Search Results (56)

Background/Objectives: The consumption of fructose-sweetened beverages, especially when combined with a high-fat (HF) diet, substantially contributes to obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease. Ectopic fat accumulation in skeletal muscles is a critical factor in the development of insulin resistance, a key feature of these metabolic disorders. We aimed to investigate the effects of the rare sugar, d-allulose, on fructose-induced insulin resistance. Methods: Male Wistar rats were randomly assigned to fructose-free control diet (CD), HF/fructose-free diet (HF), or HF/fructose diet (HFF) groups. After 4 weeks, an intraperitoneal glucose tolerance test (IPGTT) was performed, followed by a two-step hyperinsulinemic–euglycemic clamp (HE-clamp) test at 5 weeks. Blood, skeletal muscle, and liver samples were collected after 6 weeks, and triglyceride (TG) levels were measured. Additionally, Western blot was performed on skeletal muscle samples. The same protocol was repeated for the HFF group supplemented with either 5% d-allulose or 5% cellulose. Results: Compared to the CD and HF groups, the HFF group exhibited increased blood glucose levels during the IPGTT and greater systemic and skeletal muscle insulin resistance in the HE-clamp. Furthermore, plasma, liver, and muscle TG levels were significantly elevated in the HFF group. However, d-allulose supplementation improved insulin resistance in the HFF group and reduced blood, liver, and muscle TG levels. Additionally, insulin-stimulated AKT phosphorylation and acetyl-CoA carboxylase phosphorylation were enhanced in the skeletal muscle following d-allulose administration. Conclusions: d-allulose may improve insulin resistance by reducing TG accumulation in the skeletal muscle, potentially independent of its anti-obesity properties. Full article

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain. Quantifiable amounts of NAA are also present in the blood, but its role in the peripheral tissues is largely unknown. First, we determined the acute effects of insulin administration on NAA concentrations; second, we assessed whether circulating NAA levels associate with markers of central and peripheral insulin sensitivity. A total of 24 persons living with obesity and 19 healthy, lean controls, without neurological disorders, underwent a euglycemic hyperinsulinemic clamp combined with fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) imaging of the brain, abdomen, and femoral area. Plasma concentrations of NAA were measured at baseline and ~2 h into the clamp using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS-MS). Glucose uptake (GU) rates were analysed using a fractional uptake rate. Serum acetate levels were also assessed using nuclear magnetic resonance (NMR) metabolomics. From baseline to steady-state, insulin levels increased from a mean level of 66 to 447 pmol/L (p < 0.0001). Over this period, circulating NAA concentrations decreased by 5% (p = 0.01), similarly in both groups. The change in NAA was inversely related with the change in plasma acetate (r = −0.36, p = 0.048). Circulating NAA was associated with waist–hip ratio (rho = −0.54, p = 0.0002), steady-state free fatty acids (rho = −0.44, p = 0.003), and directly with HDL cholesterol (rho = 0.54, p = 0.0002), adiponectin (rho = 0.48, p = 0.003), and whole-body insulin sensitivity (rho = 0.34, p = 0.03). Circulating NAA was directly related with skeletal muscle (rho = 0.42, p = 0.01) and visceral adipose tissue GU (rho = 0.41, p = 0.02). Insulin administration leads to a small decrease in circulating NAA levels, and NAA associates consistently with markers of insulin sensitivity. While plasma NAA may be relevant to aspects of whole-body homeostasis, mechanistic insights are needed. Full article

