Impaired succinate response to a mixed meal in obesity and type 2 diabetes is normalized after metabolic surgery

Abstract

<div><b><i>Objective</i></b> To explore the meal response of circulating succinate in patients with obesity and type 2 diabetes undergoing bariatric surgery, and to examine the role of gastrointestinal glucose sensing in succinate dynamics in healthy subjects. <b><i><br></i></b></div><div><b><i>Research Design and</i></b> <b><i>Methods</i></b> Cohort I comprised 45 patients with morbid obesity and type 2 diabetes (BMI 39.4±1.9 kg/m<sup>2</sup>) undergoing metabolic surgery. Cohort II was a confirmatory cohort of 13 patients (BMI 39.3±1.4 kg/m<sup>2</sup>) undergoing gastric bypass surgery. Cohort III comprised 15 healthy subjects (BMI 26.4±0.5 kg/m<sup>2</sup>). Cohorts I and II completed a 2-hour meal tolerance test (MTT) before the intervention and at one-year of follow-up, and cohort II also completed a 3-hour lipid test (LT). Cohort III underwent a 3-hour oral glucose tolerance test (OGTT) and an isoglycemic variable glucose infusion (ISO) study. </div> <p><b><i>Results</i></b><i> </i>In cohort I, succinate response to MTT at follow-up was greater than before the intervention (p<0.0001). This response was confirmed in cohort II with a greater increase after one year of surgery (p=0.009). By contrast, LT did not elicit a succinate response. Changes in succinate response were associated with changes in the area under the curve of glucose (r=0.417, p<0.0001) and insulin (r=0.204, p=0.002). In cohort III, glycemia <i>per se</i> stimulated a plasma succinate response (p=0.0004), but its response was greater in the OGTT (p=0.02; OGTT <i>versus</i> ISO). </p> <p><b><i>Conclusions</i></b><b> </b>The<b> </b>meal-related response of circulating succinate in patients with obesity and type 2 diabetes is recovered after metabolic surgery.</p>

Orally administered Odoribacter laneus improves glucose control and inflammatory profile in obese mice by depleting circulating succinate

“…We found that higher circulating succinate levels in patients with severe obesity were associated with a worse metabolic profile, as previously described in other cohorts [12,49]. Specifically, we observed significant positive correlations between circulating succinate levels and waist circumference (r = 0.461, p = 0.001), waist-tohip ratio (r = 0.403, p = 0.005), triglycerides (r = 0.306, p = 0.033), insulin (r = 0.331, p = 0.021), and uric acid (r = 0.423, p = 0.003).…”

Gemigliptin Alleviates Succinate-Induced Hepatic Stellate Cell Activation by Ameliorating Mitochondrial Dysfunction

“…Succinate concentrations in the blood are clearly elevated in inflammatory-related health conditions, including obesity and type 2 diabetes [29][30][31][32]. Therefore, we tested the level of succinate in the blood of 8-week treated mice, and our data showed that gemigliptin administration also markedly reduced succinate levels in the serum of the HFHC diet group, which showed significantly higher succinate levels than the control diet group (Fig.…”

SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

“…It was generally assumed that SUCNR1 is functionally inactive in healthy tissues, and for many years SUCNR1 was investigated mainly in inflammatory-related conditions [5][6][7][8] , in particular those associated with chronic hypersuccinemia [9][10][11][12] . Recent studies, however, have described that extracellular succinate transiently increases in response to physiological stimuli including exercise 13 , cold exposure 14 or food ingestion, as we recently reported 15 . Succinate thus emerges as a reporter of both tissue stress and metabolism, opening up the possibility of its involvement in other metabolic functions as a hormone-like metabolite 1 .…”