In a recent study published in Life Metabolism, researchers first used a diet-induced obese (DIO) murine model to check the consequences of an extract of yellow petals of Dahlia pinnata as a novel treatment of type 2 diabetes (T2D).

Next, they performed a cross-over randomized controlled study in individuals with pre-diabetes and T2D to check its dose-dependent glucose-lowering effects, safety, and efficacy.

​​​​​​​Study: A dahlia flower extract has antidiabetic properties by improving insulin function within the brain. Image Credit: Shingo76Misumaru/Shutterstock.com

Background

Glucose intolerance and insulin resistance (IR) are key features of T2D pathogenesis. Claude Bernard discovered that the brain controls blood glucose levels back in 1885.

Around 150 years later, researchers revisited his findings and located that dysregulation of the central pathways of glucose homeostasis within the hypothalamus was considered the basis explanation for T2D.

Specifically, circulating insulin reaches the hypothalamus, binds its receptor, and autophosphorylates, which, in turn, recruits and phosphorylates insulin receptor substrate (IRS).

It prompts the phosphatidylinositol 3-kinase (PI3K) – protein kinase B (AKT) pathway that initiates the cascade of metabolic effects of insulin.

Studies have shown that inflammation within the hypothalamus promotes IR via the nuclear factor kappa B kinase subunit beta (IKKβ)/nuclear factor kappa B (NF-κB) inflammatory pathway.

Thus, pharmacological inhibition of NF-κB within the arcuate nucleus (ARC) residing neurons of the hypothalamus could weaken glucose intolerance and help treat hypothalamic inflammation.

Preclinical studies have shown that IKKβ inhibitor butein markedly lowered glucose and sensitized insulin in DIO mice by targeting hypothalamic inflammation.

The bark of Toxicodendron vernicifluum, the Chinese lacquer tree, is one of the best natural source of butein, a rare flavonoid, albeit with limited medical use attributable to its toxicity.

Concerning the study

In the current study, researchers tested the effect of D. pinnata’s flower extract, a non-toxic ornamental flower plant containing butein.

They obtained 12 to 14-week-old male C57BL/6 mice and fed them a high-fat weight-reduction plan (HFD) to induce obesity. Mice fed with a low-fat weight-reduction plan (LFD) served as controls.

After 4 weeks, they administered one, 3.3, and 10mg/kg body weight (BW) dahlia extract by oral gavage to check mice. Likewise, controls received 0.9% sodium chloride (NaCl) containing 5% ethanol (EtOH). Additionally they injected 1.5 g/kg BW glucose intraperitoneally (IP). 

After one hour of dahlia extract administration, they performed an intraperitoneal glucose tolerance (ipGTT) test on all DIO mice. They used a glucometer to measure their blood glucose levels.

The team also tested the consequences of other flavonoids, 10 mg/kg butein, sulfuretin, isoliquiritigenin, or their combos in one other cohort of mice.

After the IP administration of insulin, additionally they performed an insulin tolerance test (ITT) on a cohort of HFD or LFD-fed mice. Moreover, the researchers conducted chronic treatment studies in mice fed with HFD or the LFD ad libitum for five weeks.

Further, the team performed intracerebroventricular (ICV) infusion of PI3K inhibitors in mice.

These animals then received the dahlia extract (10 mg/kg body weight) by oral gavage one hour later, and after one other 60 minutes, they were subjected to an ipGTT. The researchers also conducted immunohistochemistry (IHC) on mouse brain coronal cryosections.

Moreover, the team studied the role of the IKKβ-NF-κB pathway using epifluorescence microscopy in Zebrafish incubated for six hours in HFD and five hours later in dahlia extract (2.75 µg/mL).

Finally, the team performed a clinical study amongst 13 males aged 18−70 with glycated hemoglobin (HbA1c) concentrations between 40−65 mmol/mol to check the consequences of three doses of dahlia extract. 

They first supplemented all participants with capsules containing 5, 20, or 50 mg of powdered dahlia extract.

Next, they subjected them to a baseline oGTT. Post-12-hour overnight fasting, they asked all of the participants to drink 75 g of anhydrous glucose dissolved in water, drew their venous blood samples, and withdrew their blood samples every 30 min until three hours for glucose, C-Peptide, and insulin levels quantification.

The team compared the world under the curve (AUC) of the oGTT over three hours for the three doses of the dahlia extract to the AUC of the baseline oGTT. They monitored them for hostile reactions and tracked their complete blood count.

Results

In DIO mice, orally administered EtOH dahlia extract containing high amounts of butein improved glucose tolerance and insulin sensitivity.

These effects didn’t diminish after chronic treatment, suggesting it could help sustain glucose homeostasis in the long run. Furthermore, chronic treatment didn’t alter the mice’s liver morphology, liver fat content, or weight. 

Nonetheless, ICV application of butein in DIO mice was ineffective, reflecting the effect of leptin on intestinal barrier function and differences in blood-brain-barrier (BBB) function between HFD-fed and leptin-deficient mice.

The chalcone isoliquiritigenin and the aurone sulfuretin together with butein also elicited the glucose-lowering effects in DIO mice, likely by functionally interacting in vivo. 

Further studies should investigate whether flavonoids present within the extract or their metabolites mediated the useful effects of the dahlia extract on glucose homeostasis.

On the molecular level, HFD feeding led to low-grade inflammation within the hypothalamus, ultimately resulting in the event of T2D.

It also led to reactive astrogliosis within the hypothalamus, reflecting the pro-inflammatory nature of the HF weight-reduction plan, which contributed to the functional impairment of neuronal circuits governing energy homeostasis. 

Hypothalamic insulin signaling, particularly PI3K, mediated the dahlia extract’s glucoregulatory effects.

Further, the dahlia extract prevented the onset of astrogliosis after HFD feeding, and the development of glucose tolerance was related to suppressing inflammatory signaling pathways throughout the hypothalamus. 

In Zebrafish, the dahlia extract reduced hyperactivity of NF-κB pathway but didn’t decrease NF-κB activity to levels below controls. 

Regardless that the dahlia extract improved glucoregulation in individuals with each pre-diabetes and T2D, in five participants with HbA1c ≥ 48 mmol/mol, the glucose-lowering effect of the 60 mg/m2 dahlia extract dose was more pronounced, suggesting dahlia extract was best within the treatment of patients who had already developed T2D. 

Conclusions

To conclude, the present study results showed that the extract of yellow petals of D. pinnata restored glucose homeostasis in HFD-fed mice.

Moreover, it was secure and effective in humans, necessitating further testing of its efficacy and safety as a therapeutic for individuals with T2D.