The extent to which reduced insulin secretion during prolonged fasting reflects failure to compensate for whole body insulin resistance or a normal adjustment to potentially increased hepatic insulin ...action is unknown. We examined the effects of 36- versus 12-h fasting on insulin secretion and whole body versus hepatic insulin action in 13 healthy young males. Hepatic glucose production and insulin action were studied using stable isotopes, whereas whole body insulin action and insulin secretion were studied using an intravenous glucose tolerance test (IVGTT) and minimal modeling. Insulin, glucose, and lipid profiles were subsequently measured during a refeeding meal test. Prolonged fasting caused a minor reduction of first-phase insulin secretion in a context of improved hepatic insulin action, contrasting an increase in whole body insulin resistance. Accordingly, prolonged fasting was associated with opposite-directed effects on hepatic versus whole body insulin secretion disposition indices. Thirty-six-hour fasting compared with 12-h fasting was associated with increased serum insulin levels during the refeeding meal test. In conclusion, reduced insulin secretion during prolonged fasting may represent a healthy response to improved hepatic insulin action. Use of insulin secretion disposition indices without taking organ-specific insulin action into account may lead to erroneous conclusions.
Thirty-six-hour prolonged, compared with 12-h overnight fasting, is associated with slightly reduced first-phase insulin secretion in the face of opposite-directed changes in hepatic versus whole body insulin action in healthy young males. The paradoxical finding of increased hepatic versus decreased whole body insulin secretion disposition indices during prolonged fasting challenges the physiological understanding and validity of insulin secretion disposition indices not taking organ-specific insulin action into account.
Aims/hypothesis
The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation ...and body weight.
Methods
This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10 years), BMI of 25–40 kg/m
2
, no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5–6 times per week, combined with resistance exercise sessions 2–3 times per week, with a concomitant dietary intervention aiming for a BMI of 25 kg/m
2
. In this secondary analysis beta cell function was assessed from the 2 h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices.
Results
At baseline, individuals were 54.8 years (SD 8.9), 47% women, type 2 diabetes duration 5 years (IQR 3–8) and HbA
1c
was 49.3 mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change RGM 1.40 95% CI 1.01, 1.94) from baseline to 12 months’ follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 95% CI 0.58, 0.85). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index.
Conclusions/interpretation
Our findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight.
Trial registration
ClinicalTrials.gov
NCT02417012
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims/hypothesis
Low birthweight is a risk factor for type 2 diabetes. Most previous studies are based on cross-sectional prevalence data, not designed to study the timing of onset of type 2 diabetes ...in relation to birthweight. We aimed to examine associations of birthweight with age-specific incidence rate of type 2 diabetes in middle-aged to older adults over two decades.
Methods
Adults aged 30–60 years enrolled in the Danish Inter99 cohort in 1999–2001 (baseline examination), with information on birthweight from original birth records from 1939–1971 and without diabetes at baseline, were eligible. Birth records were linked with individual-level data on age at diabetes diagnosis and key covariates. Incidence rates of type 2 diabetes as a function of age, sex and birthweight were modelled using Poisson regression, adjusting for prematurity status at birth, parity, polygenic scores for birthweight and type 2 diabetes, maternal and paternal diabetes history, socioeconomic status and adult BMI.
Results
In 4590 participants there were 492 incident type 2 diabetes cases during a mean follow-up of 19 years. Type 2 diabetes incidence rate increased with age, was higher in male participants, and decreased with increasing birthweight (incidence rate ratio 95% CI per 1 kg increase in birthweight 0.60 0.48, 0.75). The inverse association of birthweight with type 2 diabetes incidence was statistically significant across all models and in sensitivity analysis.
Conclusions/interpretation
A lower birthweight was associated with increased risk of developing type 2 diabetes independent of adult BMI and genetic risk of type 2 diabetes and birthweight.
Graphical Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Low birth weight, indictive of a poor fetal environment, is a risk factor for type 2 diabetes (T2D) . Most previous studies were based on cross sectional prevalence data and not designed ...to study the timing of onset of T2D in relation to birth weight (BW) . Furthermore, earlier studies have not adjusted for common genetic variation influencing BW. We aimed to examine associations of BW with age-specific incidence of T2D using BW polygenetic risk scores (BWPRS) to adjust for genetic confounding.
Methods: Adults (30-60 years) enrolled in the Inter99 cohort from 1999-20with information on BW from original birth records, and without diabetes at baseline were eligible. Birth records were linked with individual-level data on T2D incidence from the Danish Diabetes Register and key covariates from the Inter99 study. Incidence rates of T2D as a function of age, sex and BW were modelled using Poisson regression and adjusted for adult BMI, socioeconomic status, maternal history of diabetes and BWPRS.
