| 1. |
- Bizzotto, Roberto, et al.
(författare)
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Processes Underlying Glycemic Deterioration in Type 2 Diabetes : An IMI DIRECT Study
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44:2, s. 511-518
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
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| 2. |
- Brand, Judith S., et al.
(författare)
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Age at Menopause, Reproductive Life Span, and Type 2 Diabetes Risk
- 2013
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 36:4, s. 1012-1019
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Age at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and reproductive life span (menopausal age minus menarcheal age) with diabetes risk.RESEARCH DESIGN AND METHODS-Data were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied.RESULTS-Mean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95% CI 1.04-1.69), 1.09 (0.90-1.31), 0.97 (0.86-1.10), and 0.85 (0.70-1.03) for women with menopause at ages <40, 40-44, 45-49, and >= 55 years, respectively, relative to those with menopause at age 50-54 years. The HR per SD younger age at menopause was 1.08 (1.02-1.14). Similarly, a shorter reproductive life span was associated with a higher diabetes risk (HR per SD lower reproductive life span 1.06 [ 1.01-1.12]). No effect modification by BMI, waist circumference, or smoking was observed (P interaction all > 0.05).CONCLUSIONS-Early menopause is associated with a greater risk of type 2 diabetes. Diabetes Care 36:1012-1019, 2013
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| 3. |
- Bray, George A., et al.
(författare)
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Long-Term Safety, Tolerability, and Weight Loss Associated With Metformin in the Diabetes Prevention Program Outcomes Study
- 2012
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 35:4, s. 731-737
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Metformin produced weight loss and delayed or prevented diabetes in the Diabetes Prevention Program (DPP). We examined its long-term safety and tolerability along with weight loss, and change in waist circumference during the DPP and its long-term follow-up. RESEARCH DESIGN AND METHODS-The randomized double-blind clinical trial of metformin or placebo followed by a 7-8-year open-label extension and analysis of adverse events, tolerability, and the effect of adherence on change in weight and waist circumference. RESULTS-No significant safety issues were identified. Gastrointestinal symptoms were more common in metformin than placebo participants and declined over time. During the DPP, average hemoglobin and hematocrit levels were slightly lower in the metformin group than in the placebo group. Decreases in hemoglobin and hematocrit in the metformin group occurred during the first year following randomization, with no further changes observed over time. During the DPP, metformin participants had reduced body weight and waist circumference compared with placebo (weight by 2.06 +/- 5.65% vs. 0.02 +/- 5.52%, P < 0.001, and waist circumference by 2.13 +/- 7.06 cm vs. 0.79 +/- 6.54 cm, P < 0.001 in metformin vs. placebo, respectively). The magnitude of weight loss during the 2-year double-blind period was directly related to adherence (P < 0.001). Throughout the unblinded follow-up, weight loss remained significantly greater in the metformin group than in the placebo group (2.0 vs. 0.2%, P < 0.001), and this was related to the degree of continuing metformin adherence (P < 0.001). CONCLUSIONS-Metformin used for diabetes prevention is safe and well tolerated. Weight loss is related to adherence to metformin and is durable for at least 10 years of treatment.
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| 4. |
- Chung, Wendy K., et al.
(författare)
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Precision Medicine in Diabetes : A Consensus Report From the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
- 2020
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 43:7, s. 1617-1635
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Forskningsöversikt (refereegranskat)abstract
- The convergence of advances in medical science, human biology, data science, and technology has enabled the generation of new insights into the phenotype known as "diabetes." Increased knowledge of this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence, and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions. This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field, and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment), and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e., monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients. This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realize its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes.
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| 5. |
- Dawed, Adem Y., et al.
(författare)
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Variation in the plasma membrane monoamine transporter (PMAT) (encoded by SLC29A4) and organic cation transporter 1 (OCT1) (encoded by SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes : An IMI direct study
- 2019
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 42:6, s. 1027-1033
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Gastrointestinal adverse effects occur in 20–30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5–10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. RESEARCH DESIGN AND METHODS The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. RESULTS Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). CONCLUSIONS These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.
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| 6. |
- Delahanty, Linda M, et al.
(författare)
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Effects of Weight Loss, Weight Cycling, and Weight Loss Maintenance on Diabetes Incidence and Change in Cardiometabolic Traits in the Diabetes Prevention Program.
