Glycaemic consequences of non-nutritive sweeteners in human health and type 2 diabtes
| dc.contributor.advisor | Young, Richard L. | |
| dc.contributor.advisor | Ivey, Kerry (Harvard Medical School) | |
| dc.contributor.author | Rose, Braden David | |
| dc.contributor.school | Adelaide Medical School | |
| dc.date.issued | 2024 | |
| dc.description.abstract | Prospective epidemiological studies have consistently shown that high habitual consumption of non-nutritive sweeteners (NNS) is positively associated with an increased risk of type 2 diabetes (T2D). However, mechanisms that underlie this association are not well defined. All sweet stimuli, including NNS, are detected by a single broadly-tuned sweet taste receptor (STR) located on taste-cells of the tongue, as well as in a range of extra-oral tissues and organs, including enteroendocrine cells of the small intestine. Activation of these intestinal STRs leads to the release of gut hormones, including glucose-dependent insulinotropic polypeptide (GIP) from K-cells and glucagon-like peptide-1 (GLP-1) and -2 (GLP-2) from L-cells. GIP and GLP-1 augment postprandial insulin release, while GLP-1 also slows gastric emptying, to control postprandial glycaemia; GLP-2 increases expression and function of the primary intestinal apical glucose transporter, sodium-glucose cotransporter-1 (SGLT-1), to augment glucose absorption. Recent randomised controlled trials have added support that dietary NNS activation of the STR-SGLT-1 axis to augment the rate of intestinal glucose absorption, and NNS perturbation of gut microbiome composition and function, can both evoke dysglycaemia in healthy individuals. However, the precise contribution of each mechanism is unclear. Moreover, the effects of high habitual NNS consumption on glycaemia in individuals with T2D remains poorly defined. Given that individuals with T2D consume NNS avidly to offset added sugars, have intrinsically augmented intestinal SGLT-1 function and glucose absorption, and perturbed gut microbiota, they are intuitively at increased risk of NNS-evoked dysglycaemia relative to healthy individuals. Using data from prospective case-control studies of T2D nested within the US Nurses’ Health Study, exploratory factor analysis and multivariable-adjusted regression revealed that a behavioural pattern of high habitual NNS-containing beverage consumption was positively associated with an increased risk of T2D, as well as perturbed leptin and IGF signalling. The first of two preclinical studies then aimed to determine the precise contribution of the gut microbiota to NNS-evoked dysglycaemia, by supplementing mice with combined NNS sucralose-acesulfame-K in drinking water over two weeks, with or without concurrent broad-spectrum antibiotic (ampicillin and neomycin) to deplete gut microbiota. Sucralose-acesulfame-K augmented jejunal glucose absorption by 31% independent of gut microbiota depletion, and altered GLP-1 responses to jejunal glucose in a partly microbiota-mediated manner, showing disruption to both intestinal and microbial mechanisms of glycaemic control. Next, an intestine-specific T1R2-knockout mouse model was pioneered to directly assess the involvement of intestinal STRs in NNS-evoked dysglycaemia. Two-week supplementation of sucralose-acesulfame-K in drinking water attenuated plasma GIP responses to intragastric glucose independent of intestinal-T1R2, while plasma GLP-1 responses were attenuated in intestine-specific T1R2-knockout mice, extending evidence on the role of intestinal-STR in gut hormone responses that regulate glucose homeostasis in rodents. Finally, a clinical study was undertaken to determine the effects of high habitual NNS consumption on glycaemia in individuals with T2D. In contrast to previous findings in health, two-week diet supplementation with encapsulated sucralose and acesulfame-K in participants with well-controlled T2D had no effect on glycaemic, absorptive, insulinaemic or gut hormone responses to enteral glucose, likely due, in part, to a T2D-intrinsic “ceiling” of intestinal SGLT-1 function and absorptive capacity. Together, findings from this thesis deepen mechanistic insight of how high habitual NNS consumption may increase T2D risk, evidencing that sucralose and acesulfame-K are not inert but have pleiotropic effects on distinct mechanisms of glycaemic control. This reinforces the concept that these NNS should not be endorsed as alternatives to added sugars for healthy individuals, or individuals at risk of T2D, and demands larger, longer-term NNS exposure randomised controlled trials to further translate findings here to public health policy and industry practices. | |
| dc.description.dissertation | Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2024 | en |
| dc.identifier.uri | https://hdl.handle.net/2440/146664 | |
| dc.language.iso | en | |
| dc.provenance | This thesis is currently under embargo and not available. | en |
| dc.subject | Non-nutritive sweeteners | |
| dc.subject | type 2 diabetes | |
| dc.subject | glycaemia | |
| dc.title | Glycaemic consequences of non-nutritive sweeteners in human health and type 2 diabtes | |
| dc.type | Thesis | en |
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