*5.2. Glucans Used in Controlling T2D and Underlying Mechanisms*

Naturally derived *β*-glucans have been promoted due to their various reported healthpromoting activities and minimal side-effects. They have been widely adopted as healthimproving ingredients to prevent some chronic diseases, especially for T2D. For example, a clinical trial showed that oat *β*-glucan can help manage glycemic index, carbohydrate metabolism and alter gut microbiota profile in T2D [89,90]. There are two main underlying mechanisms for the roles of *β*-glucans in controlling T2D, which can be explained through their detailed structural and/or conformational features.

#### 5.2.1. Retardation of Macronutrient Absorption

Macronutrients within daily diets are necessary for life. However, ongoing quick absorption of these macronutrients in T2D can induce hyperglycemia and hyperlipidemia, and thereby cause metabolic disorders [91]. Hence, a way to help manage T2D is by preventing the absorption of macronutrients, resulting in a reduction in blood cholesterol levels and suppressing the postprandial increase of blood sugar levels [92]. This retardation effect of *β*-glucans has been shown to be highly dependent on their molecular weight and concentration. Wood et al. established the relationship of plasma glucose increment (D*G*pg) and structural features of oat *β*-glucan (concentration (*c*) and weight-average molecular weight (*Mw*)) as shown in the formula: D*G*pg = *A* + *B* × log10(*c*) + 0.72B log10(*Mw*) [93]. In addition, depolymerization of *β*-glucans (reducing molecular size) as a result of processing was reported to decrease its effect on decreasing the peak blood glucose response [17].

Additionally, *β*-glucans can play a role in increasing the viscosity of a meal during gastrointestinal digestion, limiting the absorption of macronutrients, slowing down gastric emptying, and entrapping bile acids and cholesterol throughout digestion. This lowers serum sugar and cholesterol levels in T2D [94]. These benefits are highly dependent on the structure and conformation of *β*-glucans, which can be explained by the Mark–Houwink equation for the intrinsic viscosity: [*η*] ∝ *K M*α, where the values of the parameters *K* and α depend on the particular polymer solution system [95].

#### 5.2.2. Inhibition of Digestive Enzyme

a-amylase and a-glucosidase are the two main enzymes necessary to hydrolyze carbohydrates in the digestive system. a-amylase can initiate carbohydrate hydrolysis by cleaving a-(1,4)-linked glycosidic bonds and yield smaller fractions, such as sucrose and maltose [96]. Then, a-glucosidase can hydrolyze these fractions into absorbable monosaccharides, such as glucose and fructose, during intestinal digestion [97]. Adequate free glucose can be generated after this digestive process, which may be excessively ingested into the bloodstream in T2D patients, leading to hyperglycemia. Therefore, inhibition of these enzymes to cause lower carbohydrate digestion can help control T2D. Ma et al. showed that a *β*-glucan adopting a triple helix conformation from *Hericium erinaceus* reduced wheat starch digestibility from 70% to less than 60% by inhibiting the digestive enzymes [98]. Qin et al. compared the glucose availability of the digestive system after adding different modified oat *β*-glucans, and all of these *β*-glucans decreased glucose availability, which indicated their potential hypoglycemic effect [17].

Lipases play an important role in hydrolyzing diet lipids; they convert lipids into cholesterol and fatty acids, which can be absorbed by enterocytes through lipid transporters [99]. Many studies have reported that *β*-glucans can inhibit lipase activity and therefore alleviate the hyperlipidemia seen in T2D. For example, barley *β*-glucans can slow lipolysis and reduce the release of free fatty acids; these inhibition effects were highly dependent on the molecular weights of the *β*-glucans [100].

