The Use and Effectiveness of Selected Alternative Markers for Insulin Sensitivity and Secretion Compared with Gold Standard Markers in Dietary Intervention Studies in Individuals without Diabetes: Results of a Systematic Review

Background: The gold‐standard techniques for measuring insulin sensitivity and secretion are well established. However, they may be perceived as invasive and expensive for use in dietary intervention studies. Thus, surrogate markers have been proposed as alternative markers for insulin sensitivity and secretion. This systematic review aimed to identify markers of insulin sensitivity and secretion in response to dietary intervention and assess their suitability as surrogates for the gold‐standard method-ology. Methods: Three databases, PubMed, Scopus, and Cochrane were searched, intervention studies and randomised controlled trials reporting data on dietary intake, a gold standard of analysis of insulin sensitivity (either euglycaemic‐hyperinsulinaemic clamp or intravenous glucose tolerance test and secretion (acute insulin response to glucose), as well as surrogate markers for insulin sensitivity (either fasting insulin, area under the curve oral glucose tolerance tests and HOMA‐IR) and insulin secretion (disposi-tion index), were selected. Results: We identified thirty‐five studies that were eligible for inclusion. We found insufficient evidence to predict insulin sensitivity and secretion with surrogate markers when compared to gold standards in nutritional intervention studies. Conclusions: Future research is needed to investigate if surrogate measures of insulin sensitivity and secretion can be repeatable and reproduci-ble in the same way as gold standards

Impact of isocaloric exchanges of carbohydrate for fat on postprandial glucose, insulin, triglycerides, and free fatty acid responses-a systematic review and meta-analysis

Varying the macronutrient composition of meals alters acute postprandial responses, but the effect sizes for specific macronutrient exchanges have not been quantified by systematic reviews. Therefore the aim is to quantify the effect size of exchanging fat for carbohydrates in mixed meals on postprandial glucose (PPG), insulin (PPI), triglycerides (PPTG), and free fatty acids (PPFFA) responses by performing a systematic review and meta-analysis of randomized controlled trials. A systematic literature search was undertaken on randomized controlled trials comparing isocaloric high fat with high carbohydrate meals, with comparable protein contents and at least one postprandial glycemic- and one lipid outcome. The outcome data were extracted and expressed as mean postprandial levels over 2 h. Ten studies involving 14 comparisons met the eligibility criteria. Data were available for meta-analysis from 347 participants, consuming mixed meals containing 250-1003 kcal, and total fat contents of 33.3-75.6 percentage of energy (en%) (intervention) versus 0-31.7 en% (control). Each 10en% increase in fat, replacing carbohydrates produced a mean reduction in PPG of 0.32 mmol/l (95% CI -0.64 to -0.00, p = 0.047), a reduction in PPI of 18.2 pmol/l (95% CI -24.86 to -11.54), an increase in PPTG of 0.06 mmol/l (95% CI 0.02 to 0.09, p = 0.004), with no statistically significant effect on PPFFA. Modest exchange of carbohydrates for fats in mixed meals significantly reduces PPG and PPI and increases PPTG responses. The quantitative relationships derived here may be applied to predict responses, and to design and optimize meal macronutrient compositions in dietary intervention studies

Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (H-1-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our H-1-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity. Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use H-1-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.Peer reviewe

Long-term Exposure to Traffic-related Air Pollution and Type 2 Diabetes Prevalence in a Cross-sectional Screening-study in the Netherlands

<p>Abstract</p> <p>Background</p> <p>Air pollution may promote type 2 diabetes by increasing adipose inflammation and insulin resistance. This study examined the relation between long-term exposure to traffic-related air pollution and type 2 diabetes prevalence among 50- to 75-year-old subjects living in Westfriesland, the Netherlands.</p> <p>Methods</p> <p>Participants were recruited in a cross-sectional diabetes screening-study conducted between 1998 and 2000. Exposure to traffic-related air pollution was characterized at the participants' home-address. Indicators of exposure were land use regression modeled nitrogen dioxide (NO₂) concentration, distance to the nearest main road, traffic flow at the nearest main road and traffic in a 250 m circular buffer. Crude and age-, gender- and neighborhood income adjusted associations were examined by logistic regression.</p> <p>Results</p> <p>8,018 participants were included, of whom 619 (8%) subjects had type 2 diabetes. Smoothed plots of exposure versus type 2 diabetes supported some association with traffic in a 250 m buffer (the highest three quartiles compared to the lowest also showed increased prevalence, though non-significant and not increasing with increasing quartile), but not with the other exposure metrics. Modeled NO₂-concentration, distance to the nearest main road and traffic flow at the nearest main road were not associated with diabetes. Exposure-response relations seemed somewhat more pronounced for women than for men (non-significant).</p> <p>Conclusions</p> <p>We did not find consistent associations between type 2 diabetes prevalence and exposure to traffic-related air pollution, though there were some indications for a relation with traffic in a 250 m buffer.</p

