Duodenal Sodium/Glucose Cotransporter 1 Expression Under Fasting Conditions Is Associated With Postload Hyperglycemia

Fiorentino, Teresa Vanessa; Suraci, Evelina; Arcidiacono, Gaetano; Cimellaro, Antonio; Mignogna, Chiara; Presta, Ivan; Andreozzi, Francesco; Hribal, Marta Letizia; Perticone, Francesco; Donato, Giuseppe; Luzza, Francesco; Sesti, Giorgio

doi:10.1210/jc.2017-00348

Cited by 37 publications

(48 citation statements)

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“…A second potential mechanism underlying this effect may be explained by the recent observation of increased SGLT1 expression in pre-diabetes, TD2M and obesity and its positive association with intestinal glucose absorption and glucose excursion. 40,41 In response to intestinal glucose, plasma GIP, glucagon, insulin and SGLT1 were all higher in patients with obesity, compared with lean controls, while GLP-1 was lower. 41 Significant improvements in a number of metabolic parameters were also seen in this study following 12-weeks of treatment, including reduced waist circumference, a reduction in postprandial glucose and insulin and an increase in postprandial glucagon.…”

Section: Discussionmentioning

confidence: 97%

“…FDA analysis of clinical trial data revealed that a 12-week weight loss of >5% achieved with lorcaserin of phenterminetopiramate was predictive of meaningful weight loss at 12 months following treatment,38 suggesting that the weight loss seen with licogliflozin by 12 weeks is promising. A second potential mechanism underlying this effect may be explained by the recent observation of increased SGLT1 expression in pre-diabetes, TD2M and obesity and its positive association with intestinal glucose absorption and glucose excursion 40,41. A significant increase in body weight was seen in both groups between the last treatment day and the end-of-study visit (+0.66 kg [80% CI, 1.96, 2.6] with placebo; P < 0.01 and + 2.3 kg [80% CI, 0.34, 0.98] with licogliflozin; P < 0.0001), suggesting that the weight-loss effects disappeared upon discontinuing treatment.…”

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confidence: 99%

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The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes

He¹,

Haynes

Meyers³

et al. 2019

Diabetes Obesity Metabolism

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BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity.This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS:Patients with obesity (BMI, 35-50 kg/m 2 ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 − 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE 24 ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY 3-36 , and GIP), insulin and glucagon.RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC 0-4h ) and suppressed insulin by 90% (P < 0.01; incremental AUC 0-4h ). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE 24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY 3-36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes. K E Y W O R D S clinical trial, continuous glucose monitoring (CGM), incretins, obesity therapy, phase I-II study, weight control

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes

He¹,

Haynes

Meyers³

et al. 2019

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

show abstract

“…Along with insulin sensitivity, secretion and clearance, a greater 1hPG during the OGTT may be explained by a more rapid appearance of oral glucose in the systemic circulation. 25,[45][46][47] As the rates of gastric emptying and intestinal glucose absorption were not measured, we could not evaluate the impact of oral glucose appearance on 1hPG levels.…”

Section: Discussionmentioning

confidence: 99%

One‐hour post‐load plasma glucose predicts progression to prediabetes in a multi‐ethnic cohort of obese youths

Tricò

Galderisi

Mari

et al. 2019

Diabetes Obesity Metabolism

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AIMS One‐hour post‐load hyperglycaemia has been proposed as an independent predictor of type 2 diabetes in adults. We examined whether 1‐hour plasma glucose (1hPG) during an oral glucose tolerance test (OGTT) can predict changes in the glucose tolerance status of a multi‐ethnic cohort of youths with normal glucose tolerance (NGT). Materials and methods A total of 202 obese youths with NGT (33.7% Caucasian, 31.1% Hispanic, 32.2% African American) underwent a 3‐hour OGTT at baseline and after a 2‐year follow‐up period. Whole‐body insulin sensitivity, insulin secretion, β‐cell function and insulin clearance were estimated by modeling plasma glucose, insulin and C‐peptide levels. Results Obese youths with 1hPG ≥7.4 mmol/L (or 133 mg/dL; n = 83) exhibited higher body mass index (BMI), plasma triglycerides and fasting and post‐load glucose concentrations than individuals with 1hPG <7.4 mmol/L. Also, 1hPG ≥7.4 mmol/L was associated with a lower disposition index (DI) (P < 0.0001) and with alterations in whole‐body insulin sensitivity, β‐cell function and insulin clearance. Adolescents with 1hPG ≥7.4 mmol/L were approximately three times more likely to develop prediabetes (ie, impaired glucose tolerance and/or impaired fasting glucose) over time (OR, 2.92 [1.22‐6.98]; P = 0.02), independent of age, sex, race/ethnicity, BMI, insulin sensitivity, DI and plasma glucose concentrations. No differences emerged in the risk of prediabetes related to 1‐hour hyperglycaemia among different ethnic groups. Conclusions A plasma glucose concentration ≥ 7.4 mmol/L at 1 hour during an OGTT is associated with a worse clinical and metabolic phenotype and may be an independent predictor of progression to prediabetes in obese youths with NGT.

