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It is unclear how effective intermittent fasting is for losing weight and body fat, and the effects may depend on the timing of the eating window. This randomized trial compared time-restricted eating (TRE) with eating over a period of 12 or more hours while matching weight-loss counseling across groups.To determine whether practicing TRE by eating early in the day (eTRE) is more effective for weight loss, fat loss, and cardiometabolic health than eating over a period of 12 or more hours.The study was a 14-week, parallel-arm, randomized clinical trial conducted between August 2018 and April 2020. Participants were adults aged 25 to 75 years with obesity and who received weight-loss treatment through the Weight Loss Medicine Clinic at the University of Alabama at Birmingham Hospital.All participants received weight-loss treatment (energy restriction [ER]) and were randomized to eTRE plus ER (8-hour eating window from 7:00 to 15:00) or control eating (CON) plus ER (≥12-hour window).The co-primary outcomes were weight loss and fat loss. Secondary outcomes included blood pressure, heart rate, glucose levels, insulin levels, and plasma lipid levels.Ninety participants were enrolled (mean [SD] body mass index, 39.6 [6.7]; age, 43 [11] years; 72 [80%] female). The eTRE+ER group adhered 6.0 (0.8) days per week. The eTRE+ER intervention was more effective for losing weight (-2.3 kg; 95% CI, -3.7 to -0.9 kg; P = .002) but did not affect body fat (-1.4 kg; 95% CI, -2.9 to 0.2 kg; P = .09) or the ratio of fat loss to weight loss (-4.2%; 95% CI, -14.9 to 6.5%; P = .43). The effects of eTRE+ER were equivalent to reducing calorie intake by an additional 214 kcal/d. The eTRE+ER intervention also improved diastolic blood pressure (-4 mm Hg; 95% CI, -8 to 0 mm Hg; P = .04) and mood disturbances, including fatigue-inertia, vigor-activity, and depression-dejection. All other cardiometabolic risk factors, food intake, physical activity, and sleep outcomes were similar between groups. In a secondary analysis of 59 completers, eTRE+ER was also more effective for losing body fat and trunk fat than CON+ER.In this randomized clinical trial, eTRE was more effective for losing weight and improving diastolic blood pressure and mood than eating over a window of 12 or more hours at 14 weeks.ClinicalTrials.gov Identifier: NCT03459703.

Twelve years following gastric bypass surgery, a cachectic 69-year-old woman presented with both fasting and postprandial hypoglycaemia. Postprandial symptoms were relieved by dietary modification and acarbose, as is common in such cases. During a supervised fast, symptomatic hypoglycaemia occurred. Concurrent laboratory testing showed suppression of plasma insulin, c-peptide, proinsulin and insulin-like growth factor II. However, beta-hydroxybutyrate was also low, surprising given insulin deficiency. Elevated plasma free fatty acid (FFA) concentrations suggested that lipolysis was not impaired, making cachexia/malnutrition a less likely cause of hypoglycaemia. The apparent diagnosis was failure to counter-regulate—subsequent plasma carnitine measurements showed carnitine deficiency which presumably prevented FFA transport across mitochondrial membranes for ketogenesis. Repletion with high-dose oral carnitine supplements effected resolution of fasting hypoglycaemia.

Diets high in saturated fat (HFD) disrupt dopamine neurotransmission, whereas fasting alters tonic and phasic dopamine release to drive motivation and food consumption. However, functional compartments in the nucleus accumbens (NAc) influencing these effects are not well characterized, and sex comparisons have not been made. This study sought to determine whether consumption of a HFD, sex, or being fed versus fasted altered baseline dopamine release and reuptake throughout NAc subregions. Male and female C57BL/6 mice were fed a control diet or nutrient matched HFD for six weeks. Ex-vivo fast-scan cyclic voltammetry revealed females had significantly slower dopamine reuptake in the NAc core than males when fed ad lib control diet. Fasting enhanced dopamine release and reuptake in the NAc core but not the medioventral shell. Further, being fasted versus fed significantly increased dopamine release throughout the NAc core in control males but specifically promoted release and reuptake in only the ventrolateral core of HF-fed males, effects which were lacking in females. Finally, fasting promoted dopamine release and reuptake in the rostral NAc core of controls and more caudally in HFD groups. These data support that dopamine neurotransmission is heterogeneous in NAc subregions and suggest the ventrolateral core is responsive to energy state. Furthermore, a rostrocaudal gradient in the NAc core might control valence responses to fasting that could promote overeating after chronic HFD consumption.