Relative contributions of preprandial and postprandial glucose exposures, glycemic variability, and non-glycemic factors to HbA1c in individuals with and without diabetes

Background/objective: There is substantial interest in dietary approaches to reducing postprandial glucose (PPG) responses, but the quantitative contribution of PPG to longer-term glycemic control (reflected in glycated hemoglobin, HbA1c) in the general population is not known. This study quantified the associations of preprandial glucose exposure, PPG exposure, and glycemic variability with HbA1c and estimated the explained variance in HbA1c in individuals with and without type 2 diabetes (T2D). Subjects/methods: Participants in the A1c-Derived Average Glucose (ADAG) study without T2D (n = 77) or with non-insulin-treated T2D and HbA1c<6.5% (T2DHbA1c < 6.5%, n = 63) or HbA1c ≥ 6.5% (T2DHbA1c ≥ 6.5%, n = 34) were included in this analysis. Indices of preprandial glucose, PPG, and glycemic variability were calculated from continuous glucose monitoring during four periods over 12 weeks prior to HbA1c measurement. In linear regression models, we estimated the associations of the glycemic exposures with HbA1c and calculated the proportion of variance in HbA1c explained by glycemic and non-glycemic factors (age, sex, body mass index, and ethnicity). Results: The factors in the analysis explained 35% of the variance in HbA1c in non-diabetic individuals, 49% in T2DHbA1c < 6.5%, and 78% in T2DHbA1c ≥ 6.5%. In non-diabetic individuals PPG exposure was associated with HbA1c in confounder-adjusted analyses (P < 0.05). In the T2DHbA1c < 6.5% group, all glycemic measures were associated with HbA1c (P < 0.05); preprandial glucose and PPG accounted for 14 and 18%, respectively, of the explained variation. In T2DHbA1c ≥ 6.5%, these glycemic exposures accounted for more than 50% of the variation in HbA1c and with equal relative contributions. Conclusions: Among the glycemic exposures, PPG exposure was most strongly predictive of HbA1c in non-diabetic individuals, suggesting that interventions targeting lowering of the PPG response may be beneficial for long-term glycemic maintenance. In T2D, preprandial glucose and PPG exposure contributed equally to HbA1c

Plant-derived polyunsaturated fatty acids and markers of glucose metabolism and insulin resistance : A meta-analysis of randomized controlled feeding trials

The objective of this meta-analysis was to investigate the effects of plant-derived polyunsaturated fatty acids (PUFAs) on glucose metabolism and insulin resistance. Scopus and PubMed databases were searched until January 2018. Eligible studies were randomized controlled feeding trials that investigated the effects of a diet high in plant-derived PUFA as compared with saturated fatty acids (SFA) or carbohydrates and measured markers of glucose metabolism and insulin resistance as outcomes. Data from 13 relevant studies (19 comparisons of plant-derived PUFA with control) were retrieved. Plant-derived PUFA did not significantly affect fasting glucose (-0.01 mmol/L (95 % CI - 0.06 to 0.03 mmol/L)), but lowered fasting insulin by 2.6 pmol/L (-4.9 to -0.2 pmol/L) and homeostatic model assessment-insulin resistance (HOMA-IR) by 0.12 units (-0.23 to - 0.01 units). In dose-response analyses, a 5% increase in energy (En%) from PUFA significantly reduced insulin by 5.8 pmol/L (95% CI -10.2 to -1.3 pmol/L), but not glucose (change -0.07, 95% CI -0.17 to 0.04 mmol/L) and HOMA-IR (change - 0.24, 95% CI -0.56 to 0.07 units). In subgroup analyses, studies with higher PUFA dose (upper tertiles) reduced insulin (-6.7, -10.5 to -2.9 pmol/L) and HOMA-IR (-0.28, -0.45 to -0.12 units), but not glucose (-0.09, 95% CI -0.18 to 0.01 mmol/L), as compared with an isocaloric control. Subgroup analyses showed no differences in effects between SFA and carbohydrates as replacement nutrients (p interaction ≥0.05). Evidence from randomized controlled trials indicated that plant-derived PUFA as an isocaloric replacement for SFA or carbohydrates probably reduces fasting insulin and HOMA-IR in populations without diabetes.</p

The Rate of Glucose Appearance Is Related to Postprandial Glucose and Insulin Responses in Adults:A Systematic Review and Meta-analysis of Stable Isotope Studies