- 2014
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 37:10, s. 2738-2745
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Tidskriftsartikel (refereegranskat)abstract
- This study examined specific measures of weight loss in relation to incident diabetes and improvement in cardiometabolic risk factors.RESEARCH DESIGN AND METHODS: This prospective, observational study analyzed nine weight measures, characterizing baseline weight, short- versus long-term weight loss, short- versus long-term weight regain, and weight cycling, within the Diabetes Prevention Program (DPP) lifestyle intervention arm (n = 1,000) for predictors of incident diabetes and improvement in cardiometabolic risk factors over 2 years.RESULTS: Although weight loss in the first 6 months was protective of diabetes (hazard ratio [HR] 0.94 per kg, 95% CI 0.90, 0.98; P < 0.01) and cardiometabolic risk factors (P < 0.01), weight loss from 0 to 2 years was the strongest predictor of reduced diabetes incidence (HR 0.90 per kg, 95% CI 0.87, 0.93; P < 0.01) and cardiometabolic risk factor improvement (e.g., fasting glucose: β = -0.57 mg/dL per kg, 95% CI -0.66, -0.48; P < 0.01). Weight cycling (defined as number of 5-lb [2.25-kg] weight cycles) ranged 0-6 times per participant and was positively associated with incident diabetes (HR 1.33, 95% CI 1.12, 1.58; P < 0.01), fasting glucose (β = 0.91 mg/dL per cycle; P = 0.02), HOMA-IR (β = 0.25 units per cycle; P = 0.04), and systolic blood pressure (β = 0.94 mmHg per cycle; P = 0.01). After adjustment for baseline weight, the effect of weight cycling remained statistically significant for diabetes risk (HR 1.22, 95% CI 1.02, 1.47; P = 0.03) but not for cardiometabolic traits.CONCLUSIONS: Two-year weight loss was the strongest predictor of reduced diabetes risk and improvements in cardiometabolic traits.
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| 7. |
- Delahanty, Linda M., et al.
(författare)
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Genetic Predictors of Weight Loss and Weight Regain After Intensive Lifestyle Modification, Metformin Treatment, or Standard Care in the Diabetes Prevention Program
- 2012
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 35:2, s. 363-366
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-We tested genetic associations with weight loss and weight regain in the Diabetes Prevention Program, a randomized controlled trial of weight-loss inducing interventions (lifestyle and metformin) versus placebo. RESEARCH DESIGN AND METHODS-Sixteen obesity-predisposing single nucleotide polymorphisms (SNPs) were tested for association with short-term (baseline to 6 months) and long-term (baseline to 2 years) weight loss and weight regain (6 months to study end). RESULTS-Irrespective of treatment, the Ala12 allele at PPARG associated with short- and long-term weight loss (-0.63 and -0.93 kg/allele, P <= 0.005, respectively). Gene-treatment interactions were observed for short-term (LYPLAL1 rs2605100, P-lifestyle*SNP = 0.032; GNPDA2 rs10938397, P-lifestyle*SNP = 0.016; MTCH2 rs10838738, P-lifestyle*SNP = 0.022) and long-term (NEGR1 rs2815752, P-metformin*SNP = 0.028; FTO rs9939609, P-lifestyle*SNP = 0.044) weight loss. Three of 16 SNPs were associated with weight regain (NEGR1 rs2815752, BDNF rs6265, PPARG rs1801282), irrespective of treatment. TMEM18 rs6548238 and KTCD15 rs29941 showed treatment-specific effects (P-lifestyle*SNP < 0.05). CONCLUSIONS-Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention.
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| 8. |
- Ekelund, Ulf, et al.