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“…NGT individuals with a glucose concentration at 1-hour glucose ≥8.6 mmol/L were found to have impaired beta-cell function and postprandial glucose absorption was not increased. Fiorentino et al compared duodenal SGLT-1 (sodium/glucose co-transporter 1) expression from biopsy specimens in individuals with NGT and 1-hour glucose <8.6 mmol/L, with those having NGT and 1-hour glucose ≥8.6 mmol/L 31. In contrast to the findings of Adams et al , the NGT 1-hour high group showed an increase in the expression of duodenal SGLT-1 explaining the increased 1-hour absorption of glucose.…”

Section: Discussionmentioning

confidence: 99%

Metabolic characteristics of Africans with normal glucose tolerance and elevated 1-hour glucose: insight from the Africans in America study

Briker

Hormenu

Dubose

et al. 2020

BMJ Open Diab Res Care

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IntroductionRisk of insulin resistance, dyslipidemia, diabetes and cardiac death is increased in Asians and Europeans with normal glucose tolerance (NGT) and 1-hour glucose ≥8.6 mmol/L. As African descent populations often have insulin resistance but a normal lipid profile, the implications for Africans with NGT and glucose ≥8.6 mmol/L (NGT-1-hour-high) are unknown.ObjectiveWe performed oral glucose tolerance tests (OGTTs) in 434 African born-blacks living in Washington, DC (male: 66%, age 38±10 years (mean±SD)) and determined in the NGT group if either glucometabolic or lipid profiles varied according to a 1-hour-glucose threshold of 8.6 mmol/L.MethodsGlucose tolerance category was defined by OGTT criteria. NGT was subdivided into NGT-1-hour-high (glucose ≥8.6 mmol/L) and NGT-1-hour-normal (glucose <8.6 mmol/L). Second OGTT were performed in 27% (119/434) of participants 10±7 days after the first. Matsuda Index and Oral Disposition Index measured insulin resistance and beta-cell function, respectively. Lipid profiles were obtained. Comparisons were by one-way analysis of variance with Bonferonni corrections for multiple comparisons. Duplicate tests were assessed by к-statistic.ResultsOne-hour-glucose ≥8.6 mmol/L occurred in 17% (47/272) with NGT, 72% (97/134) with pre-diabetes and in 96% (27/28) with diabetes. Both insulin resistance and beta-cell function were worse in NGT-1-hour-high than in NGT-1-hour-normal. Dyslipidemia occurred in both the diabetes and pre-diabetes groups but not in either NGT group. One-hour glucose concentration ≥8.6 mmol/L showed substantial agreement for the two OGTTs (к=0.628).ConclusionsAlthough dyslipidemia did not occur in either NGT group, insulin resistance and beta-cell compromise were worse in NGT-1 hour-high. Subdividing the NGT group at a 1-hour glucose threshold of 8.6 mmol/L may stratify risk for diabetes in Africans.

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Duodenal Sodium/Glucose Cotransporter 1 Expression Under Fasting Conditions Is Associated With Postload Hyperglycemia

Abstract: Duodenal SGLT-1 expression is increased in individuals with 1-hour postload hyperglycemia or IGT, as well as in subjects with T2DM, and it positively correlates with early postload glucose excursion.

Cited by 37 publications

References 38 publications

The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes

The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes

One‐hour post‐load plasma glucose predicts progression to prediabetes in a multi‐ethnic cohort of obese youths

Metabolic characteristics of Africans with normal glucose tolerance and elevated 1-hour glucose: insight from the Africans in America study

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