Background/Objectives: Previous studies reported impairments in insulin secretion during different stages of type 1 diabetes (T1D), while data regarding insulin sensitivity and immunological changes are still controversial. We analyzed the following: (a) insulin secretion, (b) insulin sensitivity, and (c) pro-inflammatory interleukin-17 (IL-17) levels in peripheral blood in 17 healthy first-degree relatives in stage 1 (FDRs1) (GAD⁺, IA2⁺), 34 FDRs in stage 0 (FDRs0) (GAD⁻, IA2A⁻), 24 recent-onset T1D (R-T1D) patients in the insulin-requiring state (IRS), 10 in clinical remission (CR), and 18 healthy unrelated controls (HC). Methods: Insulin secretion was evaluated by an IVGTT and a glucagon stimulation test, expressed as a first-phase insulin response (FPIR) and a basal/stimulated C-peptide. Insulin sensitivity was tested by the euglycemic hyperinsulinemic clamp, expressed as an M value. Results: FDRs1 had a lower FPIR than FDRs0 (p < 0.05) and HC (p < 0.001) but higher than RT1D-IRS (p < 0.001) and RT1D-CR (p < 0.01). Moreover, FDRs1 had lower basal/stimulated C-peptide than FDRs0 (p < 0.01/p < 0.05) and HC (p < 0.001/p = 0.001) but higher levels than RT1D-IRS (p < 0.001/p < 0.001). However, the M value was similar among FDRs1, FDRs0, and HC (p = 1.0) but higher than RT1D-IRS (p < 0.001) and RT1D-CR (p < 0.01), while RT1D-IRS and RT1D-CR had lower M than HC (p < 0.001; p < 0.001; respectively). FDRs1 had higher IL-17 than FDRs0 (p < 0.001) and HC (p < 0.05). RT1D-IRS had higher IL-17 than FDRs0 (p < 0.001) and HC (p < 0.001), which was similar to RT1D-CR vs. FDRs0 (p < 0.001) and HC (p < 0.05). Conclusions: Early changes in pre-T1D might involve an initial decline of insulin secretion associated with a pro-inflammatory attack, which does not influence insulin sensitivity, whereas later, insulin sensitivity deterioration seems to be associated with the prominent reduction in insulin secretion. Full article

Background: Bariatric surgery is known to induce weight loss and diabetes remission in patients with type 2 diabetes (T2D), but the exact mechanism of glycemic normalization needs to be defined. Methods: The study included patients with BMI ≥ 35 kg/m², obesity history ≥ 10 years, and planned bariatric surgery. At baseline and 3 and 6 months after surgery, all patients underwent anthropometric measurements, body composition and blood tests (including insulin, glucagon, and incretins during oral glucose tolerance test (OGTT)), and hyperinsulinemic euglycemic clamp tests. Diabetes remission was defined if the person reached HbA1c < 6.5% after surgery and glucose-lowering therapy withdrawal. Results: The study included 86 patients, divided into groups with no diabetes (control group, n = 44) and T2D (n = 42). Most patients with T2D reached normoglycemia at 6 months. BMI and insulin resistance (according to M-index) decreased in T2D group comparably to people without diabetes. At 6 months, people with T2D at baseline had less insulin and GLP-1 secretion and higher glucagon level during OGTT when compared to the control group. Conclusions: We conclude that weight and insulin resistance reduction is sufficient for T2D remission. The absence of insulin, glucagon, and incretin restoration is not crucial for the glucose metabolism in the short-term, but it may explain the relapse of T2D years after bariatric surgery. Full article

8-oxoguanine DNA glycosylase-1 (OGG1) is a DNA glycosylase mediating the first step in base excision repair which removes 7,8-dihydro-8-oxoguanine (8-oxoG) and repairs oxidized nuclear and mitochondrial DNA. Previous studies showed that OGG1 deficiency results in an increased susceptibility to high-fat diet (HFD)-induced obesity and metabolic dysfunction in mice, suggesting a crucial role of OGG1 in metabolism. However, the tissue-specific mechanisms of how OGG1 deficiency leads to insulin resistance is unknown. Thus, in the current study, we used a hyperinsulinemic-euglycemic clamp to evaluate in-depth glucose metabolism in male wild-type (WT) mice and Ogg1−/− (Ogg1-KO) mice fed an HFD. Ogg1-KO mice fed HFD were more obese, with significantly lower hepatic insulin action compared to WT/HFD mice. Targeting human OGG1 to mitochondria protected against HFD-induced obesity, insulin resistance, oxidative mitochondrial DNA damage in the liver and showed decreased expression of liver gluconeogenic genes in Ogg1-KO mice, suggesting a putative protective mechanism. Additionally, several subunits of oxidative phosphorylation protein levels were noticeably increased in Ogg1-KO/Tg compared to Ogg1-KO mice fed an HFD which was associated with improved insulin signaling. Our findings demonstrate the crucial role of mitochondrial hOGG1 in HFD-induced insulin resistance and propose several protective mechanisms which can further direct the development of therapeutic treatment. Full article

