Corrigendum: The PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study: Rationale, Design and Preliminary Screening Results.

[This corrects the article DOI: 10.3389/fnut.2021.694568.].

The PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study: Rationale, Design and Preliminary Screening Results.

Background: It is well-established that the etiology of type 2 diabetes differs between individuals. Insulin resistance (IR) may develop in different tissues, but the severity of IR may differ in key metabolic organs such as the liver and skeletal muscle. Recent evidence suggests that these distinct tissue-specific IR phenotypes may also respond differentially to dietary macronutrient composition with respect to improvements in glucose metabolism. Objective: The main objective of the PERSON study is to investigate the effects of an optimal vs. suboptimal dietary macronutrient intervention according to tissue-specific IR phenotype on glucose metabolism and other health outcomes. Methods: In total, 240 overweight/obese (BMI 25 - 40 kg/m2) men and women (age 40 - 75 years) with either skeletal muscle insulin resistance (MIR) or liver insulin resistance (LIR) will participate in a two-center, randomized, double-blind, parallel, 12-week dietary intervention study. At screening, participants undergo a 7-point oral glucose tolerance test (OGTT) to determine the hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), classifying each participant as either "No MIR/LIR," "MIR," "LIR," or "combined MIR/LIR." Individuals with MIR or LIR are randomized to follow one of two isocaloric diets varying in macronutrient content and quality, that is hypothesized to be either an optimal or suboptimal diet, depending on their tissue-specific IR phenotype (MIR/LIR). Extensive measurements in a controlled laboratory setting as well as phenotyping in daily life are performed before and after the intervention. The primary study outcome is the difference in change in disposition index, which is the product of insulin sensitivity and first-phase insulin secretion, between participants who received their hypothesized optimal or suboptimal diet. Discussion: The PERSON study is one of the first randomized clinical trials in the field of precision nutrition to test effects of a more personalized dietary intervention based on IR phenotype. The results of the PERSON study will contribute knowledge on the effectiveness of targeted nutritional strategies to the emerging field of precision nutrition, and improve our understanding of the complex pathophysiology of whole body and tissue-specific IR. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03708419, clinicaltrials.gov as NCT03708419.

Postprandial skeletal muscle metabolism following a high-fat diet in sedentary and endurance-trained males.

Our objective was to determine the influence of a high-fat diet (HFD) on fasting and postprandial skeletal muscle substrate metabolism in endurance-trained (ET) compared with sedentary (SED) humans. SED (n = 17) and ET (n = 7) males were control-fed a 10-day moderate-fat diet followed by a 5-day isocaloric HFD (55% fat, 30% carbohydrate). Skeletal muscle biopsies were taken in the fasted condition and 4 h after a high-fat meal (820 kcals; 63% fat and 25% carbohydrate). Palmitate-induced suppression of pyruvate oxidation, an indication of substrate preference, and oxidation of fat and glucose were measured in homogenized skeletal muscle in fasted and fed states. Postprandial responses were calculated as percent changes from fasting to fed states. Postprandial suppression of pyruvate oxidation was maintained after the HFD in ET, but not SED skeletal muscle, suggesting greater adaptability to dietary intake changes in the former. Fasting total fat oxidation increased due to the HFD in ET skeletal muscle (P = 0.006), which was driven by incomplete fat oxidation (P = 0.008). Fasting fat oxidation remained unchanged in skeletal muscle of SED individuals. Yet, postprandial fat oxidation was similar between groups. Fasting glucose oxidation was elevated after the HFD in ET (P = 0.036), but not SED, skeletal muscle. Postprandial glucose oxidation was reduced due to the HFD in SED (P = 0.002), but not ET, skeletal muscle. These findings provide insight into differing substrate metabolism responses between SED and ET individuals and highlight the role that the prevailing diet may play in modulating fasting and postprandial metabolic responses in skeletal muscle.NEW & NOTEWORTHY The relationship between high dietary fat intake and physical activity level and their combined effect on skeletal muscle substrate metabolism remains unclear. We assessed the influence of the prevailing diet in modulating substrate oxidation in skeletal muscle of endurance-trained compared with sedentary humans during a high-fat challenge meal. Collectively, our findings demonstrate the adaptability of skeletal muscle in endurance-trained individuals to high dietary fat intake.

Serum endotoxin, gut permeability and skeletal muscle metabolic adaptations following a short term high fat diet in humans.