Results: Among 4584 participants there were 438 incident cases of T2D during a mean follow-up of 18 years. BW was inversely associated with T2D with a higher incidence in men. T2D incidence increased with age and the rate of increase was higher in persons with lower BW compared with higher BW in a dose-response manner.
Conclusion: A lower birth weight is associated with a greater increase in incidence rate of T2D in a non-genetic manner.
Disclosure
R.Wibaek: Stock/Shareholder; Novo Nordisk A/S. G.S.Andersen: Stock/Shareholder; Novo Nordisk A/S. A.Linneberg: None. N.Grarup: None. T.Hansen: None. C.Brøns: Stock/Shareholder; Novo Nordisk. D.Vistisen: Research Support; Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi, Stock/Shareholder; Novo Nordisk A/S. A.A.Vaag: Stock/Shareholder; AstraZeneca.
Funding
Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation (NNF17SA0031406)
Context:
Offspring of women with diabetes during pregnancy have an increased risk of glucose intolerance in adulthood, but the underlying mechanisms are unknown.
Objective:
We aimed to investigate ...the effects of intrauterine hyperglycemia on insulin secretion and action in adult offspring of mothers with diabetes.
Design, Setting, and Participants:
A cohort of 587 Caucasian offspring, without known diabetes, was followed up at the age of 18–27 years. We included 2 groups exposed to maternal diabetes in utero: offspring of women with gestational diabetes mellitus (n = 167) or type 1 diabetes (n = 153). Two reference groups were included: offspring of women with risk factors for gestational diabetes mellitus but normoglycemia during pregnancy (n = 139) and offspring from the background population (n = 128).
Main Outcome Measures:
Indices of insulin sensitivity and insulin release were calculated using insulin and glucose values from a standard oral glucose tolerance test (120 minutes, 75 g glucose). Pancreatic β-cell function taking the prevailing insulin sensitivity into account was estimated by disposition indices.
Results:
Both groups of offspring exposed during pregnancy to either maternal gestational diabetes or type 1 diabetes had reduced insulin sensitivity compared with offspring from the background population (both P < .005). We did not find any significant difference in absolute measures of insulin release. However, the disposition index was significantly reduced in both the diabetes-exposed groups (both P < .005).
Conclusion:
Reduced insulin sensitivity as well as impaired pancreatic β-cell function may contribute to the increased risk of glucose intolerance among adult offspring born to women with diabetes during pregnancy.
Aims/hypothesis
Women with a history of gestational diabetes mellitus (GDM) are advised to control their weight after pregnancy. We aimed to examine how adiposity and weight change influence the ...long-term risk of developing type 2 diabetes after GDM.
Methods
We included 1,695 women who had incident GDM between 1991 and 2001, as part of the Diabetes & Women’s Health study, and followed them until the return of the 2009 questionnaire. Body weight and incident type 2 diabetic cases were reported biennially. We defined baseline as the questionnaire period when women reported an incident GDM pregnancy. We estimated HRs and 95% CIs using Cox proportional hazards models.
Results
We documented 259 incident cases of type 2 diabetes during up to 18 years of follow-up. The adjusted HRs of type 2 diabetes associated with each 1 kg/m
2
increase in BMI were 1.16 (95% CI 1.12, 1.19) for baseline BMI and 1.16 (95% CI 1.13, 1.20) for most recent BMI. Moreover, each 5 kg increment of weight gain after GDM development was associated with a 27% higher risk of type 2 diabetes (adjusted HR 1.27; 95% CI 1.04, 1.54). Jointly, women who had a BMI ≥30.0 kg/m
2
at baseline and gained ≥5 kg after GDM had an adjusted HR of 43.19 (95% CI 13.60, 137.11), compared with women who had a BMI <25.0 kg/m
2
at baseline and gained <5 kg after GDM.