Aims: Various dietary risk factors for type 2 diabetes have been identified. A short assessment of dietary patterns related to the risk for type 2 diabetes mellitus may be relevant in clinical practice given the largely preventable nature of the disease. The aim of this study was to investigate the reproducibility of a short food frequency questionnaire based on available knowledge of diabetes-related healthy diets. In addition, we aimed to investigate whether a Diabetes Dietary Quality Index based on this questionnaire was related to metabolic risk factors, including measures of beta cell function and insulin sensitivity. Methods: A short food frequency questionnaire was composed by selecting fourteen questions (representing eight dietary factors) from existing food frequency questionnaires on the basis of their reported relationship with diabetes risk. Healthy participants (N = 176) from a Dutch family study completed the questionnaire and a subgroup (N = 123) completed the questionnaire twice. Reproducible items from the short questionnaire were combined into an index. The association between the Diabetes Dietary Quality index and metabolic risk factors was investigated using multiple linear regression analysis. Measures of beta cell function and insulin sensitivity were derived from a mixed meal test and an euglycemic–hyperinsulinemic and modified hyperglycemic clamp test. Results: Our results show that this new short food frequency questionnaire is reliable (Intraclass Correlations ranged between 0.5 and 0.9). A higher Diabetes Dietary Quality index score was associated with lower 2 h post-meal glucose (β −0.02, SE 0.006, p < 0.05), HbA1c (β −0.07, SE 0.02, p < 0.05), total cholesterol, (β −0.02, SE 0.07, p < 0.05), LDL cholesterol, (β −0.19, SE 0.07, p < 0.05), fasting (β −0.4, SE 0.16, p < 0.05) and post-load insulin, (β −3.9, SE 1.40, p < 0.05) concentrations and the incremental AUC of glucose during MMT (β −1.9, SE 0.97, p < 0.05). The scores obtained for the oral glucose insulin sensitivity-derived mixed meal test were higher in subjects who scored higher on the Diabetes Dietary Quality index (β 0.89, 0.39, p < 0.05). In contrast, we found no significant associations between the Diabetes Dietary Quality index and clamp measures of beta cell function. Conclusions: We identified a questionnaire-derived Diabetes Dietary Quality index that was reproducible and inversely associated with a number of type 2 diabetes mellitus and metabolic risk factors, like 2 h post-meal glucose, Hba1c and LDL, and total cholesterol. Once relative validity has been established, the Diabetes Dietary Quality index could be used by health care professionals to identify individuals with diets adversely related to development of type 2 diabetes. Full article

Introduction: Health systems are confronted with not only the growing worldwide childhood obesity epidemic but also associated comorbidities. These subsequently cause variations in distinct metabolic pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this evidence map is to systematically evaluate the evidence and to identify research gaps on glucagon-induced amino acid (AA) turnover and its metabolic interaction with MASLD. Methodology: A systematic literature search was conducted up to April 2023 in three electronic databases. Studies were required to include at least two of the main research areas, glucagon, AA metabolism and MASLD. Two independent reviewers screened titles and abstracts according to prespecified eligibility criteria, as well as full-text articles. Results are summarized in tables stratified by human and animal studies and study population age. Results: Thirty-four references were ultimately included. The publication years dated back to 1965 showed a great increase from 2012 to 2023. In total, there were 19 animal studies and 15 human studies. Among the human studies, except for two studies in adolescents, all the studies were conducted in adults. In human studies, the methods used to evaluate metabolic changes differed among hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests. Thirteen studies focused on the metabolic effects of MASLD, while only two studies explored the interaction between MASLD, glucagon and AA metabolism in humans. The other 19 studies focused on metabolomics, beta cell function or just one topic of a research area and not on interactions between one another. Conclusion: Research on the interaction between MASLD, glucagon and AA metabolism in humans is sparse and complete lacking in pediatrics. Furthermore, longitudinal studies with a focus on hyperglucagonemia independent of diabetes but related to MASLD present an unambiguous research gap. Full article

