Chronic sucralose consumption induces elevation of serum insulin in young healthy adults: a randomized, double blind, controlled trial.

BACKGROUND: Non-nutritive sweeteners (NNS) are widely consumed by humans due to their apparent innocuity, especially sucralose. However, several studies link sucralose consumption to weight gain and metabolic derangements, although data are still contradictory. OBJECTIVE: To determine the effect of acute and chronic consumption of sucralose on insulin and glucose profiles in young healthy adults. MATERIAL AND METHODS: This was a randomized, parallel, double-blind, placebo-controlled trial conducted in healthy young adults from 18 to 35 years old, without insulin resistance. A hundred thirty seven participants were randomized into three groups: a) volunteers receiving 48 mg sucralose, b) volunteers receiving 96 mg sucralose, and c) controls receiving water as placebo. All participants underwent a 3-h oral glucose tolerance test (OGTT) preceded by consuming sucralose or placebo 15 min before glucose load, at two time points: week zero (Wk0) and week ten (Wk10). Serum insulin and glucose were measured every 15 min during both OGTTs. RESULTS: Compared to Wk0, consumption of sucralose for 10 weeks provoked 1) increased insulin concentrations at 0 min (7.5 ± 3.4 vs 8.8 ± 4.1 µIU/mL; p = 0.01), 30 min (91.3 ± 56.2 vs 110.1 ± 49.4 µIU/mL; p = 0.05), 105 min (47.7 ± 24.4 vs 64.3 ± 48.2 µIU/mL; p = 0.04) and 120 min (44.8 ± 22.1 vs 63.1 ± 47.8 µIU/mL; p = 0.01) in the 48 mg sucralose group; 2) increased blood glucose at - 15 min (87.9 ± 4.6 vs 91.4 ± 5.4 mg/dL; p = 0.003), 0 min (88.7 ± 4 vs 91.3 ± 6 mg/dL; p = 0.04) and 120 min (95.2 ± 23.7 vs 106.9 ± 19.5 mg/dL; p = 0.009) in the 48 mg sucralose group; 3) increased area under the curve (AUC) of insulin in both 48 and 96 mg sucralose groups (9262 vs 11,398; p = 0.02 and 6962 vs 8394; p = 0.12, respectively); and 4) reduced Matsuda index in the 48 mg sucralose group (6.04 ± 3.19 vs 4.86 ± 2.13; p = 0.01). CONCLUSIONS: These data show that chronic consumption of sucralose can affect insulin and glucose responses in non-insulin resistant healthy young adults with normal body mass index (between 18.5 and 24.9 kg/m2), however, the effects are not consistent with dose; further research is required. CLINICAL TRIAL REGISTRY: NCT03703141.

Serum levels of interleukin-1 beta associate better with severity of simple steatosis than liver function tests in morbidly obese patients.

BACKGROUND: In high-fat diet-fed mice, interleukin-1 beta (IL-1 beta) has been shown to play a key role in hepatic steatosis. However, it remains unknown whether IL-1 beta could be associated with different grades of steatosis in obese humans. MATERIALS AND METHODS: Morbidly obese patients (n = 124) aged 18-65 years were divided into four groups: no steatosis (controls), mild steatosis, moderate steatosis, and severe steatosis using abdominal ultrasound. IL-1 beta serum levels and liver function tests were measured and significant differences were estimated by one-way ANOVA followed by Tukey test. RESULTS: IL-1 beta serum levels significantly increased in morbidly obese patients with mild (11.38 ± 2.40 pg/ml), moderate (16.72 ± 2.47 pg/ml), and severe steatosis (23.29 ± 5.2 pg/ml) as compared to controls (7.78 ± 2.26 pg/ml). Liver function tests did not significantly change among different grades of steatosis. CONCLUSION: IL-1 beta serum levels associate better with steatosis degree than liver function tests in morbidly obese population.

A Single 48 mg Sucralose Sip Unbalances Monocyte Subpopulations and Stimulates Insulin Secretion in Healthy Young Adults.

Sucralose is a noncaloric artificial sweetener that is widely consumed worldwide and has been associated with alteration in glucose and insulin homeostasis. Unbalance in monocyte subpopulations expressing CD11c and CD206 hallmarks metabolic dysfunction but has not yet been studied in response to sucralose. Our goal was to examine the effect of a single sucralose sip on serum insulin and blood glucose and the percentages of classical, intermediate, and nonclassical monocytes in healthy young adults subjected to an oral glucose tolerance test (OGTT). This study was a randomized, placebo-controlled clinical trial. Volunteers randomly received 60 mL water as placebo (n = 20) or 48 mg sucralose dissolved in 60 mL water (n = 25), fifteen minutes prior to an OGTT. Blood samples were individually drawn every 15 minutes for 180 minutes for quantifying glucose and insulin concentrations. Monocyte subsets expressing CD11c and CD206 were measured at -15 and 180 minutes by flow cytometry. As compared to controls, volunteers receiving sucralose exhibited significant increases in serum insulin at 30, 45, and 180 minutes, whereas blood glucose values showed no significant differences. Sucralose consumption caused a significant 7% increase in classical monocytes and 63% decrease in nonclassical monocytes with respect to placebo controls. Pearson's correlation models revealed a strong association of insulin with sucralose-induced monocyte subpopulation unbalance whereas glucose values did not show significant correlations. Sucralose ingestion decreased CD11c expression in all monocyte subsets and reduced CD206 expression in nonclassical monocytes suggesting that sucralose does not only unbalance monocyte subpopulations but also alter their expression pattern of cell surface molecules. This work demonstrates for the first time that a 48 mg sucralose sip increases serum insulin and unbalances monocyte subpopulations expressing CD11c and CD206 in noninsulin-resistant healthy young adults subjected to an OGTT. The apparently innocuous consumption of sucralose should be reexamined in light of these results.

