NEFA Dynamics in Adults With Severe Obesity and Insulin Resistance: No Coupling to the rs9939609 FTO Risk Allele.

Context: The FTO gene is highly expressed in adipose tissues; however, whether nonesterified fatty acids (NEFA) dynamics are impacted by FTO has not been rigorously tested for in a uniformly obese study population comprising both sexes. Objective: To test for associations of the rs9939609 FTO risk allele with NEFA suppression. Methods: We investigated 97 subjects with severe obesity but without diabetes, having genotype TT (n = 32), AT (n = 31), or AA (n = 34) in a cross-sectional observation study. NEFA suppression was assessed from a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer as well as from the response to a standardized meal. Insulin sensitivity was assessed by hepatic and total insulin sensitivity measurements in the clamp and by the Matsuda index during the meal. Variables of possible importance for NEFA dynamics were primarily assessed by linear regression. Results: No genotype associations with fasting or suppressed NEFA were found, whether in the clamp or meal situation (P > .7 for all comparisons). Independent of genotype, higher fasting concentrations of NEFA and larger NEFA suppression were found in female compared with male subjects. Fasting NEFA or degree of suppression were not associated with total fat mass or body mass index. The respiratory quotient was negatively associated with NEFA suppression. Conclusion: In a gender-mixed adult population of obese individuals, an FTO obesity-risk allele did not affect fasting NEFA nor suppression thereof. These negative results on NEFA dynamics appear strengthened by the documentation of gender influence and associations with parameters reflective of insulin resistance.

A 1-year pilot study of intralymphatic injections of GAD-alum in individuals with latent autoimmune diabetes in adults (LADA) with signs of high immunity: No safety concerns and resemblance to juvenile type 1 diabetes.

AIMS: To test, for the first time in latent autoimmune diabetes in adults (LADA), the effects of autoantigen-specific immunotherapy by intralymphatic administration of aluminium-formulated recombinant human glutamic acid decarboxylase 65 (GAD-alum); specifically, to test if this treatment is safe, to test whether it induces a strong immunological response akin to a similar protocol in type 1 diabetes and to look for associations with preserved beta-cell function. MATERIALS AND METHODS: Three GAD-alum injections, 4 µg each, were administered 1 month apart into an inguinal lymph node in 14 people with newly diagnosed LADA (age 30-62 years) presenting with high levels of antibodies against glutamic acid decarboxylase (GADA). Adverse effects, immunological variables and beta-cell function were monitored, with detailed measurements at 5 and 12 months from baseline. RESULTS: Clinical adverse effects were minor and transient and measured laboratory variables were unaffected. All participants completed the study. Treatment raised levels of GADA, elicited strong effects on reactivity of peripheral blood mononuclear cells to GAD and raised cytokine/chemokine levels. Beta-cell function appeared stable preferentially in the seven participants carrying human leukocyte antigen (HLA) haplotypes DR3DQ2, as assessed by C-peptide glucagon tests (P < 0.05 vs. seven non-carriers). CONCLUSION: Intralymphatic treatment with GAD-alum in LADA is without clinical or other safety concerns over a 12-month period. As in a similar protocol used in type 1 diabetes, treatment exerts a strong immunological impact and is compatible with protection of beta-cell function preferentially in HLA-DR3DQ2 LADA patients. These findings pave the way for a randomized controlled trial in this important subgroup of LADA patients.

Exploring Dietary Intake in Adults with Severe Obesity and Associations with the FTO rs9939609 Genotypes.

Background: Few have studied the associations between rs9939609 genotypes in the obesity candidate locus FTO and energy and nutrient intakes and meal frequencies in adults with severe obesity. We are unaware of studies that have assessed adherence to key dietary recommendations in this population, at least in Norway. Increased knowledge of genotype associations with dietary factors could improve personalized obesity therapy. Objectives: The present study aimed to explore how the rs9939609 genotypes associate with dietary variables and adherence to key dietary recommendations in a sample of adults with severe obesity. Methods: A cross-sectional observation study designed to have similar numbers of participants with genotypes TT, AT, and AA included 100 patients (70% women) with median (25th, 75th percentile) age 42 (32, 50) y and BMI 42.8 (39.5, 46.4) kg/m2. We assessed intakes of food groups, energy, and macro- and micronutrients from three 24-h dietary recalls and meal frequencies. Genotype associations were analyzed using regression analyses. Reported intakes were evaluated against national diet recommendations. Results: Using a significance level of 0.01, we found no genotype associations with energy intake, energy density, adherence to recommendations, or meal frequency but tendencies of associations with energy adjusted protein intake (AA > AT, P = 0.037; AT > TT, P = 0.064), food groups milk and cream (AT > TT, P = 0.029), and Mixed dishes (AA > TT, P = 0.039). Few participants complied with recommendations for intakes of whole grains (21%), fruits and vegetables (11%), and fish (37%); however, 67% followed the recommendation to limit added sugar. Less than 20% had recommended intakes of vitamin D and folate. Conclusions: In our patients with severe obesity, we found tendencies of associations between the FTO rs9939609 genotypes and diet but no significant associations at the 0.01 level and below. Few met key food-based diet recommendations, suggesting that the food habits in this population pose an increased risk of nutrient deficiencies. Curr Dev Nutr 2023;xx:xx.

