Improved Beta Cell Glucose Sensitivity Plays Predominant Role in the Decrease in HbA1c with Cana and Lira in T2DM

2020 ◽  
Vol 105 (10) ◽  
pp. 3226-3233 ◽  
Author(s):  
Ali Muhammed Ali ◽  
Andrea Mari ◽  
Robert Martinez ◽  
Hussein Al-Jobori ◽  
John Adams ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Function ◽  
Tolerance Test ◽  
Additive Effect ◽  
Oral Glucose ◽  
Significant Difference ◽  
Beta Cell Glucose Sensitivity ◽  
Glucose Sensitivity ◽  
Cell Glucose

Abstract Aim To examine the effect of combination therapy with canagliflozin plus liraglutide versus each agent alone on beta cell function in type 2 diabetes mellitus (T2DM) patients. Research Design and Methods A total of 45 poorly controlled (HbA1c = 7%-11%) T2DM patients received an oral glucose tolerance test (OGTT) before and after 16 weeks of treatment with: (i) liraglutide (LIRA); (ii) canagliflozin (CANA); (iii) liraglutide plus canagliflozin (CANA/LIRA). Results Both liraglutide and canagliflozin significantly lowered HbA1c with no significant additive effect of the combination on HbA1c (0.89%, 1.43%, and 1.67% respectively). Insulin secretion during the OGTT, measured with (∆C-Pep/∆G)0-120, increased in the 3 groups (from 0.30 ± 0.06 to 0.48 ± 0.10; 0.29 ± 0.05 to 0.98 ± 0.23; and 0.24 ± 0.06 to 1.09 ± 0.12 in subjects receiving CANA, LIRA and CANA/LIRA respectively; P = 0.02 for CANA vs LIRA, P < 0.0001, CANA/LIRA vs CANA), and the increase in insulin secretion was associated with an increase in beta cell glucose sensitivity (29 ± 5 to 55 ± 11; 33 ± 6 to 101 ± 16; and 28 ± 6 to 112 ± 12, respectively; P = 0.01 for CANA vs LIRA, P < 0.0001, CANA/LIRA vs CANA). No significant difference in the increase in insulin secretion or beta cell glucose sensitivity was observed between subjects in LIRA or CANA/LIRA groups. The decrease in HbA1c strongly and inversely correlated with the increase in beta cell glucose sensitivity (r = 0.71, P < 0.001). In multivariate regression model, improved beta cell glucose sensitivity was the strongest predictor of HbA1c decrease with each therapy. Conclusion Improved beta cell glucose sensitivity with canagliflozin monotherapy and liraglutide monotherapy or in combination is major factor responsible for the HbA1c decrease. Canagliflozin failed to produce an additive effect to improve beta cell glucose sensitivity above that observed with liraglutide.

Impact of incretin hormones on β-cell function in subjects with normal or impaired glucose tolerance

2006 ◽  
Vol 291 (6) ◽  
pp. E1144-E1150 ◽  
Author(s):  
Elza Muscelli ◽  
Andrea Mari ◽  
Andrea Natali ◽  
Brenno D. Astiarraga ◽  
Stefania Camastra ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Cell Function ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Cell Glucose

The mechanisms by which the enteroinsular axis influences β-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate β-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 ± 0.18, P = 0.004] amounted to 18 ± 2 nmol/m2 (32 ± 4% of oral response), and its time course matched that of total insulin secretion. The β-cell glucose sensitivity (OGTT/IV ratio = 1.52 ± 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 ± 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, β-cell glucose sensitivity (75 ± 14 vs. 156 ± 28 pmol·min−1·m−2·mM−1 of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of β-cell glucose sensitivity (OGTT/IV ratio = 1.73 ± 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of β-cell function, particularly β-cell glucose sensitivity. In IGT, β-cell function is inherently impaired, whereas the incretin effect is only partially affected.

scholarly journals Risk Factors for Spontaneously Self-Reported Postprandial Hypoglycemia After Bariatric Surgery

2016 ◽  
Vol 101 (10) ◽  
pp. 3600-3607 ◽  
Author(s):  
Monica Nannipieri ◽  
Anna Belligoli ◽  
Daniela Guarino ◽  
Luca Busetto ◽  
Diego Moriconi ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Cell Function ◽  
Tolerance Test ◽  
The Body ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Β Cell ◽  
Fasting Glycemia ◽  
Glucose Sensitivity ◽  
Cell Glucose

Context: Postprandial hypoglycemia (PPHG) is a recognized complication of Roux-en-Y gastric bypass (RYGB) surgery. Data on PPHG after laparoscopic sleeve gastrectomy (LSG) are scant. Objective: The objective of the study was to identify preoperative predictors of PPHG in subjects spontaneously self-reporting PPHG after RYGB or LSG. Patients, Setting, and Intervention: Nondiabetic patients spontaneously self-reporting symptoms/signs of PPHG (PPHG group, 21 RYGB and 11 LSG) were compared in a case-control design with subjects who never experienced spontaneous or oral glucose tolerance test (OGTT)-induced hypoglycemia over 24 months after surgery (No-PPHG group, 13 RYGB and 40 LSG). Paired pre- and postoperative 3-hour OGTTs were analyzed in all participants. Main Outcome Measures: Insulin sensitivity was assessed by the oral glucose insulin sensitivity index and β-cell function by mathematical modeling of the C-peptide response to glucose. Results: Before surgery, the body mass index was lower in PPHG than No-PPHG patients in the RYGB (P = .002) and trended similarly in the LSG group (P = .08). Fasting glycemia and the glucose-OGTT nadir were lower in the PPHG than the No-PPHG subjects in both surgery groups. Before surgery, insulin sensitivity was higher in PPHG than No-PPHG in the RYGB (393 ± 55 vs 325 ± 44 mL/min−1 · m−2, P = .001) and LSG groups (380 ± 48 vs 339 ± 60 mL/min−1 · m−2, P = .05) and improved to a similar extent in all groups after surgery. Before surgery, β-cell glucose sensitivity was higher in PPHG than No-PPHG in both RYGB (118 ± 67 vs 65 ± 24 pmol/min−1 · m2 · mM−1) and LSG patients (114 ± 32 vs 86 ± 33) (both P = .02) and improved in all subjects after surgery. Conclusions: In subjects self-reporting PPHG after surgery, lower presurgery plasma glucose concentrations, higher insulin sensitivity, and better β-cell glucose sensitivity are significant predictors of PPHG after both RYGB and LSG.

scholarly journals Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity

2020 ◽  
Vol 106 (1) ◽  
pp. 80-90
Author(s):  
Harshal A Deshmukh ◽  
Anne Lundager Madsen ◽  
Ana Viñuela ◽  
Christian Theil Have ◽  
Niels Grarup ◽  
...  
Keyword(s):  
Beta Cell ◽  
Meta Analysis ◽  
Pancreatic Beta Cell ◽  
P Value ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Beta Cell Glucose Sensitivity ◽  
Glucose Sensitivity ◽  
Cell Glucose

Abstract Context Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. Objective To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. Design We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. Results Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10−9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10−9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. Conclusion We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.

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