High-Density Lipoprotein Reduction Differentially Modulates to Classical and Nonclassical Monocyte Subpopulations in Metabolic Syndrome Patients and in LPS-Stimulated Primary Human Monocytes In Vitro.

The effect of metabolic syndrome on human monocyte subpopulations has not yet been studied. Our main goal was to examine monocyte subpopulations in metabolic syndrome patients, while also identifying the risk factors that could directly influence these cells. Eighty-six subjects were divided into metabolic syndrome patients and controls. Monocyte subpopulations were quantified by flow cytometry, and interleukin- (IL-) 1ß secretion levels were measured by ELISA. Primary human monocytes were cultured in low or elevated concentrations of high-density lipoprotein (HDL) and stimulated with lipopolysaccharide (LPS). The nonclassical monocyte (NCM) percentage was significantly increased in metabolic syndrome patients as compared to controls, whereas classical monocytes (CM) were reduced. Among all metabolic syndrome risk factors, HDL reduction exhibited the most important correlation with monocyte subpopulations and then was studied in vitro. Low HDL concentration reduced the CM percentage, whereas it increased the NCM percentage and IL-1ß secretion in LPS-treated monocytes. The LPS effect was abolished when monocytes were cultured in elevated HDL concentrations. Concurring with in vitro results, IL-1ß serum values significantly increased in metabolic syndrome patients with low HDL levels as compared to metabolic syndrome patients without HDL reduction. Our data demonstrate that HDL directly modulates monocyte subpopulations in metabolic syndrome.

Serum Levels of Interleukin-13 Increase in Subjects with Insulin Resistance but Do Not Correlate with Markers of Low-Grade Systemic Inflammation.

Experimental evidence in mice suggests a role for interleukin- (IL-) 13 in insulin resistance and low-grade systemic inflammation. However, IL-13 serum levels have not been assessed in subjects with insulin resistance, and associations of IL-13 with parameters of low-grade systemic inflammation are still unknown. Our main goal was to examine the systemic levels of IL-13 in patients with insulin resistance, while also studying the relationship of IL-13 with anthropometric, metabolic, and low-grade systemic inflammatory markers. Ninety-two participants were included in the study and divided into insulin-resistant patients and noninsulin-resistant controls. Blood levels of IL-13, glucose, insulin, triglycerides, cholesterol, tumor necrosis factor-alpha (TNF-α), IL-10, proinflammatory (Mon-CD11c+CD206-), and anti-inflammatory (Mon-CD11c-CD206+) monocytes, as well as anthropometric parameters, were measured in all volunteers. Insulin-resistant patients showed 2.5-fold higher serum levels of IL-13 than controls (P < 0.0001) and significantly increased values of TNF-α and Mon-CD11c+CD206-, with concomitant reductions in IL-10 and Mon-CD11c-CD206+. Increased IL-13 was extraordinarily well associated with hyperglycemia (r = 0.7362) and hypertriglyceridemia (r = 0.7632) but unexpectedly exhibited no significant correlations with TNF-α (r = 0.2907), IL-10 (r = -0.3882), Mon-CD11c+CD206- (r = 0.2745) or Mon-CD11c-CD206+ (r = -0.3237). This study demonstrates that IL-13 serum levels are elevated in patients with insulin resistance without showing correlation with parameters of low-grade systemic inflammation.

Human monocytes and macrophages undergo M1-type inflammatory polarization in response to high levels of glucose.

Emerging data suggest that elevated glucose may promote inflammatory activation of monocytic lineage cells with the ability to injure vascular endothelial tissue of diabetic patients, however evidence in primary human monocytes and macrophages is still insufficient. We investigated the effect of high glucose concentration on the inflammatory capacity of human macrophages in vitro and examined whether similar responses were detectable in circulating monocytes from prediabetic patients. Primary monocytes were isolated from healthy blood donors and differentiated into macrophages. Differentiated macrophages were exposed to normal levels of glucose (NG), high glucose (HG) or high mannitol as osmotic pressure control (OP) for three days. Using PCR, ELISA and flow cytometry, we found that HG macrophages showed overexpression of CD11c and inducible nitric oxide synthase as well as down-regulation of arginase-1 and interleukin (IL)-10 with respect to NG and OP macrophages. Consistent with in vitro results, circulating monocytes from hyperglycemic patients exhibited higher levels of CD11c and lower expression of CD206 than monocytes from normoglycemic controls. In subjects with hyperglycemia, elevation in CD11c(+) monocytes was associated with increased obesity, insulin resistance, and triglyceridemia as well as low serum IL-10. Our data suggest that human monocytes and macrophages undergo M1-like inflammatory polarization when exposed to high levels of glucose on in vitro culture conditions and in patients with hyperglycemia. These results demonstrate that excess glucose has direct effects on macrophage activation though the molecular mechanisms mediating such a response remain to be elucidated.