Incidence of LADA and Type 2 Diabetes in Relation to Tobacco Use and Genetic Susceptibility to Type 2 Diabetes and Related Traits: Findings From a Swedish Case-Control Study and the Norwegian HUNT Study.

OBJECTIVE: Smoking and Swedish smokeless tobacco (snus) are associated with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). Our aim was to investigate whether genetic susceptibility to T2D, insulin resistance (IR), and insulin secretion (IS) aggravate these associations. RESEARCH DESIGN AND METHODS: We used data from two population-based Scandinavian studies with case subjects with LADA (n = 839) and T2D (n = 5,771), matched control subjects (n = 3,068), and 1,696,503 person-years at risk. Pooled, multivariate relative risks (RR) with 95% CI were estimated for smoking/genetic risk scores (T2D-GRS, IS-GRS, and IR-GRS), and ORs for snus or tobacco/GRS (case-control data). We estimated additive (proportion attributable to interaction [AP]) and multiplicative interaction between tobacco use and GRS. RESULTS: The RR of LADA was elevated in high IR-GRS heavy smokers (≥15 pack-years; RR 2.01 [CI 1.30, 3.10]) and tobacco users (≥15 box/pack-years; RR 2.59 [CI 1.54, 4.35]) compared with low IR-GRS individuals without heavy use, with evidence of additive (AP 0.67 [CI 0.46, 0.89]; AP 0.52 [CI 0.21, 0.83]) and multiplicative (P = 0.003; P = 0.034) interaction. In heavy users, there was additive interaction between T2D-GRS and smoking, snus, and total tobacco use. The excess risk conferred by tobacco use did not differ across GRS categories in T2D. CONCLUSIONS: Tobacco use may confer a higher risk of LADA in individuals with genetic susceptibility to T2D and insulin resistance, whereas genetic susceptibility does not seem to influence the increased T2D incidence associated with tobacco use.

Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults.

AIMS/HYPOTHESES: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. METHODS: Analyses were based on Swedish case-control data (collected 2010-2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984-2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case-control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. RESULTS: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. CONCLUSIONS/INTERPRETATION: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. DATA AVAILABILITY: Analysis codes are shared through GitHub ( https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA ).

Latent Autoimmune Diabetes in Adults: Background, Safety and Feasibility of an Ongoing Pilot Study With Intra-Lymphatic Injections of GAD-Alum and Oral Vitamin D.

Background: Latent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study). Material and Methods: Fourteen GADA-positive (>190 RU/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within < 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 µg GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol/L (40 ng/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed. Results: Preliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months). Conclusions: Intra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials.

Small RNAs are differentially expressed in autoimmune and non-autoimmune diabetes and controls.

Objective: Diabetes is a heterogeneous disease and a precise diagnosis of diabetes subgroups is necessary to initiate proper early treatment and clinical management of the disease. Circulating small RNAs (sRNAs) are potentially diagnostic biomarkers in diseases, including diabetes. Here we aimed to examine whether profiles of circulating sRNAs differed between patients with autoimmune and non-autoimmune diabetes and non-diabetic controls. Design: This cross-sectional case-control study included participants from the third survey of the HUNT study. Methods: We performed sRNA sequencing in serum from adult-onset type 1 diabetes (n = 51), type 2 diabetes (n = 50) and latent autoimmune diabetes in adult (LADA, n = 51), as well as non-diabetic HUNT3 participants as control group (n = 51). Differential expression analysis of the sRNAs was performed in R using limma-voom. Results: We identified differences in sRNA expression between autoimmune (type 1 diabetes and LADA) and non-autoimmune diabetes (type 2 diabetes) and between patients with diabetes and non-diabetic controls. Focusing on miRNA, we identified 10 differentially expressed mature miRNAs and 30 differentially expressed miRNA variants (isomiRs). We also identified significant changes within other sRNA classes, including a pronounced downregulation of a tRNA fragment in patients with diabetes compared to non-diabetic controls. We created cross-validated sRNA signatures based on the significant sRNAs that distinguished patients with diabetes from non-diabetic controls, and autoimmune from non-autoimmune diabetes, with high specificity and sensitivity. sRNA profiles did not distinguish between type 1 diabetes and LADA. Conclusions: Circulating sRNAs are differentially expressed between patients with diabetes and non-diabetic controls and between autoimmune and non-autoimmune diabetes.

