From classical dualistic antagonism to hormone synergy: potential of overlapping action of glucagon, insulin and GLP-1 for the treatment of diabesity.

The increasing prevalence of 'diabesity', a combination of type 2 diabetes and obesity, poses a significant global health challenge. Unhealthy lifestyle factors, including poor diet, sedentary behaviour, and high stress levels, combined with genetic and epigenetic factors, contribute to the diabesity epidemic. Diabesity leads to various significant complications such as cardiovascular diseases, stroke, and certain cancers. Incretin-based therapies, such as GLP-1 receptor agonists and dual hormone therapies, have shown promising results in improving glycaemic control and inducing weight loss. However, these therapies also come with certain disadvantages, including potential withdrawal effects. This review aims to provide insights into the cross-interactions of insulin, glucagon, and GLP-1, revealing the complex hormonal dynamics during fasting and postprandial states, impacting glucose homeostasis, energy expenditure, and other metabolic functions. Understanding these hormonal interactions may offer novel hypotheses in the development of 'anti-diabesity' treatment strategies. The article also explores the question of the antagonism of insulin and glucagon, providing insights into the potential synergy and hormonal overlaps between these hormones.

Comparator Data Characteristics and Testing Procedures for the Clinical Performance Evaluation of Continuous Glucose Monitoring Systems.

Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems.

Impact of a 4-week intensive track and field training intervention on glycaemia in adolescents with type 1 diabetes: The ChilDFiT1 study.

AIM: To investigate the safety and efficacy of track and field training compared with intensification of insulin treatment only in adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS: Eighteen adolescents (seven females) with T1D were included (age 15.1 ± 1.1 years, HbA1c 7.3% ± 1.0% [56.3 ± 10.9 mmol/mol]). After a 4-week observational control phase, participants were randomized to either stand-alone intensive glycaemic management (IT; telemedicine or on-site visits, three times/week) or additionally performed track and field exercise (EX; three 60-minute sessions/week) for 4 weeks. Glycaemia was assessed via continuous glucose monitoring during observational control and intervention phases. RESULTS: Time in range (70-180 mg/dL; 3.9-10.0 mmol/L) significantly improved from the observational control phase to the exercise intervention phase in EX (69% ± 13% vs. 72% ± 11%, P = .049), but not in IT (59% ± 22% vs. 62% ± 16%, P = .399). Time below range 1 (54-69 mg/dL; < 3.9 mmol/L) improved in IT (3.1% ± 1.9% vs. 2.0% ± 0.8%, P = .017) and remained stable in EX (2.0% ± 1.7 vs. 1.9% ± 1.1%, P = .999). The EX group's HbA1c ameliorated preintervention to postintervention (mean difference: ΔHbA1c -0.19% ± 0.17%, P = .042), which was not seen within the IT group (ΔHbA1c -0.16% ± 0.37%, P = .40). Glucose standard deviation was reduced significantly in EX (55 ± 11 vs. 51 ± 10 mg/dL [3.1 ± 0.6 vs. 2.8 ± 0.6 mmol/L], P = .011), but not in IT (70 ± 24 vs. 63 ± 18 mg/dL [3.9 ± 1.3 vs. 3.5 ± 1.0 mmol/L], P = .186). CONCLUSION: Track and field training combined with intensive glycaemic management improved glycaemia in adolescents with T1D, which was not observed in the non-exercise group.

Effect of combined aerobic-resistance training and subsequent detraining on brain-derived neurotrophic factor (BDNF) and depression in women with type 2 diabetes mellitus: A randomized controlled trial.

