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Few studies have demonstrated reproducible gene–diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient–glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], −0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry–enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate–HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry. Article Highlights: We aimed to identify genetic modifiers of the dietary macronutrient–glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry–enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene–macronutrient interactions. [ABSTRACT FROM AUTHOR]

Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be folded for export through the secretory pathway of pancreatic β-cells. The substitution proinsulin-R(B22)E is known to yield a bioactive insulin, although R(B22)Q has been reported as a mutation that falls within the spectrum of mutant INS-gene-induced diabetes of youth. Here, we have studied mice expressing heterozygous (or homozygous) proinsulin-R(B22)E knocked into the Ins2 locus. Neither females nor males bearing the heterozygous mutation developed diabetes at any age examined, but subtle evidence of increased proinsulin misfolding in the endoplasmic reticulum is demonstrable in isolated islets from the heterozygotes. Moreover, males have indications of glucose intolerance, and within a few weeks of exposure to a high-fat diet, they developed frank diabetes. Diabetes was more severe in homozygotes, and the development of disease paralleled a progressive heterogeneity of β-cells with increasing fractions of proinsulin-rich/insulin-poor cells as well as glucagon-positive cells. Evidently, subthreshold predisposition to proinsulin misfolding can go undetected but provides genetic susceptibility to diet-induced β-cell failure. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here, we report that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine tumor necrosis factor-α. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated, which, in turn, targeted the 3'-untranslated region of PPARα mRNA, impaired mitochondrial fatty acid β-oxidation, and induced mitochondrial and endoplasmic reticulum stress. More importantly, the upregulated miR-378a can directly bind to and activate the double-strand RNA (dsRNA)-dependent protein kinase R (PKR) to sustain the metabolic stress. In vivo, genetic depletion of miR-378a prevented PKR activation and ameliorated inflammatory stress and insulin resistance. Counterbalancing the upregulated miR-378a using nanoparticles encapsulated with an anti-miR-378a oligonucleotide restored PPARα activity, inhibited PKR activation and ER stress, and improved insulin sensitivity in fructose-fed mice. Our study delineated a novel mechanism of miR-378a in the pathogenesis of metabolic inflammation and insulin resistance through targeting metabolic signaling at both mRNA (e.g., PPARα) and protein (e.g., PKR) molecules. This novel finding of functional interaction between miRNAs (e.g., miR-378a) and cellular RNA binding proteins (e.g., PKR) is biologically significant because it greatly broadens the potential targets of miRNAs in cellular pathophysiological processes. [ABSTRACT FROM AUTHOR]

High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulinsensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater b-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3-hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine pro le and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice. [ABSTRACT FROM AUTHOR]

This section presents abstracts of research on diabetes, including "An Investigation Into the Anti-Diabetic Effects of Ginsenoside Rbl and Rg1, Resulting From Their Suppression of Lipogenesis and Their Enhancement of β-Cell Function and Survival via PKA Dependent Pathways," "Carbohydrate-Rich Diet Increases Postprandial Adipose, UCP2 Gene Expression, Circulating Nitrotyrosine and ox-LDL Levels Compared With MUFA-Rich Diet in Insulin-Resistant Patients," and "Chronic Leucine Exposure Results in Reduced but Reversible Glucose-Stimulated Insulin Secretion and PDX-1 Expression in INS-1 Cells."

Investigates the use of c deoxyribonucleic acid array in identifying genes induced in islets by high-carbohydrate diet. Prevalence of hyperinsulinemia secondary to high-carbohydrate in milk; Role of gene expression in the phenotypes of cells; Regulation of gene expression in the islets.

The glycemic index (GI) of carbohydrate-containing foods is often employed in observational studies as a surrogate measure for insulin demand. However, the relationship between the GI of individual foods and the relative insulin response (ie. insulin index) has been questioned. Our aim was to evaluate the correlation between the glycemic index and insulinemic index (II) for a range of carbohydrate-rich foods commonly consumed in a typical diet. The GI and II values of individual foods was determined simultaneously using standardised methodology with the corresponding 2 h incremental area under the response curve for 25 g or 50 g available carbohydrate test portions. Values were obtained from both published studies and unpublished sources including data from our own research facility. The food groups that were studied included beverages (n = 10), breads (n = 31), breakfast cereals (n = 23), cookies and crackers (n = 33), chocolate confectionery (n = 12), dairy products (n = 15), fruit and vegetables (n = 19), high-carbohydrate staples (including legumes, pasta and flee; n = 55), mixed meals (n = 13), snack foods (including bars and cakes; n = 21), and sweeteners and sugars (n = 21). Using linear regression analysis, the insulin index of the 253 individual foods was significantly correlated with the corresponding GI values (r = 0.65, p = 0.0001). Correlations were highest within the carbohydrate-rich food categories (eg. breads (r = 0.64, p = 0.0001), breakfast cereals (r = 0.84, p = 0.0001) and high-carbohydrate staples (r = 0.64, p = 0.0001)) and lowest for dairy products (r = 0.11, NS) and chocolate confectionery (r = 0.50, NS). When dairy foods and chocolate confectionery were excluded (n = 27) from the overall analysis, the relationship between the glucose and insulin responses was stronger (n = 226, r = 0.72, p = 0.0001). We conclude that the glycemic index is likely to be a reliable predictor of insulin demand in high carbohydrate diets but less so in diets based on high intake of dairy foods or chocolate products. [ABSTRACT FROM AUTHOR]