Aims: To assess the independent and joint impact of visit-to-visit fasting blood glucose variability (VVV-FBG) and mean fasting glucose level (M-FBG) on all-cause mortality.Materials and methods: This prospective cohort study included 48,843 Chinese with type 2 diabetes. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) to evaluate the association of VVV-FBG and M-FBG with all-cause mortality. The potential nonlinear associations were examined by restricted cubic splines, and additive interaction was evaluated by the relative excess risk due to interaction (RERI). Cox generalized additive models (CGAM) and bivariate response surface models were further used to assess the joint effects of VVV-FBG and M-FBG.Results: A total of 4087 deaths was observed during a median follow-up of 6.99 years. Compared with patients with values at the 5th percentile of ARV and M-FBG, we observed a 23% and 38% increased risk of premature deaths among those with values at the 95th percentile of ARV (HR: 1.23, 95% CI 1.10,1.37) and M-FBG (HR: 1.38, 95% CI 1.26,1.51), respectively. The interaction between glycemic variability (ARV) and M-FBG was significant on both the additive scale [RERI: 0.80 (0.29, 1.32)] and multiplicative scale [HR: 1.90 (1.10, 3.28)]. Subjects with high VVV-FBG and high M-FBG conferred the highest risk of all-cause mortality (HR: 1.89, 95% CI: 1.64,2.17), compared to low VVV-FBG and low M-FBG. The CGAM revealed significant synergistic effects between glycemic variability and M-FBG (P < 0.05). Moreover, bivariate surface plot revealed that the risk of death increased more rapidly in type 2 diabetes patients at the lower M-FBG level combined with lower glycemic variability level.Conclusions: The coexistence of great glycemic variability and high level of glucose might exacerbate the independent risk of premature mortality in type 2 diabetes patients, highlighting the importance of achieving normal and stable glucose levels simultaneously in the management of glucose. This article is protected by copyright. All rights reserved.

Elderly patients have higher risks for complications during Ramadan fasting. Educating patients is essential for fasting safely.To evaluate the impact of pre-Ramadan education in reducing risk of hypoglycemia and achieving glycemic control in elderly.A prospective study carried out in outpatients clinics of Internal Medicine department in Assiut university hospital. It included 316 type 2 diabetic patients who intended to fast. They were grouped into 2 groups; 65 years and ≥ 65 years patients. The patients received pre-Ramadan individual education sessions. A semi-structured questionnaire was used to collect the data to stratify the risk of fasting. The study was carried out in 3 phases. Assessment of hypoglycemia and biochemical parameters after the education was the primary outcome.Fasting blood glucose decreased during and after Ramadan in elderly significantly (p = 0.0001). The patients who achieved fasting blood glucose less than 8 mmol/L increased from 29.3% to 46.6% after Ramadan in elderly patients. HbA1c decreased significantly after Ramadan (p = 0.001). The main cause of breaking fast was hypoglycemia in both groups; 9% vs.7.7% in patients 65 and ≥ 65 years respectively. The waist circumference showed significant decrease in patient with 65 years old or more (p = 0.05). Total cholesterol and LDL increased with no statistical significance in patients ≥ 65 years (p = 0.512, 0.470). Both groups showed improvement of HDL cholesterol during and after Ramadan (P = 0.0001).Pre-fasting education had positive impact on decreasing the risk of symptomatic hypoglycemia in elderly diabetic patients.

While glucose tolerance is widely known to deteriorate with age, there are individuals whose borderline elevated glucose does not presage development of diabetes, but there are people who do develop overt diabetes. In addition, elevated glucose may also presage other morbidities, particularly for those who show progressive deterioration in glucose control over time. This concept of the glucose trajectory has taken on recent significance with sophisticated mathematical modeling that can identify several different arcs, primarily based on longitudinal changes in fasting plasma glucose. Other trajectories, calculated on changes in glycated hemoglobin, or integrated responses to oral glucose tolerance tests, are less well characterized. The author has reviewed the literature in an attempt to clarify these different themes of age-related deterioration in glucose control, highlight conflicting definitions of glucose trajectory, and potentially identify avenues of further investigation. Genetic contributions to the risk of development of type 2 diabetes, artificial intelligence and mathematical models of diabetes risk, and the discrepancy between fasting glucose and postprandial measures, including glycated hemoglobin, in risk prediction are also considered.