Conclusions/interpretation
Baseline BMI, most recent BMI and weight gain after GDM were significantly and positively associated with risk of progression from GDM to type 2 diabetes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The objective of the study was to assess whether gestational and early infancy exposure to low dose vitamin D from a mandatory margarine fortification programme in Denmark influenced the risk of ...developing type 1 diabetes (T1D) before age of 15 years. The study population included all individuals born in Denmark from 1983 to 1988 and consisted of 331,623 individuals. The 1st of June 1985, which was the date of issue of the new ministerial order cancelling mandatory fortification of margarine with vitamin D in Denmark, served as a reference point separating the studied population into various exposure groups. We further modelled birth cohort effects in children developing T1D as a linear spline, and compared the slopes between the birth cohorts with various prenatal and infancy exposures to vitamin D fortification. In total, 886 (0.26%) individuals developed T1D before the age of 15 years. The beta coefficients (95% CI), or slopes, for linear birth cohort effect in log Hazard Ratio (HR) per one month of birth in individuals born during the periods of gestational exposure, wash-out, and non-exposure were: 0.010 (-0.002/0.021), -0.010 (-0.035/0.018), and 0.008 (- 0.017/0.032), respectively. The beta coefficients (95% CI) for individuals born during the periods of first postnatal year exposure, wash-out, and non-exposure were: 0.007 (-0.016/0.030), 0.006 (-0.004/0.016), and 0.007 (-0.002/0.016), respectively. In conclusion, we found no evidence to support that exposure to low dose vitamin D from the Danish mandatory margarine fortification regimen during gestational and first postnatal year of life changed the risk of developing T1D before the age of 15 years.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
This study investigated how a wide spectrum of body mass index (BMI) values at ages 7 to 13 years are associated with type 2 diabetes throughout adulthood, including potential modifying ...effects of sex and birth weight.
Methods
From the Copenhagen School Health Records Register, 292,827 individuals, born between 1930 and 1989, were followed in national registers for type 2 diabetes (women, n = 7,472; men, n = 11,548). Heights and weights were measured at ages 7 to 13 years.
Results
Below‐average BMIs, with few exceptions, were not associated with type 2 diabetes. Above‐average BMIs had positive associations that were stronger in women than men, stronger in younger birth cohorts, and weaker with older age at diagnosis. Women born 1930‐1947, 1948‐1965, and 1966‐1983 with above‐average BMIs at 13 years (≥18.2 kg/m2) had hazard ratios (95% confidence intervals) ranging from 2.12 (1.91‐2.36) to 2.84 (2.31‐3.49) per z score when diagnosed at 30 to 47 years. Birth weight did not modify these associations.
Conclusions
Childhood BMIs below average are not associated with type 2 diabetes, whereas childhood BMIs above average are strongly associated with type 2 diabetes in adulthood, corresponding to excess risks even at levels below international definitions of overweight. The associations are stronger in women than men but are not affected by birth weight.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This secondary analysis aimed to investigate the effects of a 12 months intensive exercise-based lifestyle intervention on systemic markers of oxidative stress in persons with type 2 diabetes. We ...hypothesized lifestyle intervention to be superior to standard care in decreasing levels of oxidative stress.
The study was based on the single-centre, assessor-blinded, randomised, controlled U-turn trial (ClinicalTrial.gov NCT02417012). Persons with type 2 diabetes ˂ 10 years, ˂ 3 glucose lowering medications, no use of insulin, BMI 25–40 kg/m2 and no severe diabetic complications were included. Participants were randomised (2:1) to either intensive exercise-based lifestyle intervention and standard (n = 64) or standard care alone (n = 34). Standard care included individual education in diabetes management, advice on a healthy lifestyle and regulation of medication by a blinded endocrinologist. The lifestyle intervention included five to six aerobic exercise sessions per week, combined with resistance training two to three times per week and an adjunct dietary intervention aiming at reduction of ∼500 kcal/day (month 0–4). The diet was isocaloric from months 5–12. The primary outcome of this secondary analysis was change in oxidative stress measured by 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and secondarily in 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), as markers of RNA and DNA oxidation, respectively, from baseline to 12-months follow-up.
A total of 77 participants, 21 participants receiving standard care and 56 participants receiving the lifestyle intervention, were included in the analysis. Mean age at baseline was 54.1 years (SD 9.1), 41% were women and mean duration of type 2 diabetes was 5.0 years (SD 2.8). From baseline to follow-up the lifestyle group experienced a 7% decrease in 8-oxoGuo (−0.15 nmol/mmol creatinine 95% CI -0.27, −0.03), whereas standard care conversely was associated with a 8.5% increase in 8-oxoGuo (0.19 nmol/mmol creatinine 95% CI 0.00, 0.40). The between group difference in 8-oxoGuo was −0.35 nmol/mmol creatinine 95% CI -0.58, −0.12,, p = 0.003. No between group difference was observed in 8-oxodG.
A 12 months intensive exercise-based lifestyle intervention was associated with a decrease in RNA, but not DNA, oxidation in persons with type 2 diabetes.
Display omitted
•Oxidative stress might be the common driver of complications in type 2 diabetes.•Advanced glycation endproducts may contribute considerably to the redox imbalance.•Exercise intervention decreases RNA oxidation.•Exercise intervention increase decoy receptors for advanced glycation endproducts.•Decrease in oxidative stress associated with increase in the decoy receptors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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