Time-dependent effects on circulating cytokines in patients with LADA: A decrease in IL1-ra and IL-1 beta is associated with progressive disease.

BACKGROUND: Cytokines and chemokines participate in autoimmune processes at cellular targets which include insulin-producing beta cells. To which extent such participation is reflected in the circulation has not been conclusively resolved. AIM: We compared the time course of cytokines/chemokines in Latent Autoimmune Diabetes in Adults (LADA) patients heterogeneous for high or low autoimmune activity as determined by levels of antibodies against glutamic acid decarboxylase (GADA). METHODS: Serum samples to be measured were from a two-armed randomized controlled trial (RCT) in 68 LADA patients. The study encompassed 21 months with C-peptide as primary endpoint. We measured 27 immune mediators at baseline, at 9 and at 21 months (end of study). Results of measurements were analyzed by multiple linear regression. RESULTS: At baseline, a high body mass index (BMI) (>26 kg/m2) was associated with elevated levels of the interleukins (IL) IL-1 beta, IL-1ra, IL-2, IL-5, IL-6 and IL-13. Treatment during RCT (sitagliptin vs. insulin) did not affect the time course (21 months) of levels of cytokines/chemokines (by univariate analyses). However, levels of the cytokines IL-1ra and IL-1 beta decreased significantly (p < 0.04 or less) in patients with high vs. low GADA when adjusted for BMI, age, gender (male/female), treatment (insulin/sitagliptin) and study site (Norwegian/Swedish). CONCLUSIONS: In LADA, high levels of GADA, a proxy for high autoimmune activity and linked to a decline in C-peptide, was associated with a decrease of selected cytokines over time. This implies that the decline of IL-1ra and IL-1 beta in the circulation reflects autoimmune activity and beta cell demise in LADA.

Alterations in Biomarkers Related to Glycemia, Lipid Metabolism, and Inflammation up to 20 Years Before Diagnosis of Type 1 Diabetes in Adults: Findings From the AMORIS Cohort.

OBJECTIVE: Type 1 diabetes is described to have an acute onset, but autoantibodies can appear several years preceding diagnosis. This suggests a long preclinical phase, which may also include metabolic parameters. Here we assessed whether elevations in glycemic, lipid, and other metabolic biomarkers were associated with future type 1 diabetes risk in adults. RESEARCH DESIGN AND METHODS: We studied 591,239 individuals from the Swedish AMORIS cohort followed from 1985-1996 to 2012. Through linkage to national patient, diabetes, and prescription registers, we identified incident type 1 diabetes. Using Cox regression models, we estimated hazard ratios for biomarkers at baseline and incident type 1 diabetes. We additionally assessed trajectories of biomarkers during the 25 years before type 1 diabetes diagnosis in a nested case-control design. RESULTS: We identified 1,122 type 1 diabetes cases during follow-up (average age of patient at diagnosis: 53.3 years). The biomarkers glucose, fructosamine, triglycerides, the ratio of apolipoprotein (apo)B to apoA-I, uric acid, alkaline phosphatase, and BMI were positively associated with type 1 diabetes risk. Higher apoA-I was associated with lower type 1 diabetes incidence. Already 15 years before diagnosis, type 1 diabetes cases had higher mean glucose, fructosamine, triglycerides, and uric acid levels compared with control subjects. CONCLUSIONS: Alterations in biomarker levels related to glycemia, lipid metabolism, and inflammation are associated with clinically diagnosed type 1 diabetes risk, and these may be elevated many years preceding diagnosis.

Low C-peptide together with a high glutamic acid decarboxylase autoantibody level predicts progression to insulin dependence in latent autoimmune diabetes in adults: The HUNT study.