The relationship between fasting blood glucose (FBG) variability and colorectal cancer (CRC) remains ill-defined. This study aimed to evaluate the association of FBG variability with CRC risk in the healthy population without overt diabetes.In the data from the Korean National Health Insurance Service-Health Screening Cohort, we included individuals examined by FBG testing at least 3 times between 2002 and 2007. FBG variability was calculated using standard deviation (SD) and coefficient of variation (CV).Regarding FBG variability, an increase in the quintile of SD or CV was independently associated with CRC risk (all p for trend0.01). When the change in FBG was classified into six trajectory patterns, unfavorable trajectory patterns (high stable and upward) were significantly associated with increased CRC risk (hazard ratio [HR] 2.30, p=0.003; HR 1.19, p=0.007, respectively). In subgroup analyses according to the sex, a significant association between FBG variability (SD or CV) and CRC risk was observed in men but not in women. The high stable and upward pattern were also associated with CRC risk in men (HR 2.47, p=0.002; HR 1.21, p=0.012) but not in women.This study identified that FBG variability and unfavorable trajectory patterns were significantly associated with increased CRC risk in the healthy population without overt diabetes. Our findings suggest that FBG variability as well as FBG itself may be a predictive factor for the development of CRC.

OBJECTIVE The aim of this study was to assess whether exendin-(9-39) will increase fasting and postprandial plasma glucose and decrease the incidence of hypoglycemia in children with hyperinsulinism (HI). RESEARCH DESIGN AND METHODS This was an open-label, four-period crossover study. In periods 1 and 2, the effect of three different dosing regimens of exendin-(9-39) (group 1, 0.28 mg/kg; group 2, 0.44 mg/kg; group 3, 0.6 mg/kg) versus vehicle on fasting glucose was assessed in 16 children with HI. In periods 3 and 4, a subset of eight subjects received either vehicle or exendin-(9-39) (0.6 mg/kg) during a mixed-meal tolerance test (MMTT) and an oral protein tolerance test (OPTT). RESULTS Treatment group 2 showed 20% (P = 0.037) increase in the area under the curve (AUC) of fasting glucose. A significant increase in AUC of glucose was also observed during the MMTT and OPTT; treatment with exendin-(9-39) resulted in 28% (P ≤ 0.001) and 30% (P = 0.01) increase in AUC of glucose, respectively. Fasting AUC of insulin decreased by 57% (P = 0.009) in group 3. In contrast, AUC of insulin was unchanged during the MMTT and almost twofold higher (P = 0.004) during the OPTT with exendin-(9-39) treatment. In comparison with vehicle, infusion of exendin-(9-39) resulted in significant reduction in likelihood of hypoglycemia in group 2, by 76% (P = 0.009), and in group 3, by 84% (P = 0.014). Administration of exendin-(9-39) during the OPTT resulted in 82% (P = 0.007) reduction in the likelihood of hypoglycemia. CONCLUSIONS These results support a therapeutic potential of exendin-(9-39) to prevent fasting and protein-induced hypoglycemia in children with HI.

Metals play an important role in diabetes mellitus. This cross-sectional study aimed to evaluate the overall, individual and interactive effects of multi-metal exposure on the prevalence of diabetes mellitus, impaired fasting glucose (IFG) rate and fasting blood glucose (FBG) levels.The FBG levels of a study population from a cadmium (Cd)-polluted area (n = 250) and an unpolluted area (n = 204), and the metal levels, including magnesium, calcium (Ca), iron (Fe), zinc (Zn), arsenic (As), Cd, copper and lead (Pb) in blood and urine were detected. The study population was divided into a normal fasting glucose group, an IFG group and a diabetes mellitus group on the basis of FBG levels.The IFG rate and diabetes mellitus prevalence were negatively associated with blood Cd and urine Zn levels (IFG rate: odds ratio [OR] 0.780, 95% confidence interval [CI] 0.655-0.928; OR 0.622, 95% CI 0.465-0.831. Diabetes mellitus prevalence: OR 0.506, 95% CI 0.288-0.888; OR 0.609, 95% CI 0.395-0.939), the IFG rate was positively associated with urine Fe levels (OR 1.876, 95% CI 1.290-2.778), and diabetes mellitus prevalence was positively associated with urine Pb and blood Fe levels (OR 1.185, 95% CI 1.022-1.376; OR 1.008, 95% CI 1.001-1.014). A linear negative correlation was observed between FBG levels and blood Cd, and non-linear inverted U-shaped associations were found between FBG levels and Zn, Pb and copper in urine.This research suggests that multi-metal exposure, especially Cd, Fe, Zn, copper and Pb, is linked to diabetes mellitus, and the interactive effects of multiple metals require further exploration.

Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) improve glycemic control and weight, but might be associated with dehydration, hypotension and ketoacidosis, especially in patients with type 2 diabetes mellitus who fast during Ramadan. This meta-analysis evaluates the effects of Ramadan fasting on patients with type 2 diabetes mellitus treated with SGLT-2i.A literature search was carried out in PubMed, Embase and the Cochrane Library. Quality assessment was carried out using the ROBINS-I and Cochrane tools for risk of bias, and analyses were carried out using RevMan version 5.3.A total of five studies were included in this meta-analysis. During Ramadan, there was a significant reduction in glycated hemoglobin (P 0.00001) and diastolic blood pressure (P = 0.006), with a non-significant trend for a reduction in weight (P = 0.44) and systolic blood pressure (P = 0.67). The number and severity of hypoglycemic episodes was lower in patients with type 2 diabetes mellitus treated with SGLT-2i compared with sulfonylureas. There was no significant change in estimated glomerular filtration rate, β-hydroxybutyrate, bicarbonate or anion gap. However, we identified considerable heterogeneity among studies, and a lack of head-to-head studies with structured outcome reporting on the risks and benefits of SGLT-2i during Ramadan.This systematic review and meta-analysis shows that patients with type 2 diabetes treated with SGLT2i's during Ramadan have an improvement in HbA1c, less hypoglycemia and no major adverse effects.

Severe cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with elevated blood glucose levels and metabolic complications. However, the molecular mechanisms for how SARS-CoV-2 infection alters glycometabolic control are incompletely understood. Here, we connect the circulating protein GP73 with enhanced hepatic gluconeogenesis during SARS-CoV-2 infection. We first demonstrate that GP73 secretion is induced in multiple tissues upon fasting and that GP73 stimulates hepatic gluconeogenesis through the cAMP/PKA signaling pathway. We further show that GP73 secretion is increased in cultured cells infected with SARS-CoV-2, after overexpression of SARS-CoV-2 nucleocapsid and spike proteins and in lungs and livers of mice infected with a mouse-adapted SARS-CoV-2 strain. GP73 blockade with an antibody inhibits excessive glucogenesis stimulated by SARS-CoV-2 in vitro and lowers elevated fasting blood glucose levels in infected mice. In patients with COVID-19, plasma GP73 levels are elevated and positively correlate with blood glucose levels. Our data suggest that GP73 is a glucogenic hormone that likely contributes to SARS-CoV-2-induced abnormalities in systemic glucose metabolism.

Background: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.Objectives: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.Methods: In 2566 individuals of the population-based Maastricht Study (age: 60 +/- 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in> 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using theAGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle.Results: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (beta: 0.08; 95% CI: 0.02, 0.13) and SAF (beta: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (beta: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.Conclusions: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Aims: This study aims to evaluate the stability of C-peptide over time and to compare fasting C-peptide and C-peptide response after mixed-meal tolerance test (MMTT) at T90 or T120 with C-peptide area under the curve (AUC) in long-standing type 1 diabetes. Methods: We included 607 type 1 diabetes individuals with diabetes duration >5 years. C-peptide concentrations (ultrasensitive assay) were collected in the fasting state, and in a subpopulation after MMTT (T0, just prior to, T30-T60-T90-T120, 30–120 min after ingestion of mixed-meal) (n = 168). Fasting C-peptide concentrations (in n = 535) at Year 0 and Year 1 were compared. The clinical determinants associated with residual C-peptide secretion and the correspondence of C-peptide at MMTT T90 / T120 and total AUC were assessed. Results: A total of 153 participants (25%) had detectable fasting serum C-peptide (i.e ≥ 3.8 pmol/L). Fasting C-peptide was significantly lower at Year 1 (p < 0.001, effect size = −0.16). Participants with higher fasting C-peptide had a higher age at diagnosis and shorter disease duration and were less frequently insulin pump users. Overall, 109 of 168 (65%) participants had both non-detectable fasting and post-meal serum C-peptide concentrations. The T90 and T120 C-peptide values at MMTT were concordant with total AUC. In 17 (10%) individuals, C-peptide was only detectable at MMTT and not in the fasting state. Conclusions: Stimulated C-peptide was detectable in an additional 10% of individuals compared with fasting in individuals with >5 years of diabetes duration. T90 and T120 MMTT measurements showed good concordance with the MMTT total AUC. Overall, there was a decrease of C-peptide at 1-year follow-up.

