Insulin sensitivity depends on the route of glucose administration

Geltrude Mingrone,Simona Panunzi,Esmeralda Capristo,John J Nolan,Chiara Barbieri,Valerio Spuntarelli,Amalia Gastaldelli,Isabel Bondia-Pons,Sofie Ahlin,Andrea De Gaetano

doi:10.1007/s00125-020-05157-w

Abstract

Aims/hypothesisThe small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels.MethodsIn this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (Ra) and disappearance (Rd) and endogenous glucose production (EGP) were calculated by infusing [6,6-2H2]glucose with or without oral [U-13C6]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment.ResultsGlucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min−1 kg−1 per nmol/l for oral, p< 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p< 0.001). The disposition index was significantly lower during the oral procedure: 4260 ± 1820 vs 5000 ± 2360 (ml min−1 kg−1 (nmol/l)−1 pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration.Conclusions/interpretationOur study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance.Trial registrationClinicalTrials.gov NCT03223129.Graphical abstract

Highlights

Until a few decades ago, diabetes was considered a disease essentially driven by pancreatic beta cell failure
To evaluate whether different degrees of insulin sensitivity coupled with a different insulin secretory efficiency could elicit distinct responses to the oral vs the intravenous route of glucose administration, we extended our previous investigation to different glycaemic states
A higher peak plasma glucose was observed in type 2 diabetes than in normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) (NGT 9.79 ± 1.01; IGT 9.61 ± 1.32; type 2 diabetes 12.38 ± 3.62 mmol/l; p = 0.047)

Summary

Introduction

Until a few decades ago, diabetes was considered a disease essentially driven by pancreatic beta cell failure While this concept holds true for type 1 diabetes, in type 2 diabetes insulin resistance develops long before beta cell failure and overt hyperglycaemia [1,2,3] and, it is recognised as the primary defect leading to type 2 diabetes. In the 1960s, it was shown that oral administration of 20 g of glucose in normal adults resulted in a much larger rise of plasma insulin compared with the administration of the same amount of glucose intravenously [16]. It seems likely that some form of suppression of insulin activity is at play after oral glucose dosing

Objectives

Methods

Results

Conclusion