AIM: To search for risk factors that could predict progression in latent autoimmune diabetes in adults (LADA) and compare them with those for type 2 diabetes. MATERIALS AND METHODS: This study included 175 participants with LADA (autoantibody positive, without insulin treatment ≥1 year after diagnosis) and 2331 participants with type 2 diabetes (autoantibody negative, without insulin treatment ≥1 year after diagnosis) from the HUNT2 and HUNT3 surveys. We used Cox regression models and receiver operating characteristic curve analysis to identify predictive factors for progression to insulin dependency within 10 years. RESULTS: Low C-peptide levels (<0.3 nmol/L) predicted progression to insulin dependency within 10 years in both LADA (hazard ratio [HR] 6.40 [95% CI, 2.02-20.3]) and type 2 diabetes (HR 5.01 [95% CI, 3.53-7.10]). In addition, a high glutamic acid decarboxylase autoantibody (GADA) level (HR 5.37 [95% CI, 1.17-24.6]) predicted progression in LADA. Together, these two factors had a discriminatory power between non-progressors and progressors of area under the curve (AUC) of 0.86 (95% CI, 0.80-0.93). In type 2 diabetes, younger age at diagnosis (<50 years: HR 2.83 [95% CI, 1.56-5.15]; 50-69 years: HR 2.11 [95% CI, 1.19-3.74]), high HbA1c levels (≥53 mmol/mol, HR 2.44 [95% CI, 1.72-3.46]), central obesity (HR 1.65 [95% CI, 1.06-2.55]) and a body mass index of more than 30 kg/m2 (HR 1.73 [95% CI, 1.23-2.41]) were independent predictors. Together with C-peptide they reached an AUC of 0.79 (95% CI, 0.76-0.82). CONCLUSION: Factors predicting progression to insulin dependence are partly similar and partly dissimilar between LADA and type 2 diabetes. A constellation of low C-peptide and high GADA levels identifies LADA patients who are probable to progress to insulin dependence.

The fat mass and obesity-associated (FTO) gene allele rs9939609 and glucose tolerance, hepatic and total insulin sensitivity, in adults with obesity.

The objective of the study was to assess associations of the rs9939609 FTO allele to glucose tolerance, hepatic and total insulin sensitivity (IS) in individuals with obesity. From a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer, hepatic IS was assessed by rates of basal and suppressed glucose appearance (Ra), a measure of endogenous glucose production (EGP), and the hepatic insulin resistance index (HIR). Total IS was assessed by rates of glucose infusion (GIR), disappearance (Rd), and metabolic clearance (MCR). From a meal test we assessed IS by the Matsuda index and glucose tolerance by glucose and insulin measurements in the fasted state and postprandially for 2.5 h. The meal test was performed in 97 healthy individuals with BMI ≥35 in similar-sized risk-allele groups (n = 32 T/T, 31 A/T, and 34 A/A), and 79 of them performed the clamp. We analyzed outcomes separately for males and females, and adjusted glucose Ra, Rd, MCR, GIR, and HIR for fat mass. We did not find genotype effects on EGP. Among males, genotype A/A was associated with a significantly lower glucose Rd, MCR, and Matsuda index score relative to genotype T/T. Glucose tolerance was significantly lower in males with genotype A/T vs. T/T and A/A. For females, there were no genotype effects on hepatic or total IS, or on glucose tolerance. Independently of genotypes, females displayed a significantly better hepatic and total IS, and better glucose tolerance than males. We conclude that in subjects with similar obesity we did not register any FTO risk-allele effect on hepatic IS. A FTO risk-allele effect on total IS was registered in males only, findings which need to be reproduced in further studies. Results confirm marked differences in IS between the biological sexes and extend present knowledge by demonstrating a lower endogenous glucose production in females vs. males in uniformly obese individuals.

Physical Activity, Genetic Susceptibility, and the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes.

PURPOSE: Physical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609. METHODS: We combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness. RESULTS: High PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype. MAIN CONCLUSIONS: Our findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility.

Investigating optimal ß-cell-preserving treatment in latent autoimmune diabetes in adults: Results from a 21-month randomized trial.