(författare)
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Increase in physical activity energy expenditure is associated with reduced metabolic risk independent of change in fatness and fitness
- 2007
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Ingår i: Diabetes Care. - Alexandria, Va. : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 30:8, s. 2101-2106
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We sought to examine whether change in physical activity energy expenditure (PAEE) is associated with change in metabolic risk factors and whether this association is independent of change in fat mass and aerobic fitness. Research design and methods: In a population-based sample of 176 men and 217 women followed prospectively for 5.6 years, we measured PAEE by individually calibrated heart rate monitoring, aerobic fitness, total body fat (fat mass), and metabolic risk factors (blood pressure, fasting triglycerides, HDL cholesterol, insulin, and 2-h glucose) at baseline and follow-up. Results: A 100 J · kg fat-free mass (FFM)−1 · min−1 increase in PAEE from baseline to follow-up reduced triglycerides by 3.5% (95% CI 0.03–5.7) in men and 3.2% (0.02–5.4) in women, fasting insulin by 5.3% (1.0–7.5) in men and women, and 2-h glucose by 3.2% (0.3–5.3) in men and 3.1% (0.3–5.2) in women, after adjustment for sex, age, smoking status, aerobic fitness, baseline phenotype, and change in fat mass. In general, the magnitudes of association for change in fat mass with metabolic risk factors were two to three times stronger than for PAEE. Conclusions: Increasing levels of physical activity may protect against metabolic disease even in the absence of improved aerobic fitness and reduced body fatness. Therefore, the combination of increasing levels of physical activity and avoidance of gain in fat mass is likely to be the most successful approach for preventing cardiovascular and metabolic disease.
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| 9. |
- Elks, Cathy E., et al.
(författare)
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Age at Menarche and Type 2 Diabetes Risk The EPIC-InterAct study
- 2013
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 36:11, s. 3526-3534
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVEYounger age at menarche, a marker of pubertal timing in girls, is associated with higher risk of later type 2 diabetes. We aimed to confirm this association and to examine whether it is explained by adiposity.RESEARCH DESIGN AND METHODSThe prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from 26 research centers across eight European countries. We tested the association between age at menarche and incident type 2 diabetes using Prentice-weighted Cox regression in 15,168 women (n = 5,995 cases). Models were adjusted in a sequential manner for potential confounding and mediating factors, including adult BMI.RESULTSMean menarcheal age ranged from 12.6 to 13.6 years across InterAct countries. Each year later menarche was associated with 0.32 kg/m(2) lower adult BMI. Women in the earliest menarche quintile (8-11 years, n = 2,418) had 70% higher incidence of type 2 diabetes compared with those in the middle quintile (13 years, n = 3,634), adjusting for age at recruitment, research center, and a range of lifestyle and reproductive factors (hazard ratio [HR], 1.70; 95% CI, 1.49-1.94; P < 0.001). Adjustment for BMI partially attenuated this association (HR, 1.42; 95% CI, 1.18-1.71; P < 0.001). Later menarche beyond the median age was not protective against type 2 diabetes.CONCLUSIONSWomen with history of early menarche have higher risk of type 2 diabetes in adulthood. Less than half of this association appears to be mediated by higher adult BMI, suggesting that early pubertal development also may directly increase type 2 diabetes risk.
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| 10. |
- Estampador, Angela, et al.
(författare)
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Infant body composition and adipokine concentrations in relation to maternal gestational weight gain
- 2014
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 37:5, s. 1432-1438
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE. To investigate associations of maternal gestational weight gain and body composition and their impact on offspring body composition and adipocytokine, glucose, and insulin concentrations at age 4 months.RESEARCH DESIGN AND METHODS. This was a prospective study including 31 mother-infant pairs (N = 62). Maternal body composition was assessed using doubly labeled water. Infant body composition was assessed at 4 months using air displacement plethysmography, and venous blood was assayed for glucose, insulin, adiponectin, interleukin-6 (IL-6), and leptin concentrations.RESULTS. Rate of gestational weight gain in midpregnancy was significantly associated with infant fat mass (r = 0.41, P = 0.03); rate of gestational weight in late pregnancy was significantly associated with infant fat-free mass (r = 0.37, P = 0.04). Infant birth weight was also strongly correlated with infant fat-free mass at 4 months (r = 0.63, P = 0.0002). Maternal BMI and maternal fat mass were strongly inversely associated with infant IL-6 concentrations (r = -0.60, P = 0.002 and r = -0.52, P = 0.01, respectively). Infant fat-free mass was inversely related to infant adiponectin concentrations (r = -0.48, P = 0.008) and positively correlated with infant blood glucose adjusted for insulin concentrations (r = 0.42, P = 0.04). No significant associations for leptin were observed.CONCLUSIONS. Timing of maternal weight gain differentially impacts body composition of the 4-month-old infant, which in turn appears to affect the infant's glucose and adipokine concentrations.
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