BACKGROUND: Our previous work demonstrated that a short-term high fat diet (HFD) increased fasting serum endotoxin, altered postprandial excursions of serum endotoxin, and led to metabolic and transcriptional responses in skeletal muscle in young, healthy male humans. PURPOSE: The purpose of the present study was to determine if a short-term high fat diet: 1) increases intestinal permeability and, in turn, fasting endotoxin concentrations and 2) decreases postprandial skeletal muscle fat oxidation. METHODS: Thirteen normal weight young adult males (BMI 23.1 ±â€¯0.8 kg/m2, age 22.2 ±â€¯0.4 years) were fed a control diet (55% carbohydrate, 30% fat, 9% of which was saturated, 15% protein) for two weeks, followed by 5 days of an isocaloric HFD (30% carbohydrate, 55% fat, 25% of which was saturated, 15% protein, isocaloric to the control diet). Intestinal permeability (via four sugar probe test) was assessed in the fasting state. Both before and after the HFD, a high fat meal challenge (HFM, 820 kcal, 25% carbohydrate, 63% fat, 26% of which was saturated, and 12% protein) was administered. After an overnight fast, blood samples were collected before and every hour for 4 h after the HFM to assess endotoxin, and other serum blood measures. Muscle biopsies were obtained from the vastus lateralis before and 4 h after the HFM in order to assess substrate oxidation (glucose, fatty acid and pyruvate) using radiolabeled techniques. Insulin sensitivity was assessed via intravenous glucose tolerance test. Intestinal permeability, blood samples and muscle biopsies were assessed in the same manner before and following the HFD. MAIN FINDINGS: Intestinal permeability was not affected by HFD (p > 0.05), but fasting endotoxin increased two fold following the HFD (p = 0.04). Glucose oxidation and fatty acid oxidation in skeletal muscle homogenates significantly increased after the HFM before the HFD (+97%, and +106% respectively) but declined after the HFM following 5 days of the HFD (-24% and +16% respectively). Fatty acid suppressibility of pyruvate oxidation increased significantly after the HFM (+32%) but this physiological effect was abolished following 5 days of the HFD (+7%). Insulin sensitivity did not change following the HFD. CONCLUSION: These findings demonstrate that in healthy young men, consuming an isocaloric HFD for 5 days increases fasting endotoxin, independent of changes in gut permeability. These changes in endotoxin are accompanied by a broad effect on skeletal muscle substrate metabolism including increases in postprandial fat oxidation. Importantly, the latter occurs independent of changes in body weight and whole-body insulin sensitivity.

Sweet taste perception is greater in non-Hispanic black than in non-Hispanic white adults.

OBJECTIVE: Research suggests a difference in sweet taste perception between non-Hispanic black (NHB) and non-Hispanic white (NHW) adults; however, limited research has examined sweet taste perception in relation to the dietary intake of sweet products. The aim of this study was to examine sweet taste perception and the consumption of sweet foods, beverages, and sugar in NHB and NHW adults, and to evaluate whether sweet taste perception is associated with dietary intake. METHODS: This cross-sectional study examined the association between race, sweet taste perception and sweet food, beverages, and sugar consumption in healthy, NHB and NHW adults. Seven day food records were analyzed in Nutrition Data System for Research software. Intensity of sweet taste perception was tested and the general labeled magnitude scale method was used to facilitate group comparisons. Independent t tests, Mann-Whitney tests, and Pearson correlations were used to assess associations. RESULTS: Participants were NHB (n = 98) and NHW (n = 90) adults, 41 ± 1 y of age (mean ± SEM) with energy intake of 2271 ± 53 kcal. Body mass index was higher in NHBs than in NHWs (36 ± 1 versus 32 ± 1 kg/m2, P = 0.048), but no differences were observed in age, energy consumption, or total sugar intake. Sweet taste perception rating (median [interquartile range] NHB: 73.5 [63.9-83], NHW: 52.1 [46.4-57.7]; P = 0.001) and added sugar intake (NHB: 39.4 g/1000 kcal [36.3-42.4], NHW: 30 g/1000 kcal [26.7-33.4]; P < 0.001) were greater in NHB. Perceived sweet taste intensity was positively associated with consumption of servings of sweet products among NHBs (R2 = 0.057, P = 0.018) but not NHWs (R2 = -0.012, P = 0.314). CONCLUSIONS: NHBs have a higher intensity of sweet taste perception than NHWs. The positive association of sweet taste perception and sweet product consumption in NHBs suggests that a higher intensity of sweet taste perception may be associated with an increased proportion of energy consumption from added sugars.

Ectopic Fat Accumulation in Distinct Insulin Resistant Phenotypes; Targets for Personalized Nutritional Interventions.

Cardiometabolic diseases are one of the leading causes for disability and mortality in the Western world. The prevalence of these chronic diseases is expected to rise even further in the next decades. Insulin resistance (IR) and related metabolic disturbances are linked to ectopic fat deposition, which is the storage of excess lipids in metabolic organs such as liver and muscle. Notably, a vicious circle exists between IR and ectopic fat, together increasing the risk for the development of cardiometabolic diseases. Nutrition is a key-determining factor for both IR and ectopic fat deposition. The macronutrient composition of the diet may impact metabolic processes related to ectopic fat accumulation and IR. Interestingly, however, the metabolic phenotype of an individual may determine the response to a certain diet. Therefore, population-based nutritional interventions may not always lead to the most optimal (cardiometabolic) outcomes at the individual level, and differences in the metabolic phenotype may underlie conflicting findings related to IR and ectopic fat in dietary intervention studies. Detailed metabolic phenotyping will help to better understand the complex relationship between diet and metabolic regulation, and to optimize intervention outcomes. A subgroup-based approach that integrates, among others, tissue-specific IR, cardiometabolic parameters, anthropometrics, gut microbiota, age, sex, ethnicity, and psychological factors may thereby increase the efficacy of dietary interventions. Nevertheless, the implementation of more personalized nutrition may be complex, costly, and time consuming. Future studies are urgently warranted to obtain insight into a more personalized approach to nutritional interventions, taking into account the metabolic phenotype to ultimately improve insulin sensitivity and reduce the risk for cardiometabolic diseases.

