Discussion
This study examined the application of premeal WP supplementation on daily glycemic control over 1 week in people with T2D. For the first time, we demonstrate that daily hyperglycemia can be significantly reduced by the provision of a low dose of WP (15 g) ingested prior to each main meal over 7 days of free-living. This enabled patients to achieve 2 hours more per day spent within euglycemia, without increasing the risk of hypoglycemia. These results occurred without a change in patient medication, dietary intake, or physical activity levels, thereby demonstrating the utility of premeal WP supplementation for the management of hyperglycemia.
The present study extends from previous acute laboratory work highlighting the PPG-lowering efficacy of premeal WP for people with T2D.10–13 However, for the first time, we report the translatability and reproducibility of these findings under real-world and free-living conditions. It was found that premeal ingestion of our novel WP shot effectively mitigated free-living PPG excursions, thereby reducing the prevalence of hyperglycemia by ~2 hours per day, compared with PLA. This subsequently enabled an absolute daily increase in TIR of 8.7%, the magnitude of which is substantial. Indeed, an increase in TIR of ≥5% is considered clinically significant27 and may be associated with a reduced risk of developing vascular complications.28 29 For instance, for every 10% reduction in TIR (roughly equivalent to the increase in TIR in the present study with mealtime WP supplementation), the risk of developing retinopathy or microalbuminuria was increased by 64% and 40%, respectively, in the Diabetes Control and Complications Trial cohort.29 A similar 10% reduction in TIR has also been associated with a 13% and 25% increased risk of developing cardiovascular autonomic neuropathy and peripheral neuropathy, respectively, in people with long-standing T2D.30 31 Promisingly, the preload treatments were well accepted among participants, as demonstrated by their exemplary compliance, and no adverse side effects were reported supporting the application of this novel mealtime therapy.
The findings presented herein are of interest given our data demonstrate that the intervention of available oral antihyperglycemic medications are insufficient in the protection against hyperglycemia. Current recommendations state that people with T2D should strive for <6 hours per day at glucose concentrations >10.0 mmol/L.24 However, despite the continued use of patient’s antihyperglycemic agents, our cohort spent up to 9 hours (38%) of the day at glucose concentrations >10.0 mmol/L during the PLA free-living week. This observation is similar to what has been reported by others32 and underscores the need for further strategies designed to reduce the prevalence of hyperglycemia in people with T2D.
Our primary finding that premeal WP supplementation reduces the prevalence of hyperglycemia corroborates with data demonstrating a reduction in overall hyperglycemia following the application of PPG-lowering therapies.33 Indeed, our observed reduction in time spent >10.0 mmol/L derived from the waken/feeding period, as shown by the reduction in diurnal but not nocturnal hyperglycemia. Although the free-living nature of our study makes it difficuilt to discern mechanisms associated with our findings, prior literature has demonstrated that a WP preload of similar amounts (15–20 g) elevates GLP-1 above preprandial concentrations for ~180 min following ingestion of a meal.12 13 23 The ingestion of WP also modestly stimulates the secretion of glucose-dependent insulinotropic polypeptide (GIP)12; though the relevance of this to the observed improvement in glycemic control is likely minimal since endogenous GIP has little to no effect on PPG in individuals with T2D.34 Herein, it is possible that diurnal increases in GLP-1 secretion from thrice daily WP supplementation may have enhanced β-cell glucose sensitivity and delayed the rate of gastric emptying, thereby slowing the systemic appearance of meal-derived glucose and augmenting an efficient islet response.35 36 These effects are consistent with what was previously observed following adminstration of a protein preload given prior to an oral glucose load,37 supporting this assertion. Nonetheless, literature examining the glucoregulatory effects of premeal WP have been conducted solely following an overnight fast. Considering the regulation of PPG displays a clear circadian pattern,38 whether a low dose of mealtime WP supplementation is sufficient to augmenting a PPG-lowering milieu to meals consumed later in the day is unclear and requires future study.