AIMS: In this study, we assessed the effects of a 12-week combined aerobic-resistance training and subsequent detraining on Beck Depression Inventory (BDI) score and mediating role of BDNF and also investigated whether exercise-induced alterations are maintained following a short period of detraining in women with type 2 diabetes (T2D). MATERIALS AND METHODS: Thirty-four women with T2D were randomly assigned to experimental or control group (age: 60.6 ± 6.3, body mass index (BMI): 30.2 ± 1.3 kg/m2 , HbA1c: 8.09 ± 0.73%). The exercise training comprised of combined aerobic-resistance programme (50%-70% heart rate reserve for aerobic exercise, and 50%-70% 1 repetition maximum for resistance exercise, respectively) performed three sessions per week over 12 weeks. The intervention period was followed by an 8-week detraining period. Data were collected at baseline and also following exercise intervention and detraining. Data were analysed by linear mixed model at p < 0.05. RESULTS: After 12 weeks of combined exercise training and 8 weeks of detraining, there was a significant difference in BDNF (0.08; 95% confidence interval [CI] = 0.07-0.10; p = 0.001), fasting blood glucose (FBG) (-45.41; CI = -50.83, -39.98; p = 0.001), insulin (-6.47; CI = -7.04, -5.9; p = 0.001), HOMA-IR (-3.76; CI = -4.07, -3.45; p = 0.001) and BDI score (-17.17; CI = -20.29, -14.05; p = 0.001) between the experimental and control group. Multiple mediation analysis indicated that BDNF seems to have a mediating role in exercise-induced improvement of depression (p = 0.04). After the detraining period, BDI score remained unchanged and it showed a significant increase compared to before the start of training (p = 0.001). CONCLUSIONS: It may be concluded that exercise training improves depression that is likely to be explained by increased BDNF concentration in TD2. In spite of decreased BDNF concentration following an 8-week detraining, depression score was maintained.

SGLT2 Inhibitors in Long COVID Syndrome: Is There a Potential Role?

The coronavirus disease (COVID)-19 has turned into a pandemic causing a global public health crisis. While acute COVID-19 mainly affects the respiratory system and can cause acute respiratory distress syndrome, an association with persistent inflammatory stress affecting different organ systems has been elucidated in long COVID syndrome (LCS). Increased severity and mortality rates have been reported due to cardiophysiological and metabolic systemic disorders as well as multiorgan failure in COVID-19, additionally accompanied by chronic dyspnea and fatigue in LCS. Hence, novel therapies have been tested to improve the outcomes of LCS of which one potential candidate might be sodium-glucose cotransporter 2 (SGLT2) inhibitors. The aim of this narrative review was to discuss rationales for investigating SGLT2 inhibitor therapy in people suffering from LCS. In this regard, we discuss their potential positive effects-next to the well described "cardio-renal-metabolic" conditions-with a focus on potential anti-inflammatory and beneficial systemic effects in LCS. However, potential beneficial as well as potential disadvantageous effects of SGLT2 inhibitors on the prevalence and long-term outcomes of COVID-19 will need to be established in ongoing research.

(Hybrid) Closed-Loop Systems: From Announced to Unannounced Exercise.

Physical activity and exercise have many beneficial effects on general and type 1 diabetes (T1D) specific health and are recommended for individuals with T1D. Despite these health benefits, many people with T1D still avoid exercise since glycemic management during physical activity poses substantial glycemic and psychological challenges - which hold particularly true for unannounced exercise when using an AID system. Automated insulin delivery (AID) systems have demonstrated their efficacy in improving overall glycemia and in managing announced exercise in numerous studies. They are proven to increase time in range (70-180 mg/dL) and can especially counteract nocturnal hypoglycemia, even when evening exercise was performed. AID-systems consist of a pump administering insulin as well as a CGM sensor (plus transmitter), both communicating with a control algorithm integrated into a device (insulin pump, mobile phone/smart watch). Nevertheless, without manual pre-exercise adaptions, these systems still face a significant challenge around physical activity. Automatically adapting to the rapidly changing insulin requirements during unannounced exercise and physical activity is still the Achilles' heel of current AID systems. There is an urgent need for improving current AID-systems to safely and automatically maintain glucose management without causing derailments - so that going forward, exercise announcements will not be necessary in the future. Therefore, this narrative literature review aimed to discuss technological strategies to how current AID-systems can be improved in the future and become more proficient in overcoming the hurdle of unannounced exercise. For this purpose, the current state-of-the-art therapy recommendations for AID and exercise as well as novel research approaches are presented along with potential future solutions - in order to rectify their deficiencies in the endeavor to achieve fully automated AID-systems even around unannounced exercise.