There are some possible underlying mechanisms related to the enzyme inhibitor role of *β*-glucans, as shown in Figure 4. For example, these *β*-glucans, which can only be fermented in the large intestine, play a physical barrier role in the digestive system to inhibit the activity of these digestive enzymes [101]. At the same time, *β*-glucans can inhibit these digestive enzymes by mixed competitive and uncompetitive inhibition to suppress enzyme–substrate interactions and therefore reduce the digestion of substrates [102]. Both of these proposed mechanisms rely on the physiological conformations of the *β*-glucans *in vivo*. For example, the binding between *β*-glucans and enzymes follows the lock-and-key principle; therefore, the shapes (confirmations) of *β*-glucans under physiological conditions are a decisive factor for binding efficiency, thereby controlling the inhibition effect of these *β*-glucans [20,103].

It should be noted that other possible anti-diabetic mechanisms of *β*-glucans have been proposed. For example, the modulation effects of *β*-glucan on gut microbiota have been widely reported [89,104]. *β*-glucans can function as prebiotics, as they are mainly fermented in the large bowel and benefit the host-microbiota interactions in the whole gastrointestinal process. As a prebiotic, *β*-glucans alter the microbiota compositions by improving the number of beneficial bacteria, such as *Lactobacillus*, during large bowel fermentation [105,106], leading to an increase in short-chain fatty acids (SCFA), which can improve the colonic defense barrier in T2D [107]. In addition, *β*-glucans can regulate the superoxide dismutase and malondialdehyde levels in the livers of diabetic mice [108]. However, these reported effects need to be further explored. For example some particular structural features of *β*-glucans may be preferred by these beneficial bacteria. Again a better understanding of the structure and function relationship of *β*-glucans may help yield more potent health benefits.

**Figure 4.** The proposed mechanism of enzyme inhibition. (**A**) The normal enzyme–substrate interactions during digestion. (**B**) *β*-glucans play as a physical barrier to inhibit enzyme–substrate interactions. (**C**) *β*-glucans bind to enzymes to inhibit enzyme–substrate interactions.

#### **6. Conclusions**

*β*-glucans are sustainable polymers that widely exist in natural resources. These biomacromolecules mainly contain *β*-(1,3)-linked, *β*-(1,4)-linked and *β*-(1,6)-linked glycosidic bonds, and adopt several different conformations in solutions, such as a helical conformation, which seems to be the origin of their versatile biofunctions and thus furnish a target for targeting efficacy. For a detailed characterization of *β*-glucans, both chemical and instrumental methods should be combined to give accurate structural and conformational features, which can then be linked to an understanding of their functionalities. Although there are many reported anti-diabetic mechanisms of *β*-glucans, only two mechanisms, retardation of macronutrient absorption and inhibition of digestive enzymes, can be well explained through their detailed structures and conformations. However, current research on the anti-diabetic functions of *β*-glucans is focused on naturally derived *β* -glucans. It would be worthwhile to explore the underlying anti-diabetic mechanisms using synthetic *β*-glucans with detailed structural information. With improved understanding of the structure/function relationship of these molecules, precision designs of *β*-glucans with particular structures and/or conformations could be produced to help control T2D.

**Author Contributions:** Y.W.: writing—original draft, writing—review & editing. X.X.: writing review & editing, funding acquisition. M.A.S.: writing—review & editing, supervision, funding acquisition. R.G.G.: writing—review & editing, supervision, project administration, funding acquisition. All authors have read and agreed to the published version of the manuscript.

**Funding:** Y.W. gratefully acknowledges the support of a University of Queensland Research Training Scholarship. X.X. gratefully acknowledges financial support from National Natural Science Foundation of China (22075213, 21875167, and 21574102), National Key Research and Development Program of China (2016YFD0400202), and Key Research & Development Program of Hubei province (2020BCA079). M.A.S. is supported by an Advance Queensland Industry Research Fellowship, Mater Foundation, Equity Trustees and the L G McCallam Est and George Weaber Trusts. For R.G.G., partial funding was from the National Natural Science Foundation of China, grant number C1304013151101138, and the Priority Academic Program of Jiangsu Higher Education Institutions.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