Objective: Central obesity is associated with insulin resistance but the factors implicated are not fully understood. To study the effects of three different models of isocaloric diets on body fat distribution, insulin sensitivity and peripheral adiponectin gene expression. Research Design and Methods: Eleven volunteers, offspring of obese type 2 diabetic patients with abdominal fat deposition were studied. These subjects were considered insulin resistant as indicated by their Matsuda index < 4 after OGTT and maintained HBA1c < 6.5% without therapeutic intervention. All subjects underwent three dietary periods of 28 days each in a crossover design: a) diet enriched in saturated fat (SAT), b) diet rich in monounsaturated fat (MUFA; Mediterranean diet) and c) diet rich in carbohydrate (CHO). Results: Weight, body composition and resting energy expenditure remained unchanged during the three sequential dietary periods. Using dual energy X-ray absorptiometry we observed that when patients were fed a CHO enriched diet they redistributed their fat mass towards the abdominal depot while decreasing fat accumulation in periphery compared with isocaloric MUFA-rich or high SAT diets (Anova < 0.05, respectively). These changes were associated with decreased posprandial mRNA adiponectin levels in peripheral adipose tissue and lower insulin Sensitivity indexes (Si) from a frequently sampled insulin-assisted intravenous when patients were feeding a CHO-rich diet compared with a MUFA-rich diet (Anova < 0.05, respectively). Conclusions: Isocaloric MUFA-rich diet prevents central fat redistribution associated with posprandial decreases of peripheral adiponectin gene expression and insulin resistance induced by carbohydrate-rich diet in insulin-resistant subjects. [ABSTRACT FROM AUTHOR]

Body: The aim of this study was to examine the association between dietary patterns and glucose abnormalities using Korean dietary evaluation program. This was a part of 2[sup nd] Incheon Chronic Disease Management System Study(2006). We surveyed 1,000 subjects in Hwasu-Dong by a cross-sectional observational study on September to December 2006. Among them, 178 subjects (55 male, 123 female) were evaluated about dietary patterns using CAN-Pro 3.0. CAN-Pro 3.0 is a dietary evaluation program authorized by the Korean Nutrition Association in 2005. Subjects diagnosed three groups (normal, prediabetes and diabetes) by American Diabetes Association criteria using 75g oral glucose tolerance test. Prediabetes includes impaired fasting glucose, impaired glucose tolerance and combined state. We also performed physical and laboratory examinations. Mean age is 49.7+12.7 years. Among 178 subjects, normal person was 21 (11.8%), IFG 41 (23.0%), IGT 37(20.8%) and combined 20(11.2%) and newly diagnosed diabetes was 39(21.9%). In IFG, IGT, combined and newly diagnosed diabetes group, intake of carbohydrate(g) were higher than normal group, respectively (303.9±96.8g, 294.8±77.1g, 266.3±64.0g and 309.6±100.9g vs 235.1±39.1g, p<0.01). In IFG, IGT, combined and newly diagnosed diabetes group, intake of total daily calories(kcal) were higher than normal group, respectively(1974.4±543.8kcal, 1880.5±480.9kcal, 1681.1±384.3kcal and 1843.7±429.7kcal vs 1564.3±238.6kcal, p<0.01). Among the groups, there were no differences with dietary total fatty acid, cholesterol, protein, fiber and vitamin. The high consumption of carbohydrate and over-dosed total daily calories were positively associated with glucose abnormalities or risk factors for diabetes in Korean population. [ABSTRACT FROM AUTHOR]