Speckle-Tracking Analysis of the Right and Left Heart after Peak Exercise in Healthy Subjects with Type 1 Diabetes: An Explorative Analysis of the AppEx Trial.

In eight healthy participants with Type 1 diabetes (T1D) exercise-related dynamic cardiac remodeling was analyzed by performing two-dimensional echocardiography, including deformation analysis of the left-ventricular (LV) global longitudinal strain (LV-GLS), and the deformation pattern of the left atrium (LA) and right ventricle (RV) at rest and post-peak performance on a bicycle. The feasibility echocardiographic speckle-tracking analysis was performed on eight asymptomatic participants with T1D (n = 8, male n = 5, age: 23-65 years). The obtained echocardiographic data were compared for various echocardiographic parameters at rest and post exercise. Across our participating T1D individuals no structural echocardiographic abnormalities of concern could be revealed. All participating T1D subjects showed preserved contractile reserve of the LV and no significant diastolic dysfunction. Significant differences were found for the phasic LA contractile strain pattern at rest and post exercise (p < 0.001), whereby the dynamic RV (p = 0.5839 and p = 0.7419) and LV strain pattern (p = 0.5952) did not reveal significant differences in comparison to resting conditions. This descriptive secondary outcome analysis describes preserved contractile reserve of the LV and elucidates dynamic modification of the phasic LA contractile deformation pattern in asymptomatic T1D individuals after exhaustive exercise on a bicycle.

High Intensity Interval Training can Ameliorate Hypothalamic Appetite Regulation in Male Rats with Type 2 Diabetes: The Role of Leptin.

Disruption of leptin (LEP) signaling in the hypothalamus caused by type 2 diabetes (T2D) can impair appetite regulation. The aim of this study was to investigate whether the improvement in appetite regulation induced by high-intensity interval training (HIIT) in rats with T2D can be mediated by LEP signaling. In this study, 20 male Wister rats were randomly assigned to one of four groups: CO (non-type 2 diabetes control), T2D (type 2 diabetes), EX (non-type 2 diabetes exercise), and T2D + EX (type 2 diabetes + exercise).To induce T2D, a combination of a high-fat diet for 2 months and a single dose of streptozotocin (35 mg/kg) was administered. Rats in the EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of their maximum velocity (Vmax). Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), serum levels of insulin (INS) and LEP (LEPS) as well as hypothalamic expression of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin cocaine (POMC), amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1) were assessed. ANOVA and Tukey post hoc tests were used to compare the results between the groups. The levels of LEPS and INS, as well as the levels of LEP-R, JAK-2, STAT-3, POMC, and CART in the hypothalamus were found to be higher in the T2D + EX group compared to the T2D group. On the other hand, the levels of HOMA-IR, NPY, AGRP, SOCS3, and FOXO1 were lower in the T2D + EX group compared to the T2D group (P < 0.0001). The findings of this study suggest that HIIT may improve appetite regulation in rats with T2D, and LEP signaling may play a crucial role in this improvement. Graphical abstract (leptin signaling in the hypothalamus), Leptin (LEP), Leptin receptor (LEP-R), Janus kinase 2 (JAK2), Signal transducer and activator of transcription 3 (STAT3), expressing Neuropeptide Y (NPY), Agouti-related protein (AGRP), anorexigenic neurons (expressing pro-opiomelanocortin cocaine (POMC), Amphetamine-related transcript (CART), suppressor of cytokine signaling (SOCS3), forkhead box protein O1 (FOXO1).

Comparative Analysis of Predictive Interstitial Glucose Level Classification Models.

