Applied nutritional investigationEffects of intraduodenal hydroxycitrate on glucose absorption, incretin release, and glycemia in response to intraduodenal glucose infusion in health and type 2 diabetes: A randomised controlled trial
Introduction
In type 2 diabetes, poor glycemic control, indicated by glycated hemoglobin (HbA1c), predicts the development and progression of micro- [1] and to a lesser extent macrovascular [2] complications. In patients with type 2 diabetes who have an HbA1c ≤ 7.5% (58 mmol/mol), postprandial hyperglycemia predominates over fasting blood glucose in determining HbA1c [3]. Even when HbA1c levels are comparable, patients with larger glycemic fluctuations may be at greater risk [4]. Therefore, there is considerable interest in exploring interventions that have the potential to minimize postprandial hyperglycemia.
The dried rind of the fruit of Garcinia cambogia has been used traditionally in India and Southeast Asia as a culinary ingredient to render meals more filling. Extracts from this fruit, which contain hydroxycitric acid (HCA) as the active ingredient, have gained popularity as a dietary supplement to reduce appetite and facilitate weight loss [5], although with limited support for efficacy from short-term clinical trials [6]. Proposed mechanisms of weight loss, based on rodent studies, include a reduction in lipogenesis through inhibition of ATP-citrate-lyase [7], suppression of appetite by elevating brain serotonin levels [8], reductions in plasma insulin levels [9], and inhibition of enteral absorption of glucose [10]. HCA has been shown to delay glucose absorption in rodents, with consequent reductions in peak blood glucose and plasma insulin concentrations in response to intragastric or intraduodenal glucose administration, although the overall area under the curve (AUC) for blood glucose was not affected [10].
A delay in glucose absorption could potentially alter the secretion of the “incretin” hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), which are known to augment insulin secretion in healthy humans when glucose is given by the enteral route compared to an isoglycemic intravenous infusion (ie, the “incretin effect”) [11]. In type 2 diabetes, the insulinotropic effect of GIP is diminished, whereas that of GLP-1 remains relatively intact [12]. The α-glucosidase inhibitor, acarbose, which delays the postmeal glucose release in the gut, has been shown to attenuate GIP release from the proximal small intestinal K cells, and augment the release of GLP-1 from the L cells, located more densely in the distal gut [13].
Here, we report the effects of intraduodenal administration of HCA on blood glucose concentrations, glucose absorption, and incretin hormone release in response to a subsequent intraduodenal glucose infusion, in both healthy individuals and patients with type 2 diabetes. Our hypothesis was that pretreatment with HCA would reduce the glycemic excursion in response to intraduodenal glucose, via inhibition of glucose absorption and augment the release of the distal gut hormone, GLP-1, at the expense of the proximal intestinal hormone, GIP.
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Participants
We studied 12 healthy individuals (7 men and 5 women; age [mean ± SEM] 33.4 ± 4.6 y; body mass index [BMI] 23 ± 0.8 kg/m2) and 8 older and overweight patients with type 2 diabetes (4 men and 4 women; age 65.8 ± 2.2 y; BMI 31 ± 1.4 kg/m2; known duration of diabetes 85 ± 24 mo; HbA1c 6.7 ± 0.3% [49.7 ± 3.3 mmol/mol]). All participants provided written informed consent. Diabetes was managed by diet alone (four patients), or metformin (500−1000 mg) in addition to diet (four patients); metformin was
Results
None of the individuals who completed the study reported any adverse effects from the use of HCA (Fig. 1).
Discussion
Results of this study demonstrated that, in healthy individuals, acute small intestinal exposure to HCA (2800 mg) resulted in a modest reduction of blood glucose during fasting and after an intraduodenal glucose load. The latter was not accounted for by changes in glucose absorption or stimulation of GLP-1 or insulin, but was associated with enhanced GIP and glucagon responses to intraduodenal glucose. However, in patients with type 2 diabetes, small intestinal infusion of HCA neither lowered
Conclusion
Intraduodenal administration of HCA in advance of a small intestinal glucose load resulted in a modest reduction in glycemia in healthy individuals, but not in patients with type 2 diabetes. The mechanism of glycemic reduction in the former group was apparently unrelated to inhibition of small intestinal glucose absorption or stimulation of insulin secretion, despite an increase in GIP concentrations. Our findings do not support the use of HCA for the management of postprandial hyperglycemia in
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Cited by (0)
This study was supported by funding from the National Health and Medical Research Council of Australia (NHMRC, Project grant 1066815). SST received scholarship funding from the University of Adelaide and the Rebecca L. Cooper Foundation. TW was supported by Royal Adelaide Hospital Research Committee Early Career Fellowship. Hydroxycitric acid (SuperCitriMax®) was provided free of charge, by the InterHealth Nutraceuticals Incorporated, Benicia, California, USA. None of these supporting bodies had any influence on study design; on the collection, analysis, or interpretation of data; on the writing of the report; or on the decision to submit the article for publication. SST was involved in participant recruitment, coordination, data collection and interpretation, statistical analysis, and drafting of the manuscript. TW was involved in data interpretation, statistical analysis, and drafting of the manuscript. MJB and HLC assisted in recruitment and data collection. SS was involved in the data analysis. KLJ was involved in the conception and design of the study and data interpretation. MH was involved in the conception and design of the study and data interpretation. CKR was involved in the conception and design of the study, data interpretation, and had overall responsibility for the study. All authors critically reviewed the manuscript, and approved the final version of the manuscript. The authors have no conflicts of interest to declare.