The hypothalamic AMP-kinase regulates feeding behavior in response to hormonal and nutrient signals. Decrease of AMP-kinase activity in the paraventricular (PVH) and arcuate hypothalamus plays an important role in anorexic effect of leptin. However, the effect of AMP-kinase on long-term energy balance remains to be established. In the present study, we examined the effect of chronic expression of constitutively-active AMP-kinase (CA-AMPK) in the PVH on food intake and body weight in male C57/BL6 mice, using lenti-viral vector with synapsin 1 promotor. CA-AMPK in the PVH significantly increased body weight (CA-AMPK mice: 11.0 ± 1.5 g vs. the control mice: 3.5 ± 0.3 g, during 3 months after the infection). CA-AMPK mice also increased food intake before the increase in body weight (CA-AMPK mice: 14.8 ± 0.9 kcal vs. control mice: 12.9 ± 0.1 kcal/day, I month after the infection). Interestingly, CA-AMPK mice increased food intake only under high carbohydrate diet (lob chow or high sucrose diet) but not under high fat diet (60% Fat). In contrast, the control mice increased the intake of high fat diet but not high carbohydrate diet (intake of high fat diet in CA-AMPK mice: 11.7 ± 0.9 kcal and in the control mice: 16.5 ± 0.9 kcal/day). When both high sucrose and high fat diets were simultaneously available, CA-AMPK mice chose high sucrose diet, whereas the control mice chose high fat diet. CA-AMPK increased the mRNA expression of fatty acid oxidation-related genes in the PVH such as PPAR alpha, FATP1, acyl-CoA synthetase 1 and CPT1c. Direct administration of etomoxir, an inhibitor of CPT-1 and fatty acid oxidation in mitochondria, into the PVH in the CA-AMPK mice, reversed to the high preference for high fat diet. Thus, these findings suggest that AMP-kinase in the PVH regulates not only calorie intake but also the preference for carbohydrate and fat diets. AMP-kinase in the PVH may control the food preference by changing fatty acid metabolism in the nucleus. [ABSTRACT FROM AUTHOR]

Objective: We studied the effects of three weigh-maintenance diets on glucose and lipid metabolism, insulin and incretin responses, in insulin-resistant subjects. Methods: Were studied eleven (7W, 4M) offspring of obese and type 2 diabetes patients. Subjects had a BMI > 25 Kg/m2, waist circumference (men/women) > 102/88, HBA1c < 6.5% and were considered insulin-resistant after an OGTT (Matsuda ISIm <4). They were randomly divided into three groups and underwent three dietary periods of 28 days each in a crossover design: a) diet high in saturated fat (SAT), b) diet rich in monounsaturated fat (MUFA; Mediterranean diet) and c) diet rich in carbohydrate (CHO). Results: Body weight and resting energy expenditure were not changed during the three dietary periods. Fasting serum glucose concentrations decreased during MUFA-rich and CHO-rich diets. MUFA-rich diet improved insulin sensitivity as indicated by decreased HOMA-ir. An acute challenge after a standard MUFA-rich breakfast (443 Kcal) decreased the posprandial integrated area under curve (AUC) of glucose and insulin while AUCs of triacylglycerol and GLP-1 responses were increased as compared with isocaloric CHO-rich meals. Fasting proinsulin (PI) concentration was decreased while stimulated ratio PI/I was not changed by MUFA-rich diet. Fasting and postprandial HDL cholesterol concentrations were increased by MUFA-rich diets. Conclusions: Weight-maintenance with a rich-MUFA diet improves HOMA-ir and fasting proinsulin levels in insulin resistant subjects. Ingestion of an olive oil based breakfast decreased posprandial glucose and insulin concentrations, and increased HDL-C and GLP-1 concentrations. [ABSTRACT FROM AUTHOR]

The ideal macronutrient composition of diets for individuals with type 2 diabetes has been much debated but not yet resolved. While short-term studies have shown benefits of both diets high in carbohydrate (CHO) and diets high in monounsaturated fat (MUFA), no long-term trials have compared their relative effectiveness in free-living diabetic subjects. We conducted a one-year trial of high-CHO and high-MUFA diets in a group of men (n=46) and women (n=78) with moderately well-controlled type 2 diabetes (mean BMI = 35.9; mean age = 55.7; mean HbA1c = 7.3). Subjects were randomly assigned to a high-MUFA diet with 40% of kcal from fat (20% from MUFA) and 45% from CHO, or a high-CHO diet with 60% of kcal from CHO and 25% from fat; a modest caloric restriction was prescribed with both diets. Registered dietitians counseled subjects in individual and group sessions on a regular basis. Anthropometric and metabolic parameters were assessed at baseline and after 4, 8, and 12 months of dieting. The overall retention rate was 77% (69% for high-MUFA; 84% for high-CHO, p < 0.36). Based on 3-day food records, both groups had similar daily energy intake; however, the high-MUFA group consumed approximately 45%, 17%, and 38% of total kcal as carbohydrate, protein, and fat, respectively, compared to 54%, 18%, and 28% in the high-CHO group. As expected, there was a significant difference in MUFA intake between the groups (p < .05). Both groups showed similar weight loss over one year (3.93 ± 0.82 kg vs. 3.78 ± 0.64 kg) and improvement in body fat, diastolic blood pressure, HDL-cholesterol, HbA1c, and fasting glucose and insulin (p ≤ 0.01). However, there were no differences in any of these parameters between the diet groups. These results suggest that high-MUFA diets can be healthy alternatives to lower fat, high-CHO diets without negative impact on anthropometrics, cardiovascular risk factors, or glycemic control. Based on the high completion rate for this study, both diets are well accepted by diabetic persons. ADA-Funded Research [ABSTRACT FROM AUTHOR]