BACKGROUND: New methods of continuous glucose monitoring (CGM) provide real-time alerts for hypoglycemia, hyperglycemia, and rapid fluctuations of glucose levels, thereby improving glycemic control, which is especially crucial during meals and physical activity. However, complex CGM systems pose challenges for individuals with diabetes and healthcare professionals, particularly when interpreting rapid glucose level changes, dealing with sensor delays (approximately a 10 min difference between interstitial and plasma glucose readings), and addressing potential malfunctions. The development of advanced predictive glucose level classification models becomes imperative for optimizing insulin dosing and managing daily activities. METHODS: The aim of this study was to investigate the efficacy of three different predictive models for the glucose level classification: (1) an autoregressive integrated moving average model (ARIMA), (2) logistic regression, and (3) long short-term memory networks (LSTM). The performance of these models was evaluated in predicting hypoglycemia (<70 mg/dL), euglycemia (70-180 mg/dL), and hyperglycemia (>180 mg/dL) classes 15 min and 1 h ahead. More specifically, the confusion matrices were obtained and metrics such as precision, recall, and accuracy were computed for each model at each predictive horizon. RESULTS: As expected, ARIMA underperformed the other models in predicting hyper- and hypoglycemia classes for both the 15 min and 1 h horizons. For the 15 min forecast horizon, the performance of logistic regression was the highest of all the models for all glycemia classes, with recall rates of 96% for hyper, 91% for norm, and 98% for hypoglycemia. For the 1 h forecast horizon, the LSTM model turned out to be the best for hyper- and hypoglycemia classes, achieving recall values of 85% and 87% respectively. CONCLUSIONS: Our findings suggest that different models may have varying strengths and weaknesses in predicting glucose level classes, and the choice of model should be carefully considered based on the specific requirements and context of the clinical application. The logistic regression model proved to be more accurate for the next 15 min, particularly in predicting hypoglycemia. However, the LSTM model outperformed logistic regression in predicting glucose level class for the next hour. Future research could explore hybrid models or ensemble approaches that combine the strengths of multiple models to further enhance the accuracy and reliability of glucose predictions.

Efficacy of Fasting in Type 1 and Type 2 Diabetes Mellitus: A Narrative Review.

Over the last decade, studies suggested that dietary behavior modification, including fasting, can improve metabolic and cardiovascular markers as well as body composition. Given the increasing prevalence of people with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) and the increasing obesity (also in combination with diabetes), nutritional therapies are gaining importance, besides pharmaceutical interventions. Fasting has demonstrated beneficial effects for both healthy individuals and those with metabolic diseases, leading to increased research interest in its impact on glycemia and associated short- and long-term complications. Therefore, this review aimed to investigate whether fasting can be used safely and effectively in addition to medications to support the therapy in T1DM and T2DM. A literature search on fasting and its interaction with diabetes was conducted via PubMed in September 2022. Fasting has the potential to minimize the risk of hypoglycemia in T1DM, lower glycaemic variability, and improve fat metabolism in T1DM and T2DM. It also increases insulin sensitivity, reduces endogenous glucose production in diabetes, lowers body weight, and improves body composition. To conclude, fasting is efficient for therapy management for both people with T1DM and T2DM and can be safely performed, when necessary, with the support of health care professionals.

Leptin Signaling Could Mediate Hippocampal Decumulation of Beta-Amyloid and Tau Induced by High-Intensity Interval Training in Rats with Type 2 Diabetes.