The present analyses demonstrates that the addition of premeal WP to patient care has the potential to reduce daily hyperglycemia and increase TIR without increasing the risk of hypoglycemia, as shown by the low blood glucose index and time spent below range. An increase in TIR is also suggestive that the frequency of erratic glycemic swings were reduced with mealtime WP.39 Fluctuations in glycemia are posited to be implicated in the pathogenesis of diabetes-related vascular complications, supporting the development of strategies designed to reduce glycemic variability.40 Although there were no changes in amplitude markers of glycemic variability with WP supplementation (ie, %CV), this likely reflects the relative glycemic stability of the cohort studied since all patients had a %CV <36%.24 Nevertheless, the risk of microvascular complications has recently been shown to be inversely related to TIR, independent of %CV.28 Therefore, although there were no changes in amplitude markers of glycemic variability with the WP treatment, this is unlikely to affect the clinical value of our results.
To the best of the authors’ knowledge, this is the first study designed and powered to examine the use of premeal WP on free-living glycemic management captured by masked CGM. Our study is rendered timely as its design benefits from incorporating current recommendations that endorse the use of CGM when assessing glycemic control at the individual level.26 Offering ecological validity to our findings, patient’s GMI during PLA was identical to their laboratory-measured HbA1c. This suggests that our reported data reflects a true change from participant’s habitual glycemic control.25 In this regard, an increase in TIR of ~9% with premeal WP supplementation is projected to confer a ~5–7 mmol/mol (0.6%) reduction in HbA1c.16 27 This assertion is supported by our findings of a reduction in mean daily glucose concentrations (−0.6 mmol/L). In the context of available treatments for T2D, the magnitude of this projected reduction in HbA1c is akin to what would be expected from the adminstration of thiazolidinediones, sodium–glucose cotransporter 2 inhibitors and dipeptidyl peptidase-IV inhibitors.41 Considering adherence to pharmacological agents can be poor,7 the data presented herein may hold important implications for the management of hyperglycemia.
When accounting for the energy associated with the preloads, daily energy intake was similar between treatments. This was despite patients consuming an additional ~836 kJ/day when adherent to the WP shot, compared with PLA. Therefore, patients may modestly adjust their energy intake to account for the caloric load associated with a small WP preload. This is in line with previous observations that reported no change in body mass following the long-term ingestion of mealtime WP supplementation (~753 kJ/day) in people with T2D.14 These collective findings are appealing and suggest that the adherence to a low dose of premeal WP is unlikely to compromise weight management in obese and dysglycemic populations.
There are several strengths associated with our study including our randomized, placebo-controlled, crossover design, and the counterbalanced administration of treatments to minimize treatment order effects. Furthermore, and unique to this study, patients were provided with premeal WP and PLA shots created specifically for the real-world application of mealtime WP supplementation. Nonetheless, our study is not without its limitations. First, our analyses were conducted on people of white, Europid descent; thus, the applicability of these results to other ethnic groups and races is unclear. Second, although our study was powered to test the primary outcome, we acknowledge that our analyses are conducted on a small sample of people with T2D (n=18). Since our patients were of relatively controlled diabetes and treated with oral therapies, our findings cannot be extrapolated to the wider T2D population. Finally, although our findings indicate an improvement in glycemic control with mealtime WP supplementation, the long-term evidence supporting our data is lacking with only one study to date reporting a modest improvement in HbA1c with premeal WP supplementation.14 Whether the results presented herein are sustainable longer term or are associated with improvements in clinically relevant end points cannot be inferred and require further investigation. Importantly, however, the glucose-lowering mechanisms by which premeal WP supplementation regulates PPG remain functionable after its chronic application14 supporting these findings.
In summary, we show that thrice daily consumption of a novel preload shot containing a low dose of WP reduces daily hyperglycemia, increasing the time spent in euglycamia by ~2 hours per day during 7 days of free-living. This is of importance given our analysis clearly demonstrates that the prevelance of hyperglycemia is an underappreciated problem for people with controlled T2D treated with available oral medications. The provision of a contemporary WP preload shot may represent an effective sole or adjunctive therapy for the treatment of hyperglycemia, which could also have important financial implications at a time where public health budgets are constrained.