle intervention program: retrospective cohort study.

BACKGROUND: To assess the association between cardiorespiratory fitness (CRF) and weight changes in treatment seeking patients with severe obesity who underwent a 1-year intensive lifestyle intervention (ILI) program. METHODS: Retrospective cohort study conducted at a tertiary care outpatient rehabilitation center from November 1, 2013 through January 1, 2017. CRF was measured as maximal oxygen consumption during a maximal oxygen uptake (VO2max) test on a treadmill or bicycle at baseline and after 3 months. RESULTS: A total of 180 patients had a baseline mean (SD) BMI 41.1 (4.8) kg/m2 and CRF of 79.4 (14.9) mL·kg-0.75·min- 1. Patients with a baseline CRF above median achieved a greater 3-month and 1-year weight loss compared with patients with CRF below median; mean (95% CI) 2.5 kg (1.3, 3.8) and 4.0 kg (0.8, 7.2), respectively. In addition, patients with 3-month changes of CRF above median had 4.0 kg (0.9, 7.1) greater weight loss at 1-year follow-up than those below median. CONCLUSIONS: Among patients with severe obesity who underwent a 1-year ILI program, higher baseline CRF was associated with significantly larger weight loss after 3 months and 1 year. In addition, those with higher initial 3-month CRF changes had greater weight loss at 1 year. TRIAL REGISTRATION: Retrospectively registered in Regional Committees for Medical and Health Research Ethics (REC) south east September 22, 2016 (2016/1414) and clinicaltials.gov August 13, 2018 (identifier: NCT03593798 ).

Severe obesity is a limitation for the use of body mass index standard deviation scores in children and adolescents.

AIM: We analysed the distribution of the body mass index standard deviation scores (BMI-SDS) in children and adolescents seeking treatment for severe obesity, according to the International Obesity Task Force (IOTF), World Health Organization (WHO) and the national Norwegian Bergen Growth Study (BGS) BMI reference charts and the percentage above the International Obesity Task Force 25 cut-off (IOTF-25). METHODS: This was a cross-sectional study of 396 children aged four to 17 years, who attended a tertiary care obesity centre in Norway from 2009 to 2015. Their BMI was converted to SDS using the three growth references and expressed as the percentage above IOTF-25. The percentage of body fat was assessed by bioelectrical impedance analysis. RESULTS: Regardless of which BMI reference chart was used, the BMI-SDS was significantly different between the age groups, with a wider range of higher values up to 10 years of age and a more narrow range of lower values thereafter. The distributions of the percentage above IOTF-25 and percentage of body fat were more consistent across age groups. CONCLUSIONS: Our findings suggest that it may be more appropriate to use the percentage above a particular BMI cut-off, such as the percentage above IOTF-25, than the IOTF, WHO and BGS BMI-SDS in paediatric patients with severe obesity.

Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls.

BACKGROUND: Rare sequence variants in at least five genes are known to cause monogenic obesity. In this study we aimed to investigate the prevalence of, and characterize, rare coding and splice site variants in LEP, LEPR, MC4R, PCSK1 and POMC in patients with morbid obesity and normal weight controls. METHOD: Targeted next-generation sequencing of all exons in LEP, LEPR, MC4R, PCSK1 and POMC was performed in 485 patients with morbid obesity and 327 normal weight population-based controls from Norway. RESULTS: In total 151 variants were detected. Twenty-eight (18.5%) of these were rare, coding or splice variants and five (3.3%) were novel. All individuals, except one control, were heterozygous for the 28 variants, and the distribution of the rare variants showed a significantly higher carrier frequency among cases than controls (9.9% vs. 4.9%, p=0.011). Four variants in MC4R were classified as pathogenic or likely pathogenic. CONCLUSION: Four cases (0.8%) of monogenic obesity were detected, all due to MC4R variants previously linked to monogenic obesity. Significant differences in carrier frequencies among patients with morbid obesity and normal weight controls suggest an association between heterozygous rare coding variants in these five genes and morbid obesity. However, additional studies in larger cohorts and functional testing of the novel variants identified are required to confirm the findings.

The association between severity of King's Obesity Staging Criteria scores and treatment choice in patients with morbid obesity: a retrospective cohort study.