Background & aims: Individuals with fasting triglycerides (TG) 130 mg/dL (>1.50 mmol/L) exhibited PPTG 220 mg/dL ( 2.50 mmol/L), while 100% of individuals with fasting TG

Many kidney donor candidates with impaired fasting glucose (IFG) and all candidates with diabetes are currently excluded from kidney donation, fearing the development of an accelerated course of diabetic kidney disease in the remaining kidney.We studied mortality, proteinuria, and end-stage kidney disease (ESKD) in 8280 donors who donated between 1963 and 2007 according to donation fasting plasma glucose (FPG):100 mg/dL (n = 6204), 100-125 mg/dL (n = 1826), and ≥126 mg/dL (n = 250).Donors with IFG and those with FPG ≥126 mg/dL were older, less likely to be non-Hispanic White, had a higher body mass index, and were more likely to be related to their recipient. After 15.7 ± 10.5 y from donation to study close, 4.4% died, 29.4% developed hypertension, 13.8% developed proteinuria, and 41 (0.5%) developed ESKD. In both the logistic and Cox models, IFG was associated with a higher diabetes risk (adjusted hazard ratio [aHR], 1.65; 95% confidence interval [CI], 1.18-2.30) and hypertension (aHR, 1.35; 95% CI, 1.10-1.65; P = 0.003 for both), but not higher risk of proteinuria or ESKD. The multivariable risk of mortality in donors with ≥126 mg/dL was higher than the 2 other groups, but risks of proteinuria, cardiovascular disease, and reduced estimated glomerular filtration rate were similar to those with FPG126 mg/dL. Three cases of ESKD developed in the 250 donors with FPG ≥126 mg/dL at 18.6 ± 10.3 y after donation (aHR, 5.36; 95% CI, 1.0-27.01; P = 0.04).Donors with IFG and the majority of donors with ≥126 mg/dL do well and perhaps should not be routinely excluded from donation.

Background: Pre-eclampsia contributes significantly to both maternal and perinatal morbidities and mortalities. One of the identified pathophysiologies of pre-eclampsia is the deranged serum lipid profile of which some components have been found to be elevated early in pregnancy in women destined to develop pre-eclampsia. Objective: To compare the serum fasting lipid profiles of pre-eclamptic primigravidas with normal primigravidas at week 20, 28, and 34. Methods: We conducted a nested case-control study at Obafemi Awolowo University, Ile-Ife between November 2016 and April 2018. A cohort of 290 primigravidas was recruited at week 20 and followed up until delivery. Serum fasting lipid profiles were quantified at weeks 20, 28 and 34 for all participants. Twenty four women that developed pre-eclampsia were compared with 48 women that had a normal pregnancy. Data were analyzed with SPSS version 22. We used a linear mixed-effect regression model with random intercept and slope. Significance was established using p Results: Serum lipid profiles showed an average weekly increase in both groups. Primigravidas that developed pre-eclampsia had a weekly increase of 0.2(SE0.14) mmol/l in serum total cholesterol more than those with normal pregnancies. (p Conclusion: The average weekly increase in serum total cholesterol and low density lipoprotein were higher significantly in primigravidas that developed pre-eclampsia when compared to the control group. These findings depicted an association between serum lipid profile and pre-eclampsia among the primigravidas.

Aim: A prospective cohort study in a Japanese urban general population was performed to investigate whether triglyceride (TG) and its related indices were associated with the risk for the incidence of ischemic cardiovascular disease (CVD) after the adjustment for low-density lipoprotein cholesterol (LDL-C) in Asian community dwellers. Methods: A 15.1-year prospective cohort study was performed in 6,684 Japanese community dwellers aged 30–79 years without a history of CVD and whose fasting TG levels were ＜400 mg/dL. After adjusting for covariates, including LDL-C, the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the deciles (D) of TG and those of 1-standard deviation (SD) increment of log-transformed TG (1-SD of TG) according to LDL-C level (≥ 140 and ＜140 mg/dL) for ischemic CVD incidence were estimated. The multivariable-adjusted HRs and 95%CIs of the quintiles (Q) of TG, TG/HDL-C, and the cardiometabolic index (CMI) for ischemic CVD were also estimated. Results: In 101,230 person-years, 464 ischemic CVD cases occurred. For D 10 of TG, the HR (95%CI) was 1.56 (1.05–2.32), and for 1-SD of TG, it was 1.30 (1.00–1.70) in participants with LDL-C ＜140 mg/dL and 1.07 (0.77–1.50) in those with LDL-C ≥ 140 mg/dL. For Q 5 of the CMI, the multivariable-adjusted HR was higher than those of TG and TG/HDL-C. Conclusions: Fasting TG was an independent predictor for ischemic CVD incidence after adjusting for LDL-C in Japanese community dwellers with TG ＜400 mg/dL. Among TG, TG/HDL-C, and the CMI, the CMI could be the most powerful predictor for ischemic CVD.

In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD+ also participates in redox reactions, the extent to which NAD(H) couples nutrient state with circadian transcriptional cycles remains unknown. Here we show that nocturnal animals subjected to time-restricted feeding of a calorie-restricted diet (TRF-CR) only during night-time display reduced body temperature and elevated hepatic NADH during daytime. Genetic uncoupling of nutrient state from NADH redox state through transduction of the water-forming NADH oxidase from Lactobacillus brevis (LbNOX) increases daytime body temperature and blood and liver acyl-carnitines. LbNOX expression in TRF-CR mice induces oxidative gene networks controlled by brain and muscle Arnt-like protein 1 (BMAL1) and peroxisome proliferator-activated receptor alpha (PPARα) and suppresses amino acid catabolic pathways. Enzymatic analyses reveal that NADH inhibits SIRT1 in vitro, corresponding with reduced deacetylation of SIRT1 substrates during TRF-CR in vivo. Remarkably, Sirt1 liver nullizygous animals subjected to TRF-CR display persistent hypothermia even when NADH is oxidized by LbNOX. Our findings reveal that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1., Using a model of time-restricted feeding in mice, Levine et al. show that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.

DNA methylation plays an important role in the development and etiology of type 2 diabetes; however, few epigenomic studies have been conducted on twins. Herein, a two-stage study was performed to explore the associations between DNA methylation and type 2 diabetes, fasting plasma glucose, and HbA1c. DNA methylation in 316 twin pairs from the Chinese National Twin Registry (CNTR) was measured using Illumina Infinium BeadChips. In the discovery sample, the results revealed that 63 CpG sites and 6 CpG sites were significantly associated with fasting plasma glucose and HbA1c, respectively. In the replication sample, cg19690313 in TXNIP was associated with both fasting plasma glucose (P = 1.23 × 10-17, FDR < 0.001) and HbA1c (P = 2.29 × 10-18, FDR < 0.001). Furthermore, cg04816311, cg08309687, and cg09249494 may provide new insight in the metabolic mechanism of HbA1c. Our study provides solid evidence that cg19690313 on TXNIP correlates with HbA1c and fasting plasma glucose levels.

Major depressive disorder (MDD) is characterized by dysregulation of stress systems and by abnormalities in cerebral energy metabolism. Stress induction has been shown to impact neurometabolism in healthy individuals. Contrarily, neurometabolic changes in response to stress are insufficiently investigated in MDD patients. Metabolic stress was induced in MDD patients (MDD, N = 24) and in healthy individuals (CTRL, N = 22) by application of an established fasting protocol in which calorie intake was omitted for 72 h. Both study groups were comparable regarding age, gender distribution, and body mass index (BMI). Fasting-induced effects on brain high-energy phosphate levels and membrane phospholipid metabolism were assessed using phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Two-way repeated measures ANOVAs did not reveal significant interaction effects (group x fasting) or group differences in adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), phosphodiesters (PDE), or pH levels between MDD and CTRL. Fasting, independent of group, significantly increased ATP and decreased Pi levels and an overall increase in PME/PDE ratio as marker for membrane turnover was observed. Overall these results indicate reactive changes in cerebral energetics and in membrane phospholipid metabolism in response to fasting. The observed effects did not significantly differ between CTRL and MDD, indicating that neurometabolic adaptation to metabolic stress is preserved in MDD patients.

Background/Objectives High egg consumption is associated with poor glycemic control. Considering the widespread consumption of eggs, it is crucial to determine causality in this association. We tested if egg consumption acutely alters glucose disposal in the absence or presence of saturated fat, which is frequently consumed with eggs. Subjects/Methods In a randomized partial crossover clinical trial, 48 subjects (consuming ≥ 1 egg/week) received two of four isocaloric, macronutrient-matched breakfasts. The groups were defined based on the main ingredient of the breakfasts offered: eggs (EB); saturated fat (SB); eggs and saturated fat (ES); and control, which included a cereal based breakfast (CB). The breakfasts were offered in two testing sessions spaced seven days apart. Six blood samples (pre breakfast (fasting); 30, 60, 90, 120, and 180 minutes post breakfast) were collected to measure glucose and insulin levels. Area under the curves (AUC) were analyzed controlling for the baseline concentrations using mixed-effects models accounting for within-subject dependencies to compare these across breakfast assignments. Results Forty-eight patients (46% males, age 25.8 ± 7.7 years, BMI 25.7 ± 4.6 kg/m2) were included. Neither EB, SB nor ES was associated with a significant difference in AUC of glucose or insulin compared to CB (p > 0.1). Conclusions Acutely, consumption of egg breakfast with or without accompanying saturated fat does not adversely affect glucose disposal in healthy adults. While this is reassuring for continued egg consumption, a long-term evaluation of egg intake with or without saturated fat would be the next step.

Using a multicatheterized pig model, we identified the portal-drained viscera as the main releasing compartment of the short-chain fatty acids acetate, propionate, butyrate, isovalerate, and valerate in the fasted and postprandial states. Low hepatic acetate metabolism resulted in a high splanchnic release, whereas all other SCFAs were extensively cleared resulting in low but significant splanchnic releases. Muscle and kidneys are the main peripheral SCFA metabolizing organs during fasting and in the postprandial state.

This study aimed to investigate the effects of blood glucose control and the kidneys' functions, depending on fasting, in the streptozotocin-induced diabetes model in rats via TNF-α, NLRP-3, TGF-β1 and VCAM-1 mRNA expression in the present study. 32 Wistar albino rats were allocated randomly into four main groups; H (Healthy, n = 6), HF (Healthy fasting, n = 6), D (Diabetes, n = 10), DF (Diabetes and fasting, n = 10). Blood glucose and HbA1c levels significantly increased in the D group compared to the healthy ones (p 0.05). However, the fasting period significantly improved blood glucose and HbA1c levels 14 days after STZ induced diabetes in rats compared to the D group. Similar findings we obtained for serum (BUN-creatinine) and urine samples (creatinine and urea levels). STZ induced high glucose levels significantly up-regulated TNF-α, NLRP-3, TGF-β1 and VCAM-1 mRNA expression and fasting significantly decreased these parameters when compared to diabetic rats. Histopathological staining also demonstrated the protective effects of fasting on diabetic kidney tissue. In conclusion, intermittent fasting regulated blood glucose level as well as decreasing harmful effects of diabetes on kidney tissue. The fasting period significantly decreased the hyperglycemia-related inflammatory cytokine damage on kidneys and also reduced apoptosis in favor of living organisms.

BackgroundThe purpose of this study was to examine the correlation between fasting blood glucose and new-onset hypertension and examine any synergistically effect modification with multiple risk factors.MethodsWe conducted post-hoc analyses of repeated-measures data in the original Dongzhi osteoporosis cohort study. In total, 3985 participants without hypertension aged 25–64 years were included in the current analyses. Generalized estimating equation models were used to assess the relationship between fasting blood glucose and risk of new-onset hypertension after adjusting for pertinent covariates and autocorrelations among siblings.Results393 men (19.4%) and 398 women (20.3%) without hypertension at the baseline developed hypertension by the end of the study period. Compared to lower baseline fasting blood glucose levels (Q1–Q3: ConclusionsHigh fasting blood glucose may be significantly associated with risk of new-onset hypertension in Chinese women, especially in women with higher total cholesterol. Further randomized studies are needed to confirm our findings.

Purpose To assess whether dysglycemia diagnosed during severe acute respiratory syndrome coronavirus 2 pneumonia may become a potential public health problem after resolution of the infection. In an adult cohort with suspected coronavirus disease 2019 (COVID-19) pneumonia, we integrated glucose data upon hospital admission with fasting blood glucose (FBG) in the year prior to COVID-19 and during postdischarge follow-up. Methods From February 25 to May 15, 2020, 660 adults with suspected COVID-19 pneumonia were admitted to the San Raffaele Hospital (Milan, Italy). Through structured interviews/ medical record reviews, we collected demographics, clinical features, and laboratory tests upon admission and additional data during hospitalization or after discharge and in the previous year. Upon admission, we classified participants according to American Diabetes Association criteria as having (1) preexisting diabetes, (2) newly diagnosed diabetes, (3) hyperglycemia not in the diabetes range, or (4) normoglycemia. FBG prior to admission and during follow-up were classified as normal or impaired fasting glucose and fasting glucose in the diabetes range. Results In patients with confirmed COVID (n = 589), the proportion with preexisting or newly diagnosed diabetes, hyperglycemia not in the diabetes range and normoglycemia was 19.6%, 6.7%, 43.7%, and 30.0%, respectively. Patients with dysglycemia associated to COVID-19 had increased markers of inflammation and organs’ injury and poorer clinical outcome compared to those with normoglycemia. After the infection resolved, the prevalence of dysglycemia reverted to preadmission frequency. Conclusions COVID-19–associated dysglycemia is unlikely to become a lasting public health problem. Alarmist claims on the diabetes risk after COVID-19 pneumonia should be interpreted with caution.

Most preconditioning techniques before fat grafting require external manipulation. Since nutrition is the main factor maintaining the balance of lipogenesis and lipolysis, we hypothesized that fasting before undergoing autologous fat grafting may increase lipolysis and reduce adipocyte size, thereby improving the fat graft survival rate. C57BL/6 mice were divided into 24 h starved or fed groups. Adipose tissue lipolysis, adipogenesis, and angiogenesis-related gene expression, in fat from both groups, were analyzed. The volume and weight of the grafted fat at 4–8 weeks postoperatively were measured using micro-computed tomography. Immunohistochemistry staining and mRNA expression analysis were also performed to evaluate the effect of fasting on fat graft survival. Fasting decreased adipocyte size by inducing adipose tissue lipolysis. Adipogenesis-related genes were remarkably downregulated while lipolysis-related genes and angiogenesis inducer genes were significantly upregulated in the starved adipose tissue. The mice grafted with the fat from the 24 h starved group had approximately 20% larger volumes and considerably heavier weights than those from the fed group. Increased viable adipocytes and vessels, and reduced macrophages in the fat grafts obtained from the 24 h starved group were also observed. Fasting for 24 h before harvesting fat increased the retention volume of fat graft by increasing angiogenesis via VEGF induction. Therefore, fasting would be a novel and reliable preconditioning strategy to improve graft survival in autologous fat grafting. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring’s epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 × 10-4), maternal height (P = 1.1 × 10-4), pregnancy weight gain (P = 2.2 × 10-3), prepregnancy alcohol consumption (P = 4.6 × 10-4), and tobacco exposure (P = 1.9 × 10-3) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring’s DNA methylome.

Objectives Peroxisome proliferator activated receptor gamma (PPARγ) agonists used for the treatment of Diabetes Mellitus (DM), has important roles on the regulation of metabolism including ketogenesis in fasting and low glucose states. Recently PPARγ was proven to have anti-oxidant and anti-inflammatory effects on neuronal cells. Methods In the present study, effects of pioglitazone (PPARγ agonist) on cell survival, energy metabolism and mitochondrial functions were investigated in glucose deprived fasting model applied SH-SY5Y (ATCC/CRL 2266) cell lines. Before and after pioglitazone treatment; energy metabolites (glucose, lactate, ketone (βOHB), lactate dehydrogenase activity), mitochondrial citrate synthase activity and cell viability were investigated. Results and Conclusions PPARγ agonist addition to glucose deprived, ketone added neurons provided positive improvements in energy metabolites (p

BACKGROUND: The human thrifty phenotype is characterized by a greater decrease in 24-h energy expenditure (24EE) during fasting due to relatively higher eucaloric 24EE in sedentary conditions, both of which are indicative of greater propensity to weight gain. Thriftiness is also associated with a smaller increase in 24EE (i.e., reduced adaptive thermogenesis) during overfeeding. OBJECTIVES: We investigated whether short-term measures of adaptive thermogenesis during overfeeding with low/normal/high protein content characterize thriftiness. METHODS: In this secondary cross-sectional analysis of a single-arm crossover study, 24EE was measured using whole-room indirect calorimetry during energy balance, fasting, and different overfeeding conditions (low/3% protein, high/30% protein, and 3 normal/20% protein diets) with 200% of eucaloric requirements in 77 healthy individuals [63 men; BMI (in kg/m(2)): 26.4 ± 4.3; body fat by DXA: 27.7% ± 9.4%, mean ± SD] with normal glucose regulation. Relations between the 24EE during energy balance (adjusted for body composition) and 24EE during each overfeeding diet were analyzed using separate linear regression models. Participants were arbitrarily categorized as thrifty/spendthrift based on the median value (−177 kcal/d) of the difference in 24EE between fasting and energy balance conditions. RESULTS: Differences in 24EE during low/high-protein overfeeding diets (regression line slope = 0.76 and 0.68, respectively, both P 0.05 compared with slope = 1) were dependent on baseline 24EE during energy balance. Specifically, individuals with higher eucaloric 24EE (thriftier phenotype) showed smaller increases in 24EE during protein-imbalanced overfeeding. Analyzed by group, thrifty individuals had smaller increases in 24EE by 42 and 237 kcal/d during low- and high-protein overfeeding, respectively, compared with spendthrift individuals who showed greater increases in 24EE by 100 and 302 kcal/d (P ≤ 0.03 compared with thrifty group). CONCLUSIONS: During acute overfeeding conditions with low/high-protein content, thrifty participants have limited capacity to increase 24EE, indicating that impaired adaptive thermogenesis during protein-imbalanced diets further characterizes the thrifty phenotype and its susceptibility to weight gain. This trial was registered at clinicalTrials.gov as NCT00523627.