AIMS: To compare outcomes of glucagon-stimulated C-peptide tests (GSCTs) in people with latent autoimmune diabetes in adults (LADA) after a 21-month intervention with either insulin or the dipeptidyl peptidase-4 inhibitor sitagliptin. RESEARCH DESIGN AND METHODS: We included 64 glutamic acid decarboxylase (GAD) antibody-positive individuals, who were diagnosed with diabetes <3 years before the study, aged 30 to 70 years, and without clinical need for insulin treatment. We stratified participants by age and body mass index (BMI) and evaluated ß-cell function by GSCT after a 48-hour temporary withdrawal of study medication. RESULTS: Age at randomization (mean 53 years), BMI (mean 27 kg/m2 ) and metabolic markers were similar between treatment arms. Glycated haemoglobin concentrations during intervention did not differ between arms. Fasting C-peptide concentrations after the intervention were similar, as were stimulated C-peptide levels (0.82 ± 0.63 nmol/L after insulin, 0.82 ± 0.46 nmol/L after sitagliptin; nonsignificant). Autoimmunity in the study population (estimated from GAD antibody titres and positivity/no positivity for zinc transporter 8 and islet antigen 2 antibodies) affected the evolution of the GSCT results significantly, which deteriorated in participants with high but not in those with low autoimmunity. Adjustment using analysis of covariance for the degree of autoimmunity did not alter the findings of no difference between treatment arms. CONCLUSIONS: ß-cell function after intervention was similar in patients with insulin- and sitagliptin-treated LADA, regardless of the strength of autoimmunity. Further, participants with low levels of GAD antibodies did not experience progressive deterioration of ß-cell function over a 21-month period. Taken together, these findings could be useful for clinicians' choices of treatment in people with LADA.

Interaction Between Overweight and Genotypes of HLA, TCF7L2, and FTO in Relation to the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes.

OBJECTIVE: We investigated potential interactions between body mass index (BMI) and genotypes of human leukocyte antigen (HLA), TCF7L2-rs7903146, and FTO-rs9939609 in relation to the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes. METHODS: We pooled data from two population-based studies: (i) a Swedish study with incident cases of LADA [positive for glutamic acid decarboxylase autoantibodies (GADA); n = 394) and type 2 diabetes (negative for GADA; n = 1290) and matched controls without diabetes (n = 2656) and (ii) a prospective Norwegian study that included incident cases of LADA (n = 131) and type 2 diabetes (n = 1901) and 886,120 person-years of follow-up. Analyses were adjusted for age, sex, physical activity, and smoking. Interaction between overweight (BMI ≥ 25 kg/m2) and HLA/TCF7L2/FTO high-risk genotypes was assessed by attributable proportion due to interaction (AP). RESULTS: The combination of overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared with normal-weight individuals with low/intermediate genetic risk. There was a significant interaction between overweight and HLA (AP, 0.29; 95% CI, 0.10 to 0.47), TCF7L2 (AP, 0.31; 95% CI, 0.09 to 0.52), and FTO (AP, 0.38; 95% CI, 0.15 to 0.61). The highest risk of LADA was seen in overweight individuals homozygous for the DR4 genotype [RR, 26.76 (95% CI, 15.42 to 46.43); AP, 0.58 (95% CI, 0.32 to 0.83) (Swedish data)]. Overweight and TCF7L2 also significantly interacted in relation to type 2 diabetes (AP, 0.26; 95% CI, 0.19 to 0.33), but no interaction was observed with high-risk genotypes of HLA or FTO. CONCLUSIONS: Overweight interacts with HLA high-risk genotypes but also with genes associated with type 2 diabetes in the promotion of LADA.

Impact of a FTO gene risk variant on variables of energy metabolism in adults with obesity class 2 and 3.

PURPOSE: The metabolic consequences of carrying a FTO obesity-promoting risk allele have not been fully elucidated and may be confounded by obesity per se. Against this background, we investigated the impact of FTO allele (SNP rs9939609) on fasting and postprandial energy expenditure and fasting substrate expenditure in a study population of uniformly and similarly obese individuals. PROCEDURES: We studied a similar number of participants with BMI classes 2-3 (median BMI 42.8 kg/m2) who were either homozygote for the non-risk allele TT (n = 33, numbers increased by enrichment), heterozygote (AT) (n = 32), or homozygote for the risk allele AA (n = 35). MAJOR FINDINGS: Basal metabolic rate and postprandial energy expenditure did not differ between FTO-groups. However, fasting respiratory quotient (RQ) was increased in those carrying ≥1 risk allele (p = 0.008), whereas postprandial RQ was not. CONCLUSION: In this study population, the FTO-risk allele associates with fasting reduced fat and increased carbohydrate oxidation.

LADA: A Type of Diabetes in its Own Right?

Latent Autoimmune Diabetes in the Adult, LADA has been investigated less than "classical" type 1 and type 2 diabetes and the criteria for and the relevance of a LADA diagnosis have been challenged. Despite the absence of a genetic background that is exclusive for LADA this form of diabetes displays phenotypic characteristics that distinguish it from other forms of diabetes. LADA is heterogeneous in terms of the impact of autoimmunity and lifestyle factors, something that poses problems to therapy and follow-up, perhaps particularly in those with marginal positivity. Yet, there appears to be clear clinical utility in classifying individuals as LADA.