Background: It is often assumed that lower postprandial glucose (PPG) and insulin (PPI) responses are induced by slower glucose influx from the gut (e.g., by delayed carbohydrate digestion). However, changes in the rate of appearance of glucose in the peripheral circulation [rate of appearance of exogenous glucose (RaE)] may be accompanied by changes in endogenous glucose production (EGP) and the rate of disappearance of total glucose into tissues (RdT). The quantitative relationships between reductions in RaE and PPG/PPI levels are unclear. Objectives: The objective was to perform a meta-analysis to quantify the effect of changes in RaE on changes in PPG and PPI levels (primary) and EGP and RdT (secondary). Methods: We systematically searched the Scopus, Medline, and Cochrane library databases through 10 January 2019 for randomized, controlled, carbohydrate-rich interventions that aimed to reduce RaE in humans, measured using dual or triple stable isotope methods. The 2-h net incremental AUCs for all variables were extracted or calculated. Relationships between RaE and outcomes were quantified by weighted regression analyses. Results: There were 12 articles, including 17 comparisons, that satisfied the inclusion criteria. The subjects were mainly men (60%), with age and BMI ranges of 18-40 y and 20.0-27.5 kg/m(2), respectively. A 10% reduction in RaE was associated with reductions in PPG levels, PPI levels, and the RdT of 7% (95% CI: 2%, 12%; P = 0.010), 8% (95% CI: 2%, 13%; P = 0.012), and 11% (95% CI: 4%, 17%; P = 0.005), respectively, but was not significantly associated with a change in EGP (13%; 95% CI: -7%, 33%; P = 0.176). All fluxes together explained 70% and 26% of the variances in PPG and PPI levels, respectively. Conclusions: In adults, reducing glucose RaE by diet is associated with significant reductions in PPG levels, PPI levels, and the rate of glucose disposal

A prospective study on glucagon responses to oral glucose and mixed meal and 7-year change in fasting glucose

Introduction: The role of insufficient glucagon suppression after an oral load in the development of type 2 diabetes mellitus is unclear. The aim of this study was to examine the association between glucagon responses at baseline and fasting glucose levels 7 years later. Methods: Data of the Hoorn Meal Study were used, an observational cohort study among 121 persons without diabetes with a mean age of 61.1 ± 6.7 years and 50% being female. The glucagon response to an oral glucose tolerance test and mixed meal test was expressed as early and late incremental area under the curve. The association with change in fasting glucose levels at follow-up was assessed by linear regression analysis. Results: The early glucagon response following the mixed meal test was associated with an increase in fasting glucose levels of 0.18 mmol/L (95%-CI: 0.04-0.31, P = 0.01), per unit increase in the incremental area under the curve of glucagon, adjusted for confounders. No significant associations were observed for the late response after the mixed meal test or oral glucose tolerance test. Conclusions: Within a population without diabetes, relative lack of glucagon suppression early after a meal was associated with increased glucose levels over time, suggesting a role of insufficient glucagon suppression in the deterioration of glycaemic control

Sweet Snacks Are Positively and Fruits and Vegetables Are Negatively Associated with Visceral or Liver Fat Content in Middle-Aged Men and Women

Visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC) are major risk factors for cardiometabolic diseases. Objective: We aimed to investigate the association of dietary intake of the main food groups with VAT and HTGC in middle-aged men and women. Methods: We used data from the Netherlands Epidemiology of Obesity study, a population-based study including 6671 participants aged 45-65 y at baseline. In this cross-sectional analysis, VAT and HTGC were assessed by magnetic resonance imaging and spectroscopy, respectively, as the primary outcomes. Habitual intake of main food groups (dairy, meat, fish, fruits and vegetables, sweet snacks, and fats and oils) was estimated through the use of a food-frequency questionnaire. We examined associations of intake of different food groups with VAT and HTGC by linear regression analysis stratified by sex and adjusted for age, smoking, education, ethnicity, physical activity, basal metabolic rate, energy-restricted diet, menopausal state, and total energy intake. Results: In women, a 100-g/d higher intake of dairy was associated with 2.0 cm2 less VAT (95% CI: -3.4, -0.7 cm2) and a 0.95-fold lower HTGC (95% CI: 0.90-, 0.99-fold). Moreover, a 100-g/d higher intake of fruit and vegetables was associated with 1.6 cm2 less VAT (95% CI: -2.9, -0.2 cm2) in women. Fruit and vegetables were negatively associated (0.95; 95% CI: 0.91, 1.00) with HTGC, and sweet snacks were positively associated (1.29; 95% CI: 1.03, 1.63). Patterns were weaker but similar in men. Fish intake was not associated with VAT or HTGC and plant-based fat and oil intake were only associated with VAT after adjustment for total body fat. Conclusions: Despite some variation in the strength of the associations between men and women, dietary intake of sweet snacks was positively associated with HTGC, and fruit and vegetable intake were negatively associated with visceral and liver fat content. Prospective studies are needed to confirm these results. The Netherlands Epidemiology of Obesity study is registered at clinicaltrials.gov with identifier NCT03410316. J Nutr 2019;149:304-313.</p