Leptin (LEP) can cross the blood-brain barrier and facilitate cross-talk between the adipose tissue and central nerve system (CNS). This study aimed to investigate the effect of 8-week high-intensity interval training (HIIT) on the LEP signaling in the hippocampus of rats with type 2 diabetes. 20 rats were randomly divided into four groups: (i) control (Con), (ii) type 2 diabetes (T2D), (iii) exercise (EX), and (iv) type 2 diabetes + exercise (T2D + EX). The rats in the T2D and T2D + EX were fed a high-fat diet for two months, then a single dose of STZ (35 mg/kg) was injected to induce diabetes. The EX and T2D + EX groups performed 4-10 intervals of treadmill running at 80-100% of Vmax. Serum and hippocampal levels of LEP as well as hippocampal levels of LEP receptors (LEP-R), Janus kinase 2 (JAK-2), signal transducer and activator of transcription 3 (STAT-3), activated protein kinase (AMP-K), proxy zoster receptor α (PGC-1α), beta-secretase 1 (BACE1), Beta-Amyloid (Aß), Phosphoinositide 3-kinases (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), Glycogen Synthase Kinase 3 Beta (GSK3ß), and hyperphosphorylated tau proteins (TAU) were measured. One-way ONOVA and Tukey post-hoc tests were used to analyze the data. Serum and hippocampal levels of LEP as well as hippocampal levels of LEP-R, JAK-2, STAT-3, AMP-K, PGC1α, PI3K, AKT, and mTOR were increased while hippocampal levels of BACE1, GSK3B, TAU, and Aß were decreased in T2D + EX compared with T2D group. Serum LEP and hippocampal levels of LEP, LEP-R, JAK-2, STAT-3, AMP-K, PGC1α, PI3K, AKT, and mTOR were decreased. Conversely hippocampal levels of BACE1, GSK3B, TAU, and Aß were increased in T2D group compared with CON group. HIIT could improve LEP signaling in the hippocampus of rats with type 2 diabetes and decrease the accumulation of Tau and Aß, which may reduce the risk of memory impairments.

Impact of severe hypoglycaemia requiring hospitalization on mortality in people with type 1 diabetes: A national retrospective observational cohort study.

AIMS: To assess if the risk of all-cause mortality increases in people with type 1 diabetes (T1D) with increasing number of severe hypoglycaemia episodes requiring hospitalization. MATERIALS AND METHODS: We conducted a national retrospective observational cohort study in people with T1D (diagnosed between 2000 and 2018). Clinical, comorbidity and demographic variables were assessed for impact on mortality for people with no, one, two and three or more episodes of severe hypoglycaemia requiring hospitalization. The time to death (all-cause mortality) from the timepoint of the last episode of severe hypoglycaemia was modelled using a parametric survival model. RESULTS: A total of 8224 people had a T1D diagnosis in Wales during the study period. The mortality rate (95% confidence interval [CI]) was 6.9 (6.1-7.8) deaths/ 1000 person-years (crude) and 15.31 (13.3-17.63) deaths/ 1000 person-years (age-adjusted) for those with no occurrence of severe hypoglycaemia requiring hospitalization. For those with one episode of severe hypoglycaemia requiring hospitalization the mortality rate (95% CI) was 24.9 (21.0-29.6; crude) and 53.8 (44.6-64.7) deaths/ 1000 person-years (age-adjusted), for those with two episodes of severe hypoglycaemia requiring hospitalization it was 28.0 (23.1-34.0; crude) and 72.8 (59.2-89.5) deaths/ 1000 person-years (age-adjusted), and for those with three or more episodes of severe hypoglycaemia requiring hospitalization it was 33.5 (30.0-37.3; crude) and 86.3 (71.7-103.9) deaths/ 1000 person years (age-adjusted; P < 0.001). A parametric survival model showed that having two episodes of severe hypoglycaemia requiring hospitalization was the strongest predictor for time to death (accelerated failure time coefficient 0.073 [95% CI 0.009-0.565]), followed by having one episode of severe hypoglycaemia requiring hospitalization (0.126 [0.036-0.438]) and age at most recent episode of severe hypoglycaemia requiring hospitalization (0.917 [0.885-0.951]). CONCLUSIONS: The strongest predictor for time to death was having two or more episodes of severe hypoglycaemia requiring hospitalization.

[Lifestyle: physical activity and training as prevention and therapy of type 2 diabetes mellitus (Update 2023)]. / Lebensstil: körperliche Aktivität und Training in der Prävention und Therapie des Typ 2 Diabetes mellitus (Update 2023).

Lifestyle, in general and particularly regular physical activity, is known to be an important component in the prevention and therapy of type 2 diabetes.To gain substantial health benefits, a minimum of 150 min of moderate or vigorous intense aerobic physical activity and muscle strengthening activities per week should be performed. Additionally, inactivity should be recognized as health hazard and prolonged episodes of sitting should be avoided.Especially exercise is not only efficient in improving glycaemia by lowering insulin resistance and enhance insulin secretion, but to reduce cardiovascular risk. The positive effect of training correlates directly with the amount of fitness gained and lasts only as long as the fitness level is sustained. Exercise training is effective in all age groups and for all genders. It is reversible and reproducible.Standardized, regional and supervised exercise classes are well known to be attractive for adults to reach a sufficient level of health enhancing physical activity. Additionally, based on the large evidence of exercise referral and prescription, the Austrian Diabetes Associations aims to implement the position of a "physical activity adviser" in multi-professional diabetes care. Unfortunately, the implementation of booth-local exercise classes and advisers is missing so far.

Acute Fluid Intake Impacts Assessment of Body Composition via Bioelectrical Impedance Analysis. A Randomized, Controlled Crossover Pilot Trial.

Bioelectrical impedance analysis (BIA) has proven to be particularly useful due to its inexpensive and rapid assessment of total body water and body density. However, recent fluid intake may confound BIA results since equilibration of fluid between intra- and extracellular spaces may take several hours and furthermore, ingested fluids may not be fully absorbed. Therefore, we aimed to evaluate the impact of different fluid compositions on the BIA. A total of eighteen healthy individuals (10 females, mean ± SD age of 23.1 ± 1.8 years) performed a baseline measurement of body composition before they consumed isotonic 0.9% sodium-chloride (ISO), 5% glucose (GLU) or Ringer (RIN) solutions. During the visit of the control arm (CON), no fluid was consumed. Further impedance analyses were conducted every 10 min after the fluid consumption for 120 min. We found statistically significant interactions between the effects of solution ingestion and time for intra- (ICW, p < 0.01) and extracellular water (ECW, p < 0.0001), skeletal muscle mass (SMM, p < 0.001) and body fat mass (FM, p < 0.01), respectively. Simple main effects analysis showed that time had a statistically significant effect on changes in ICW (p < 0.01), ECW (p < 0.01), SMM (p < 0.01) and FM (p < 0.01), while fluid intake did not have a significant effect. Our results highlight the importance of a standardized pre-measurement nutrition, with particular attention to hydration status when using a BIA for the evaluation of body composition.

Effects of Different Fasting Interventions on Cardiac Autonomic Modulation in Healthy Individuals: A Secondary Outcome Analysis of the EDIF Trial.

The impact of a fasting intervention on electrocardiographic (ECG) time intervals and heart rate variability (HRV) is a focus that is scarcely analyzed. The main focus of these secondary outcome data was to describe the impact of a different fasting intervention on ECG and HRV analyses. Twenty-seven healthy individuals participated in this study (11 females, aged 26.3 ± 3.8 years, BMI 24.7 ± 3.4 kg/m2), including a pre-intervention controlled run-in period. Participants were randomized to one of the three fasting cohorts: (I) alternate day fasting (ADF, n = 8), (II) 16/8 fasting (16/8 h of fasting/feasting, n = 11) and (III) 20/4 fasting (20/4 h of fasting/feasting, n = 8). An analysis of baseline ECG parameters and HRV parameters following different fasting interventions demonstrated the safety of these interventions without impacting on heart rate variability parameters during Schellong-1 testing, and revealed comparable preserved autonomic cardiac modulation (ACM) independently of the fasting intervention. In conclusion, different short-term fasting interventions demonstrated no safety ECG-based concerns and showed comparable ACM based on ECG and HRV assessments. Finally, our research topic might strengthen the scientific knowledge of intermittent fasting strategies and indicate potential clinically preventive approaches with respect to occurring metabolic disease and obesity in healthy young subjects.

Glucose Metabolism and Metabolomic Changes in Response to Prolonged Fasting in Individuals with Obesity, Type 2 Diabetes and Non-Obese People-A Cohort Trial.

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting (p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.