Skeletal muscle autophagy and mitophagy in endurance-trained runners before and after a high-fat meal.

OBJECTIVE: We tested the hypothesis that skeletal muscle of endurance-trained male runners would exhibit elevated autophagy and mitophagy markers, which would be associated with greater metabolic flexibility following a high-fat meal (HFM). METHODS: Muscle biopsies were collected to determine differences in autophagy and mitophagy protein markers and metabolic flexibility under fasting conditions and 4 h following a HFM between endurance-trained male runners (n = 10) and sedentary, non-obese controls (n = 9). RESULTS: Maximal oxygen consumption (ml·kg·min-1) was approximately 50% higher (p < 0.05) in endurance-trained runners compared with sedentary controls (65.8 ± 2.3 and 43.1 ± 3.4, respectively). Autophagy markers were similar between groups. Mitophagy and mitochondrial dynamics protein markers were significantly higher in skeletal muscle of endurance-trained runners compared with sedentary controls in the fasted state, although unaffected by the HFM. Skeletal muscle metabolic flexibility was similar between groups when fasted (p > 0.05), but increased in response to the HFM in endurance-trained athletes only (p < 0.005). Key mitophagy markers, phospho-Pink1Thr257 and phospho-ParkinS65 (r = 0.64, p < 0.005), and phospo-ParkinSer65 and phospho-Drp1Ser616 (r = 0.70, p < 0.05) were correlated only within the endurance-trained group. Autophagy and mitophagy markers were not correlated with metabolic flexibility. CONCLUSION: In summary, mitophagy may be enhanced in endurance-trained runners based on elevated markers of mitophagy and mitochondrial dynamics. The HFM did not alter autophagy or mitophagy in either group. The absence of a relationship between mitophagy markers and metabolic flexibility suggests that mitophagy is not a key determinant of metabolic flexibility in a healthy population, but further investigation is warranted.

High-molecular-weight cocoa procyanidins possess enhanced insulin-enhancing and insulin mimetic activities in human primary skeletal muscle cells compared to smaller procyanidins.

Dysregulation of glucose metabolism is a primary hallmark of metabolic disease (i.e., diabetes, obesity, etc.). Complementary nonpharmaceutical strategies are needed to prevent and/or ameliorate dysregulation of glucose metabolism and prevent progression from normoglycemia to prediabetes and type 2 diabetes across the lifespan. Cocoa compounds, particularly the procyanidins, have shown promise for improving insulin sensitivity and blood glucose homeostasis. However, the molecular mechanisms by which cocoa procyanidins exert these functions remain poorly understood. Furthermore, cocoa procyanidins exhibit size diversity, and evidence suggests that procyanidin bioactivity and size may be related. Here, we show that a procyanidin-rich cocoa extract elicits an antidiabetic effect by stimulating glycogen synthesis and glucose uptake, independent of insulin. Cocoa procyanidins did not appear to act via stimulation of AMPK or CaMKII activities. Additionally, in the presence of insulin, glycogen synthesis and AKT phosphorylation were affected. These mechanisms of action are most pronounced in response to oligomeric and polymeric procyanidins. These results demonstrate (1) specific mechanisms by which cocoa procyanidins improve glucose utilization in skeletal muscle and (2) that larger procyanidins appear to possess enhanced activities. These mechanistic insights suggest specific strategies and biological contexts that may be exploited to maximize the antidiabetic benefits of cocoa procyanidins.

Beta Cell Function and the Nutritional State: Dietary Factors that Influence Insulin Secretion.

Approximately 366 million people worldwide have been diagnosed with type-2 diabetes (T2D). Chronic insulin resistance, decreased functional ß-cell mass, and elevated blood glucose are defining characteristics of T2D. Great advances have been made in understanding the pathogenesis of T2D with respect to the effects of dietary macronutrient composition and energy intake on ß-cell physiology and glucose homeostasis. It has been further established that obesity is a leading pathogenic factor for developing insulin resistance. However, insulin resistance may not progress to T2D unless ß-cells are unable to secret an adequate amount of insulin to compensate for decreased insulin sensitivity. Therefore, pancreatic ß-cell dysfunction plays an important role in the development of overt diabetes. This paper reviews recent research findings on the effects of several micronutrients (zinc, vitamin D, iron, vitamin A), leucine, and the phytochemical, genistein on pancreatic ß-cell physiology with emphasis on their effects on insulin secretion, specifically in the context of T2D.