Context/Objective: In order to better understand which metabolic differences are related to insulin resistance in metabolic syndrome (MetSyn), we used hyperinsulinemic–euglycemic (HE) clamps in individuals with MetSyn and related peripheral insulin resistance to circulating biomarkers. Design/Methods: In this cross-sectional study, HE-clamps were performed in treatment-naive men (n = 97) with MetSyn. Subjects were defined as insulin-resistant based on the rate of disappearance (Rd). Machine learning models and conventional statistics were used to identify biomarkers of insulin resistance. Findings were replicated in a cohort with n = 282 obese men and women with (n = 156) and without (n = 126) MetSyn. In addition to this, the relation between biomarkers and adipose tissue was assessed by nuclear magnetic resonance imaging. Results: Peripheral insulin resistance is marked by changes in proteins related to inflammatory processes such as IL-1 and TNF-receptor and superfamily members. These proteins can distinguish between insulin-resistant and insulin-sensitive individuals (AUC = 0.72 ± 0.10) with MetSyn. These proteins were also associated with IFG, liver fat (rho 0.36, p = 1.79 × 10⁻⁹) and visceral adipose tissue (rho = 0.35, p = 6.80 × 10⁻⁹). Interestingly, these proteins had the strongest association in the MetSyn subgroup compared to individuals without MetSyn. Conclusions: MetSyn associated with insulin resistance is characterized by protein changes related to body fat content, insulin signaling and pro-inflammatory processes. These findings provide novel targets for intervention studies and should be the focus of future in vitro and in vivo studies. Full article

Menopause is characterized by a reduction in sex hormones in women and is associated with metabolic changes, including fatty liver and insulin resistance. Lifestyle changes, including a balanced diet and physical exercise, are necessary to prevent these undesirable changes. Strength training (ST) has been widely used because of the muscle and metabolic benefits it provides. Our study aims to evaluate the effects of ST on hepatic steatosis and insulin resistance in ovariectomized mice fed a high-fat diet (HFD) divided into four groups as follows: simulated sedentary surgery (SHAM-SED), trained simulated surgery (SHAM-EXE), sedentary ovariectomy (OVX-SED), and trained ovariectomy (OVX-EXE). They were fed an HFD for 9 weeks. ST was performed thrice a week. ST efficiently reduced body weight and fat percentage and increased lean mass in OVX mice. Furthermore, ST reduced the accumulation of ectopic hepatic lipids, increased AMPK phosphorylation, and inhibited the de novo lipogenesis pathway. OVX-EXE mice also showed a better glycemic profile, associated with greater insulin sensitivity identified by the euglycemic–hyperinsulinemic clamp, and reduced markers of hepatic oxidative stress compared with sedentary animals. Our data support the idea that ST can be indicated as a non-pharmacological treatment approach to mitigate metabolic changes resulting from menopause. Full article

Recent studies have shown that obesity and insulin resistance are associated with increased insulin-stimulated glucose uptake (GU) in the brain. Thus, insulin sensitivity seems to work differently in the brain compared to the peripheral tissues like skeletal muscles, but the underlying mechanisms remain unknown. Regular exercise training improves skeletal muscle and whole-body insulin sensitivity. However, the effect of exercise on glucose metabolism in the brain and internal organs is less well understood. The CROSRAT study aims to investigate the effects of exercise training on brain glucose metabolism and inflammation in a high-fat diet-induced rat model of obesity and insulin resistance. Male Sprague Dawley rats (n = 144) are divided into nine study groups that undergo different dietary and/or exercise training interventions lasting 12 to 24 weeks. Insulin-stimulated GU from various tissues and brain inflammation are investigated using [¹⁸F]FDG-PET/CT and [¹¹C]PK11195-PET/CT, respectively. In addition, peripheral tissue, brain, and fecal samples are collected to study the underlying mechanisms. The strength of this study design is that it allows examining the effects of both diet and exercise training on obesity-induced insulin resistance and inflammation. As the pathophysiological changes are studied simultaneously in many tissues and organs at several time points, the study provides insight into when and where these pathophysiological changes occur. Full article