BACKGROUND: The King's Obesity Staging Criteria (KOSC) comprises of a four-graded set of health related domains. We aimed to examine whether, according to KOSC, patients undergoing bariatric surgery differed from those opting for conservative treatment. METHODS: We graded 2142 consecutive patients with morbid obesity attending our centre from 2005-10 into the following KOSC domains: airway/apnoea, body mass index (BMI), cardiovascular risk (CV-risk), diabetes mellitus, economic complications, functional limitations, gonadal dysfunction, and perceived health status/body image. Both patients and physicians agreed upon treatment choice through a shared decision making process. RESULTS: A total of 1329 (62%) patients opted for lifestyle intervention and 813 (37%) for bariatric surgery as their first treatment choice. The patients treated with bariatric surgery were younger (42 vs. 44 years, p < 0.001), had a higher BMI (45.4 vs. 43.8 kg/m2, p < 0.001) and had a lower ten year estimated CV-risk (9.4 vs. 10.7%, p = 0.004) than the lifestyle intervention group. Compared with having BMI < 40 kg/m2, BMI ≥ 40 kg/m2 was associated with 85% increased odds of bariatric surgery (OR 1.85 [95% CI 1.48, 2.30]). Conversely, patients with ≥20% ten year CV-risk, had lower odds of bariatric surgery than patients with <20% CV-risk (0.68 [0.53, 0.87]). CONCLUSION: BMI was the strongest KOSC-domain associated with subsequent bariatric surgery after a shared decision making process. Prospective studies are required to assess whether the use of KOSC can help guide patients and clinicians to identify the most appropriate choice of treatment for morbid obesity.

The Chromosome 9p21 CVD- and T2D-Associated Regions in a Norwegian Population (The HUNT2 Survey).

Background. Two adjacent regions upstream CDKN2B on chromosome 9p21 have been associated with type 2 diabetes (T2D) and progression of cardiovascular disease (CVD). The precise location and number of risk variants have not been completely delineated and a possible synergistic relationship between the adjacent regions is not fully addressed. By a population based cross-sectional case-control design, we genotyped 18 SNPs upstream of CDKN2B tagging 138 kb in and around two LD-blocks associated with CVD and T2D and investigated associations with T2D, angina pectoris (AP), myocardial infarction (MI), coronary heart disease (CHD; AP or AMI), and stroke using 5,564 subjects from HUNT2. Results. Single point and haplotype analysis showed evidence for only one common T2D risk haplotype (rs10757282∣rs10811661: OR = 1.19, P = 2.0 × 10(-3)) in the region. We confirmed the strong association between SNPs in the 60 kb CVD region with AP, MI, and CHD (P < 0.01). Conditioning on the lead SNPs in the region, we observed two suggestive independent single SNP association signals for MI, rs2065501 (P = 0.03) and rs3217986 (P = 0.04). Conclusions. We confirmed the association of known variants within the 9p21 interval with T2D and CHD. Our results further suggest that additional CHD susceptibility variants exist in this region.

A controlled clinical trial of the effect of gastric bypass surgery and intensive lifestyle intervention on nocturnal hypertension and the circadian blood pressure rhythm in patients with morbid obesity.

BACKGROUND: Nocturnal hypertension, increased night-to-day systolic blood pressure (BP) ratio and nondipper status (night-to-day systolic BP ratio > 0.9) are associated with an increased risk of cardiovascular disease. Our aim was to compare the 1-year effect of Roux-en-Y gastric bypass (RYGB) versus a program of intensive lifestyle intervention (ILI) only on nocturnal hypertension and circadian BP rhythm. METHODS: The study participants were part of a 1-year, controlled clinical trial comparing the effect of RYGB or ILI on obesity-related comorbidities. Ninety participants (49 in the RYGB group) successfully completed 24-hour ambulatory BP monitoring at baseline and follow-up and were eligible subsequently for analysis. RESULTS: A total of 71 subjects (79%) had nocturnal hypertension at baseline. The number of subjects with nocturnal hypertension decreased from 42 to 14 in the RYGB group (P ≤ .001) and from 29 to 27 (P = .791) in the ILI group. Subjects in the RYGB group had a lesser adjusted odds ratio (OR) of nocturnal hypertension at follow-up (OR 0.15; 95% confidence interval, 0.05-0.42; P ≤ .001); however, after further adjustment for weight loss, there was no additional beneficial effect of RYGB (P = .674). No differences between groups regarding improvement in the night-to-day systolic BP ratio were found after adjustment for 24-hour systolic pressure (P = .107). Both interventions showed a decrease in the proportion of subjects classified as nondippers, namely, 44% (P ≤ .001) and 28% (P = .002) in the RYGB and ILI groups, respectively. CONCLUSION: Only RYGB was associated with a decrease in the prevalence of nocturnal hypertension. Both interventions showed an improvement in dipper status, although RYGB was more effective.

FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC, and MPP studies.

OBJECTIVE: FTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span. RESEARCH DESIGN AND METHODS: Through regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malmö Diet and Cancer (MDC) and Malmö Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians. RESULTS: The meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 × 10(-8)) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 × 10(-8)). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/m(2) per risk allele; P = 2.0 × 10(-26)), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (ΔBMI = 0.0 [-0.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults. CONCLUSIONS: We have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter.

Evaluation of four novel genetic variants affecting hemoglobin A1c levels in a population-based type 2 diabetes cohort (the HUNT2 study).

BACKGROUND: Chronic hyperglycemia confers increased risk for long-term diabetes-associated complications and repeated hemoglobin A1c (HbA1c) measures are a widely used marker for glycemic control in diabetes treatment and follow-up. A recent genome-wide association study revealed four genetic loci, which were associated with HbA1c levels in adults with type 1 diabetes. We aimed to evaluate the effect of these loci on glycemic control in type 2 diabetes. METHODS: We genotyped 1,486 subjects with type 2 diabetes from a Norwegian population-based cohort (HUNT2) for single-nucleotide polymorphisms (SNPs) located near the BNC2, SORCS1, GSC and WDR72 loci. Through regression models, we examined their effects on HbA1c and non-fasting glucose levels individually and in a combined genetic score model. RESULTS: No significant associations with HbA1c or glucose levels were found for the SORCS1, BNC2, GSC or WDR72 variants (all P-values > 0.05). Although the observed effects were non-significant and of much smaller magnitude than previously reported in type 1 diabetes, the SORCS1 risk variant showed a direction consistent with increased HbA1c and glucose levels, with an observed effect of 0.11% (P = 0.13) and 0.13 mmol/l (P = 0.43) increase per risk allele for HbA1c and glucose, respectively. In contrast, the WDR72 risk variant showed a borderline association with reduced HbA1c levels (ß = -0.21, P = 0.06), and direction consistent with decreased glucose levels (ß = -0.29, P = 0.29). The allele count model gave no evidence for a relationship between increasing number of risk alleles and increasing HbA1c levels (ß = 0.04, P = 0.38). CONCLUSIONS: The four recently reported SNPs affecting glycemic control in type 1 diabetes had no apparent effect on HbA1c in type 2 diabetes individually or by using a combined genetic score model. However, for the SORCS1 SNP, our findings do not rule out a possible relationship with HbA1c levels. Hence, further studies in other populations are needed to elucidate whether these novel sequence variants, especially rs1358030 near the SORCS1 locus, affect glycemic control in type 2 diabetes.

[Progress in diabetes genetics]. / Fremskritt innen diabetesgenetikk.

BACKGROUND: Diabetes is classified as Type 1 diabetes, Type 2 diabetes, gestational diabetes and other types. Our goal was to provide an overview of new genetic knowledge of monogenic and type 2 diabetes. MATERIAL AND METHOD: The article is based on literature identified through a non-systematic search in PubMed and own experience concerning research in diabetes genetics and treatment of patients with monogenic diabetes. RESULTS: 18 genes have been found for which one single mutation may cause diabetes. The most common causes for such monogenic diabetes are mutations in the genes KCNJ11, ABCC8 and INS when the condition is diagnosed at the age 0 - 6 months, and in the genes HNF1A, GCK, HNF4A and HNF1B when the diagnosis is made later than six months of age. Genetic testing is appropriate in assessment of monogenic diabetes, because antidiabetic tablets rather that insulin injections can be used to treat patients with mutations in certain genes; i.e. KCNJ11, ABCC8, HNF1A and HNF4A. Genome-wide association studies have recently identified about 20 genetic variants that increase the risk of Type 2 diabetes, but which have a low predictive value for development of disease. How these genetic variants can cause Type 2 diabetes has not been assessed and clinical relevance remains to be shown. INTERPRETATION: So far, genetic findings only affect diagnosis and treatment of monogenic diabetes.

Polygenic risk variants for type 2 diabetes susceptibility modify age at diagnosis in monogenic HNF1A diabetes.

OBJECTIVE: Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis. RESEARCH DESIGN AND METHODS: Fifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient. RESULTS: We confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1 years if present, P = 1.6 x 10(-10)) and HNF1A mutation position (-5.2 years if at least two isoforms affected, P = 1.8 x 10(-2)). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 x 10(-4)) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 x 10(-38)). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 x 10(-3)). CONCLUSIONS: We show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants.