Andrea Mari’s research while affiliated with Neuroscience Institute, Italian National Research Council and other places

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Publications (386)


Greater improvement in insulin sensitivity per unit weight loss associated with tirzepatide versus semaglutide: An exploratory analysis
  • Article

January 2025

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38 Reads

Diabetes Obesity and Metabolism

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Andrea Mari

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Govinda Weerakkody

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[...]

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Melissa K Thomas

Aims To explore the relationship between weight loss and insulin sensitivity in response to tirzepatide or semaglutide. Materials and Methods We conducted a post hoc exploratory analysis of a 28‐week, double‐blind, randomized trial in people with type 2 diabetes treated with metformin, randomized to tirzepatide 15 mg, semaglutide 1 mg or placebo. We evaluated the relationship between change in body weight and change in insulin sensitivity determined from hyperinsulinemic euglycemic clamp ( M value), or from mixed‐meal tolerance testing (Matsuda index). Results Tirzepatide was associated with a greater improvement than semaglutide in insulin sensitivity assessed using hyperinsulinemic euglycemic clamps ( p < 0.001). With tirzepatide, improvements in insulin sensitivity were associated with percent change in weight ( R = −0.656, p < 0.0001). With semaglutide, change in insulin sensitivity was less strongly correlated with percent change in weight ( R = −0.268, p = 0.0820; p = 0.0242 vs. tirzepatide). In regression analyses, the slope of the relationship between change in M value and change in weight was statistically different between semaglutide and tirzepatide ( p = 0.0461). These relationships were also assessed using the Matsuda index as the metric of insulin sensitivity, and using change in fat mass as the determinant of change in insulin sensitivity. Conclusions Improvement in insulin sensitivity was proportional to weight and fat loss, with greater strength of association with tirzepatide. In regression analysis, tirzepatide was associated with greater improvement in insulin sensitivity per unit weight loss than semaglutide. The greater improvement in insulin sensitivity following treatment with tirzepatide was not simply attributable to greater weight or fat loss.



Study design. Hypo, hypoglycaemia
Plasma glucose, glucose metabolic fluxes and hormone profiles. Profiles and post-OGTT AUCs of plasma glucose (a, b); tracer-derived GCl (c, d), EGP (e, f) and RaO (g, h); and plasma insulin (i, j), C-peptide (k, l), GLP-1 (m, n) and GIP (o, p) in individuals with a history of type 2 diabetes with PPHG or without (control) after RYGB during a 75 g OGTT. Glucose tracer data are available for 23 of 24 participants. Data are mean ± SEM indicated by error bars or shaded areas. In (a), (c), (e), (g), (i), (k), (m) and (o), repeated measures were tested by two-way ANOVA; the effects of group (G) and group by time interaction (G×T) and statistically significant p values in pairwise comparisons (*p<0.05) are reported. In the other panels, group differences were tested using the Mann–Whitney test
Beta cell function, insulin clearance and insulin sensitivity. Profile of the ISR estimated from C-peptide deconvolution (a); fasting and post-glucose AUCs of the ISR (b, c); relationship between the ISR and plasma glucose concentration (d); model-derived variables of beta cell function, including β-GS (e), ISR at 5 mmol/l glucose (ISR@5) (f), the potentiation factor ratio (g) and β-RS (h); fasting and total endogenous insulin clearance (i, j); and tracer-derived indexes of whole-body insulin sensitivity (k, l) and hepatic insulin resistance (m) in individuals with a history of type 2 diabetes with PPHG or without (control) after RYGB during a 75 g OGTT. Data are mean ± SEM indicated by shaded areas or error bars. In (a), (c) and (k), repeated measures were tested by two-way ANOVA; the effects of group (G) and group by time (G×T) or group by glucose (G×Gluc) interactions are reported. In the other panels, group differences were tested using the Mann–Whitney test
Counterregulatory hormone responses and lipolytic effects. Plasma profiles and post-OGTT AUCs of glucagon (a, b); plasma concentrations at fasting, glucose peak and glucose nadir of adrenaline (c), noradrenaline (d) and cortisol (e); and plasma profiles and AUC of NEFAs (f, g) in individuals with a history of type 2 diabetes with PPHG or without (control) after RYGB during a 75 g OGTT. Data are mean ± SEM indicated by error bars. In panels (a), (c), (d), (e), and (f), repeated measures were tested by two-way ANOVA; the effects of group (G) and group by time interaction (G×T) are reported. In (b) and (g), group differences were tested using the Mann–Whitney test
Pathophysiological determinants of glucose nadir and glucose clearance. Linear correlations of post-load glucose nadir with the AUCs of tracer-derived GCl (a) and EGP (b), and multivariable analyses showing the independent effects of distinct glucose metabolic fluxes on glucose nadir (c) and of plasma insulin levels (insulin AUC0–120 min) and whole-body insulin sensitivity (OGIS index) on GCl AUC0–180 min (d) in individuals with a history of type 2 diabetes with PPHG or without (control) after RYGB during a 75 g OGTT. Best-fit lines (continuous), 95% CIs (dotted), Spearman correlation coefficients (r) and p values are shown in (a) and (b). Shaded areas in (a) and (b) indicate glucose nadir values below 3.0 mmol/l
Postprandial hypoglycaemia after gastric bypass in type 2 diabetes: pathophysiological mechanisms and clinical implications
  • Article
  • Publisher preview available

November 2024

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25 Reads

Diabetologia

Aims/hypothesis Postprandial hypoglycaemia (PPHG) is a frequent late complication of Roux-en-Y gastric bypass (RYGB) in people without diabetes. We aimed to examine the pathogenetic mechanisms of PPHG and its clinical consequences in people with a history of type 2 diabetes. Methods In this case–control study, 24 participants with type 2 diabetes treated with RYGB (14 women; median [IQR] age 53.5 [13.8] years, BMI 29.3 [6.3] kg/m², HbA1c 36.0 [6.2] mmol/mol [5.4% (0.6%)]) underwent a dual-tracer, frequently sampled, 300 min, 75 g OGTT for the diagnosis of PPHG (glucose nadir <3.0 mmol/l, or <3.3 mmol/l with symptoms). Plasma glucose, glucose tracers, insulin, C-peptide, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, adrenaline (epinephrine), noradrenaline (norepinephrine), cortisol and NEFAs were measured. Mathematical models were implemented to estimate glucose metabolic fluxes and beta cell function. ECG recordings, cognitive testing and hypoglycaemia awareness assessments were repeated during the OGTT. Glycaemic levels and dietary habits were assessed under free-living conditions. Results PPHG occurred in 12 (50%) participants, mostly without symptoms, due to excessive tracer-derived glucose clearance (mean group difference ± SE in AUC0–180 min +261±72 ml min⁻¹ kg⁻¹ × min) driven by higher whole-body insulin sensitivity and early glucose-stimulated hyperinsulinaemia, the latter depending on lower insulin clearance and enhanced beta cell function, regardless of incretin hormones. PPHG participants also had defective counterregulatory hormone responses to hypoglycaemia, preventing a physiological increase in endogenous glucose production and the appearance of symptoms and signs of sympathetic cardiovascular activation and neuroglycopenia. PPHG was associated with more frequent and prolonged hypoglycaemia on 14 day continuous glucose monitoring and alterations in free-living dietary habits. Conclusions Our results demonstrate that post-bypass PPHG occurs frequently in individuals with a history of type 2 diabetes, often without warning symptoms, and expose its complex pathogenetic mechanisms, revealing potential therapeutic targets. Graphical Abstract

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Insulin levels during the hyperglycemic clamp. The curve indicates the incremental insulin response to the different secretagogues.
Reproducibility of the 9 items retrieved from the short food-frequency questionnaire.
Cont.
Development of a Diabetes Dietary Quality Index: Reproducibility and Associations with Measures of Insulin Resistance, Beta Cell Function, and Hyperglycemia

October 2024

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81 Reads

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1 Citation

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.


Flag plots representing the results of the multivariable logistic regression models for NGR vs IGR (a), NGR vs type 2 diabetes (b) and IGR vs type 2 diabetes (c) as dependent variables and the metabolites as independent variables, adjusted for study centre, sex, age, BMI, BP, fasting HDL-cholesterol, fasting triacylglycerol, smoking status, alcohol status and health status. The x-axis shows OR (95% CI) and the y-axis shows each significant metabolite; metabolite classes are represented by different colours. SM, sphingomyelin
Flag plots representing the results of the multivariable logistic regression models for NGR vs IGR (a), NGR vs type 2 diabetes (b) and IGR vs type 2 diabetes (c) as dependent variables and the metabolites as independent variables, adjusted for study centre, sex, age, BMI, BP, fasting HDL-cholesterol, fasting triacylglycerol, smoking status, alcohol status and health status. The x-axis shows OR (95% CI) and the y-axis shows each significant metabolite; metabolite classes are represented by different colours. Asterisks (*) indicate the presence of unknown or novel metabolites
Schematic overview of mediation analysis with lysoPC a C17:0 and hexoses (a) or N-lactoylvaline, lactate, N-lactoylleucine, formiminoglutamate and X-24295 (b) as mediators. Numbers above the red arrows indicate the percentage and significance of mediation effects. T2D, type 2 diabetes
Forest plot representing causal estimates of type 2 diabetes on targeted and untargeted metabolites in the two-sample MR test. T2D, type 2 diabetes
Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study

September 2024

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75 Reads

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2 Citations

Diabetologia

Aims/hypothesis Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes. Methods As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively. Results In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA1c progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes. Conclusions/interpretation Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, significantly associated with prediabetes and diabetes, that mediate the effect of diabetes from baseline to follow-up (18 and 48 months). Causal inference using genetic variants shows the role of lipid metabolism and n-3 fatty acids as being causal for metabolite-to-type 2 diabetes whereas the sum of hexoses is causal for type 2 diabetes-to-metabolite. Identified metabolite markers are useful for stratifying individuals based on their risk progression and should enable targeted interventions. Graphical Abstract


Effects of Obesity and Exercise on Hepatic and Pancreatic Lipid Content and Glucose Metabolism: PET Studies in Twins Discordant for BMI

August 2024

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35 Reads

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1 Citation

Biomolecules

Obesity and sedentarism are associated with increased liver and pancreatic fat content (LFC and PFC, respectively) as well as impaired organ metabolism. Exercise training is known to decrease organ ectopic fat but its effects on organ metabolism are unclear. Genetic background affects susceptibility to obesity and the response to training. We studied the effects of regular exercise training on LFC, PFC, and metabolism in monozygotic twin pairs discordant for BMI. We recruited 12 BMI-discordant monozygotic twin pairs (age 40.4, SD 4.5 years; BMI 32.9, SD 7.6, 8 female pairs). Ten pairs completed six months of training intervention. We measured hepatic insulin-stimulated glucose uptake using [18F]FDG-PET and fat content using magnetic resonance spectroscopy before and after the intervention. At baseline LFC, PFC, gamma-glutamyl transferase (GT), and hepatic glucose uptake were significantly higher in the heavier twins compared to the leaner co-twins (p = 0.018, p = 0.02 and p = 0.01, respectively). Response to training in liver glucose uptake and GT differed between the twins (Time*group p = 0.04 and p = 0.004, respectively). Liver glucose uptake tended to decrease, and GT decreased only in the heavier twins (p = 0.032). In BMI-discordant twins, heavier twins showed higher LFC and PFC, which may underlie the observed increase in liver glucose uptake and GT. These alterations were mitigated by exercise. The small number of participants makes the results preliminary, and future research with a larger pool of participants is warranted.


1559-P: Heterogeneity of Trajectories of Metabolic Parameters after 50% Beta-Cell Mass Loss by Pancreatectomy

June 2024

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3 Reads

Diabetes

Temporal trajectories of metabolic parameters in the onset of dysglycemia are heterogeneous. We aimed to characterize the temporal trajectories of metabolic parameters after β cell mass reduction by pancreatectomy and to study their heterogeneity. Individuals without known diabetes diagnosis (N = 83) underwent mixed-meal/oral glucose tolerance tests (MMTT/OGTT) and/or hyperglycemic/euglycemic clamp (HC/EC) procedures, before and after surgery. We performed stepwise multivariate linear regression analysis on the glucose tolerance (GT) class (treated as ordinal number, 1 to 3) after surgery, using as independent variables the baselines and changes with surgery of anthropometrics and MMTT- and HC-derived functional parameters of insulin secretion, clearance, and sensitivity (IS), imputed via missForest algorithm when missing. We used the variables selected in this analysis (p<0.01) as input for the reversed graphed embedding (RGE) framework, to identify groups of individuals with extreme combinations of the variables (archetypes). Independent associations with after-surgery GT class (cross-validated R2 = 0.57) were observed for changes in IS and β cell glucose sensitivity (GS), and for baseline IS, GS, 1st phase insulin secretion, insulin secretion at 6 mmol/L glucose, and insulin clearance. IS and the β cell function parameters showed different trajectories combinations in each of the 5 archetypes identified via RGE (median adjusted Rand index = 0.88; N = 16, 8, 15, 13, 18). After surgery, all archetypes included individuals in each of the 3 GT classes (all proportions > 0 at 95% CI). The same β cell mass reduction determines a variety of combinations in changes of IS and β cell functional mechanisms. We identified five archetypes underlying these combinations. The same final GT class can be reached by individuals in any of the archetypes, which shed light on the hidden heterogeneity of glycaemic deterioration. Disclosure R. Bizzotto: None. G. Di Giuseppe: None. L. Soldovieri: None. F. Cinti: None. S. Moffa: None. M. Brunetti: None. G. Ciccarelli: None. S. Alfieri: None. G. Quero: None. A. Mari: Consultant; Lilly Diabetes. A. Giaccari: None. T. Mezza: None.


1555-P: Effects of 80% Pancreas Reduction on Beta-Cell Function and Glucose Metabolism

June 2024

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3 Reads

Diabetes

Introduction and Objectives: Diabetes typically develops when the endocrine pancreas fails to cope to insulin demand with adequate insulin secretion. Many studies have shown that diabetes appears when the loss of pancreatic β cell mass is approximately between 41% and 65% in humans. Near total pancreatectomy (NTP) is a surgical procedure that removes 80% of pancreatic mass.To investigate the metabolic effects of NTP in a cohort of nondiabetic subjects. Methods: We recruited 7 subjects who underwent an oral glucose tolerance test (OGTT) and a hyperglycemic clamp (HC) followed by arginine stimulation, before and 3 months after NTP. We calculated the area under the curve of glucose (AUC-Glu) and insulin (AUC-Ins) responses during OGTT. Therefore, we estimated the β cell glucose sensitivity (βCGS), an index of β cell function, and rate sensitivity (RS), an index of first phase insulin secretion. Further, we calculated the total area under the curve of insulin responses (AUC-Itot) and the area under the of the arginine-stimulated insulin secretion (AUC-Arg) during HC. Results: Compared to presurgical OGTT, we observed a 18% increase in the mean glucose levels during OGTT after surgery (AUC-Glu 19761 vs 23421 mg/dl·min) with a 57% reduction of the mean insulin concentration (AUC-Ins 6499 vs 2788 μU/ml·min p<0.05). Further, we observed a 36% reduction βCGS (61.2 vs 38.7 pmol min-1m-2mmol-1L) and a 82% reduction in the RS (763 vs 139 pmol m-2mmol-1L p<0.05) after surgery. Both total insulin secretion and arginine-stimulated insulin secretion during HC were reduced (AUC-Itot 15776 vs 6489 μU/ml·min) (AUC-Arg 7144 vs 2520 μU/ml·min), respectively by 58.8% and 64.7%. According to the ADA diagnostic criteria 3 of the 7 subjects developed diabetes. Conclusion: In conclusion, despite previous reports, 80% β cell mass loss is not always sufficient to develop hyperglycemia. Additional studies will be necessary to understand what mechanisms play a compensating role in the preservation of glucose tolerance in those patients. Disclosure L. Soldovieri: None. G. Di Giuseppe: None. G. Ciccarelli: None. M. Brunetti: None. A. Mari: Consultant; Lilly Diabetes. G. Quero: None. S. Alfieri: None. A. Giaccari: None. T. Mezza: None.



Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test

May 2024

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59 Reads

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5 Citations

The Journal of Clinical Endocrinology and Metabolism

Context In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. Objective This work aimed to evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. Methods A 28-week double–blind, randomized, placebo-controlled trial of patients with type 2 diabetes treated with metformin was conducted at 2 clinical research centers in Germany. Interventions included tirzepatide 15 mg, semaglutide 1 mg, and placebo. Main outcome measures included glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2–mmol/L glucose (ISR7.2), β-cell glucose sensitivity (β-CGS), insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. Results Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < .01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < .01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < .01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < .05), showing improved β-CGS. MMTT-derived β-CGS was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < .01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. Conclusion These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.


Citations (63)


... Diagnosing IR presents challenges due to the absence of a direct, universally accepted marker. Although the hyperinsulinemic-euglycemic clamp is considered the gold standard for measuring insulin sensitivity, its technical complexity and cost restrict its use to research settings primarily [23]. Consequently, clinical practice relies on indirect methods using biochemical indicators and mathematical models. ...

Reference:

Risk of Insulin Resistance in 44,939 Spanish Healthcare Workers: Association with Sociodemographic Variables and Healthy Habits
Development of a Diabetes Dietary Quality Index: Reproducibility and Associations with Measures of Insulin Resistance, Beta Cell Function, and Hyperglycemia

... N-lactoyltyrosine, which belongs to a class of pseudopeptides, formed by lactic acid and an amino acid (52), was associated with brain health in our study, with higher levels being linked to lower brain volume. N-lactoyl amino acids received some attention in diabetes research recently (53,54); while higher levels of N-lactoyl amino acids (including Nlactoylphenylalanine, N-lactoyltyrosine, and N-lactoylleucine) associate with decreasing is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint ...

Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study

Diabetologia

... Using the twin study design, and subsequent control for genetics and shared environmental effects, the authors found negative association between harsher parenting in communication and BMI in German twin families. Another example is Lietzén et al. (26), who studied the effects of regular exercise training on LFC, PFC, and metabolism in monozygotic twin pairs discordant for BMI. 3 The remainder of this article is organized as follows. Section 2 provides the description of data and methods. ...

Effects of Obesity and Exercise on Hepatic and Pancreatic Lipid Content and Glucose Metabolism: PET Studies in Twins Discordant for BMI

Biomolecules

... The placebo group data are provided in p < 0.001). 23 Pearson correlation analyses are presented in Figure S3 and However, the continuous relationships between improved insulin sensitivity and weight loss were steeper with tirzepatide, suggesting that the greater improvement in insulin sensitivity with tirzepatide may not be simply attributable to greater weight loss efficacy. Improvements in insulin sensitivity with weight loss are well recognized and occur irrespective of whether weight loss is in response to dietary interventions, metabolic surgery or pharmacological agents. ...

Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test
  • Citing Article
  • May 2024

The Journal of Clinical Endocrinology and Metabolism

... Thus, oncometabolites might physiologically function as cytokines and be involved in a number of cellular and organismal responses [64]. Indeed, there is evidence supporting their involvement in the regulation of the immune response, energy metabolism, neurogenesis, and organ and tissue homeostasis [59,[65][66][67][68][69][70][71]. These findings suggest that the cancerrelated functions of oncometabolites might represent, at least in part, an exaggeration (or ectopic activation) of their physiological functions. ...

SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes

The Journal of clinical investigation

... It is well-established that obesity-related diabetes is primarily linked to IR and compromised insulin secretion (7,8). However, understanding the pathophysiology of diabetes in non-obese individuals presents a challenge, as most existing models have focused on obese populations (3,9,10). The efficacy of using TG/ HDL-c ratios as a predictor for diabetes in non-obese individuals remains undetermined, with prior research primarily consisting of cross-sectional or single-center studies. ...

Effects of Hypertriglyceridemia With or Without NEFA Elevation on β-cell Function and Insulin Clearance and Sensitivity
  • Citing Article
  • April 2024

The Journal of Clinical Endocrinology and Metabolism

... Clinical trials have demonstrated the optimal efficacy and safety of this co-administration medication. DPP-4 inhibitor combination therapy is a viable approach in the treatment of T2DM [30][31][32]. ...

Low-Dose Sulfonylurea Plus DPP4 Inhibitor Lower Blood Glucose and Enhance Beta-Cell Function Without Hypoglycemia

The Journal of Clinical Endocrinology and Metabolism

... However, no correlation was found between serum and urine citrate levels. In an animal model of Heart Failure with preserved levels have recently been associated with increased insulin resistance and insulin secretion indexes [50]. Indeed, in our study we found that dapagliflozin significantly reduced the Homeostatic Model Assessment-Insulin Resistance index (HOMA-IR) by 26.2%, p = 0.023 and the decrease in mannose levels correlated with the decrease in HOMA-IR, r 2 = 0.503, p = 0.002, indicating that the decrease of mannose levels can be explained by the improvement in insulin resistance by dapagliflozin administration. ...

High Mannose Correlates With Surrogate Indexes of Insulin Resistance and Is Associated With an Increased Risk of Cardiovascular Events Independently of Glycemic Status and Traditional Risk Factors
  • Citing Article
  • December 2023

Diabetes Care

... At the hepatic level, IR results in increased gluconeogenesis and a reduced capacity to inhibit hepatic glucose production, contributing to fasting hyperglycemia [20]. In adipose tissue, impaired insulin signaling leads to uncontrolled lipolysis, releasing FFAs into the bloodstream and worsening IR in other tissues [21]. Finally, in skeletal muscle, reduced glucose uptake is a key factor in the development of glucose intolerance [22]. ...

Renal Cortical Glucose Uptake Is Decreased in Insulin Resistance and Correlates Inversely With Serum Free-fatty Acids
  • Citing Article
  • November 2023

The Journal of Clinical Endocrinology and Metabolism

... Leptin resistance can lead to increased insulin levels and IR, potentially resulting in T2D [71]. Insulin regulates leptin secretion, and leptin levels influence insulin sensitivity independently of weight [72]. All of these events comprise a regulatory loop. ...

At any Level of Adiposity, Relatively Elevated Leptin Concentrations Are Associated With Decreased Insulin Sensitivity
  • Citing Article
  • August 2023

The Journal of Clinical Endocrinology and Metabolism