Heat-stressed lactating dairy cattle exhibit unique metabolic symptoms, many of which are undoubtedly involved in heat-induced subfertility. Because of its known systemic effects, we hypothesized that γ-aminobutyric acid (GABA) participates in the regulation of insulin and progesterone during heat stress. Multiparous lactating Holstein cows (n = 6) were studied during four experimental periods: (1) thermoneutral (TN; d 1–5), (2) TN + hyperinsulinemic–hypoglycemic clamp (d 6–10), (3) heat stress (HS; d 16–20), and (4) HS + euglycemic clamp (d 21–25). Blood samples were collected once daily via coccygeal venipuncture into heparinized evacuated tubes. Analysis of GABA concentrations from all four treatment periods yielded no differences. In direct comparison to TN concentrations, plasma GABA tended to decrease during the HS period (16.57 ± 2.64 vs. 13.87 ± 2.28 ng/mL, respectively, p = 0.06). Both milk production and plasma insulin were moderately correlated with plasma GABA (r = 0.35, p < 0.01; r = −0.32, p < 0.01). Plasma progesterone was correlated with plasma GABA concentrations during TN but not HS periods. These results are the first to indicate that peripheral GABA could be involved in the regulation of factors known to affect production and reproduction during heat stress. More research is needed to determine its precise role(s). Full article

Accurate positron emission tomography (PET) data quantification relies on high-quality input plasma curves, but venous blood sampling may yield poor-quality data, jeopardizing modeling outcomes. In this study, we aimed to recover sub-optimal input functions by using information from the tail (5th–100th min) of curves obtained through the frequent sampling protocol and an input recovery (IR) model trained with reference curves of optimal shape. Initially, we included 170 plasma input curves from eight published studies with clamp [¹⁸F]-fluorodeoxyglucose PET exams. Model validation involved 78 brain PET studies for which compartmental model (CM) analysis was feasible (reference (ref) + training sets). Recovered curves were compared with original curves using area under curve (AUC), max peak standardized uptake value (maxSUV). CM parameters (ref + training sets) and fractional uptake rate (FUR) (all sets) were computed. Original and recovered curves from the ref set had comparable AUC (d = 0.02, not significant (NS)), maxSUV (d = 0.05, NS) and comparable brain CM results (NS). Recovered curves from the training set were different from the original according to maxSUV (d = 3) and biologically plausible according to the max theoretical K1 (53//56). Brain CM results were different in the training set (p < 0.05 for all CM parameters and brain regions) but not in the ref set. FUR showed reductions similarly in the recovered curves of the training and test sets compared to the original curves (p < 0.05 for all regions for both sets). The IR method successfully recovered the plasma inputs of poor quality, rescuing cases otherwise excluded from the kinetic modeling results. The validation approach proved useful and can be applied to different tracers and metabolic conditions. Full article

A short-term high-calorie high-fat diet (HCHFD) impairs insulin sensitivity in non-obese South Asian but not Caucasian men; however, the effect of short-term HCHFD on insulin sensitivity in East Asians is unknown. We recruited 21 healthy non-obese Japanese men to evaluate metabolic parameters and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus a 45% energy excess with dairy fat supplementation. We evaluated tissue-specific insulin sensitivity and metabolic clearance rate of insulin (MCRI) using a two-step hyperinsulinemic euglycemic clamp, glucose tolerance using the glucose tolerance test, and measured ectopic fat in muscle and the liver using ¹H-magnetic resonance spectroscopy. The primary outcome of this study was insulin sensitivity measured by the clamp study. The secondary/exploratory outcomes were other metabolic changes. After HCHFD, levels of circulating lipopolysaccharide binding protein (LBP), a marker of endotoxemia, increased by 14%. In addition, intramyocellular lipid levels in the tibialis anterior and soleus and intrahepatic lipid levels increased by 47%, 31%, and 200%, respectively. Insulin sensitivity decreased by 4% in muscle and 8% in liver. However, even with reduced insulin sensitivity, glucose metabolism was maintained by increased serum insulin concentrations due to lower MCRI and higher endogenous insulin secretion during the clamp. Glucose levels during the meal tolerance test were comparable before and after HCHFD. In conclusion, short-term HCHFD impaired insulin sensitivity in the muscle and livers of non-obese Japanese men with increased LBP and ectopic fat accumulation. Elevated insulin levels from modulated insulin secretion and clearance might contribute to the maintenance of normal glucose metabolism during the clamp and meal tolerance test. Full article

Sex-specific differences exist in insulin secretion (ISec) and sensitivity (IS) in humans. However, current fasting indices used to estimate them, such as HOMA and QUICKI, are not sex-specific. We aimed to develop sex-specific models to improve the prediction of ISec and IS by fasting measures in adults with overweight/obesity. A post hoc analysis was conducted on baseline data of two clinical trials completed between 2010 and 2020 (37 men and 61 postmenopausal women, 45–73 years, BMI > 25 kg/m², without chronic disease). Glucose-induced insulin or C-peptide secretions and IS were measured using gold-standard Botnia-clamps, which is a 1 h intravenous glucose tolerance test followed by a 3 h hyperinsulinemic–euglycemic clamp. Stepwise regression analysis using anthropometric and fasting plasma glucose, insulin, and lipoprotein-related measures was used to predict ISec and IS. First-phase, second-phase and total glucose-induced ISec were predicted by a combination of fasting plasma insulin and apoB without or with plasma glucose, triglyceride, and waist circumference in women (R² = 0.58–0.69), and by plasma insulin and glucose without or with BMI and cholesterol in men (R² = 0.41–0.83). Plasma C-peptide, alone in men or followed by glucose in women, predicted C-peptide secretion. IS was predicted by plasma insulin and waist circumference, followed by HDL-C in women (R² = 0.57) or by glucose in men (R² = 0.67). The sex-specific models agreed with the Botnia-clamp measurements of ISec and IS more than with HOMA or QUICKI. Sex-specific models incorporating anthropometric and lipoprotein-related parameters allowed better prediction of ISec and IS in subjects with overweight or obesity than current indices that rely on glucose and insulin alone. Full article

Excess iron is known to trigger adipose tissue dysfunction and insulin resistance. Circulating markers of iron status have been associated with obesity and adipose tissue in cross-sectional studies. We aimed to evaluate whether iron status is linked to changes in abdominal adipose tissue longitudinally. Subcutaneous abdominal tissue (SAT) and visceral adipose tissue (VAT) and its quotient (pSAT) were assessed using magnetic resonance imaging (MRI), at baseline and after one year of follow-up, in 131 (79 in follow-up) apparently healthy subjects, with and without obesity. Insulin sensitivity (euglycemic– hyperinsulinemic clamp) and markers of iron status were also evaluated. Baseline serum hepcidin (p = 0.005 and p = 0.002) and ferritin (p = 0.02 and p = 0.01)) were associated with an increase in VAT and SAT over one year in all subjects, while serum transferrin (p = 0.01 and p = 0.03) and total iron-binding capacity (p = 0.02 and p = 0.04) were negatively associated. These associations were mainly observed in women and in subjects without obesity, and were independent of insulin sensitivity. After controlling for age and sex, serum hepcidin was significantly associated with changes in subcutaneous abdominal tissue index (iSAT) (β = 0.406, p = 0.007) and visceral adipose tissue index (iVAT) (β = 0.306, p = 0.04), while changes in insulin sensitivity (β = 0.287, p = 0.03) and fasting triglycerides (β = −0.285, p = 0.03) were associated with changes in pSAT. These data indicated that serum hepcidin are associated with longitudinal changes in SAT and VAT, independently of insulin sensitivity. This would be the first prospective study evaluating the redistribution of fat according to iron status and chronic inflammation. Full article