1. Regulating the Intestinal Microbiota Disorder
The risk of development of type 2 diabetes mellitus (T2DM) could be prevented by RS through the gut microbiota, with the help of regulating the abundance of microbiota, to produce starch-degrading enzymes, and improving the intestinal barrier function 
. Gut microbiota are composed of a variety of commensal microorganisms, including certain amounts of bacteria, fungi and viruses. They play an important role in regulating the metabolic, endocrine and immune functions 
Short chain fatty acids (SCFAs) are one of the important bio products of intestinal microbiota, mainly including acetic acid (C2), propionic acid (C3) and butyric acid (C4). These three SCFAs are also the most abundant SCFAs in the human body 
. SCFAs are mainly produced from the fermentation of non-digestible carbohydrates (e.g., RS) 
. They can improve the insulin resistance (IR) and T2DM, by regulating the related metabolic pathways. Different from the mechanisms that affect glucose homeostasis directly, SCFAs impact the host health at the cellular, tissue and organ levels 
SCFAs can promote the secretion of two important key intestinal hormones, namely the glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). This secretion-boosting effect is able to increase the satiety by acting on the gut-brain axis. By this pathway, SCFAs can reduce appetite and food intake indirectly, which could prevent weight gain and thereby lower the risk of diabetes. SCFAs can also regulate the blood glucose concentrations by increasing the insulin secretion mediated by GLP-1 
. Nielsen et al. 
found that, compared with the Western-style diet (WSD) group, there were 2- to-5-fold increases of butyrate pool size in the large intestinal digesta in the RS diet (RSD) and arabinoxylan diet (AXD) groups. They inferred that the result of stimulating the insulin secretion was caused by the promotion of the intestinal endocrinology of PYY, which inhibited the timing of the gastric and intestinal translocation. Then, the appetite was suppressed while the GLP-1 secretion was promoted. Hughes et al. 
found that the fasting and peak concentration of peptide PYY3-36 increased while the peak concentration and AUC of the glucose-dependent insulinotropic peptide decreased after the healthy adult subjects ingested RS2-enriched wheat. Binou et al. 
found that the bread rich in the β-glucans (βGB) groups and the bread rich in the RS (RSB) groups elicited a lower incremental area under the curve (AUC) for the glycemic response, compared with the control group (glucose solution, GS). At 15 min after the βGB and RSB intakes, a significant reduction in appetite and an increase in satiety were detected in the healthy adults, and this trend continued up to the 180th min. The result showed that the food containing RS could retard the absorption of glucose. Maziarz et al. 
found that the total concentration of PYY in the high-amylose maize type 2 resistant starch (HAM-RS2) group was significantly higher than in the control group (p
= 0.043) at 120 min. At the same time, the AUC glucose (p
= 0.028) was decreased at the end of 6 weeks in the HAM-RS2 group, while this trend was not related to the changes in the subjects’ physical composition or total energy intake. This result might be caused by the SCFAs that are produced from the fermentation of HAM-RS2 by the bacteria in the lower GI tract. At the same time, the relevant studies have suggested that HAM-RS2 might show its benefits by increasing the SCFAs in the blood to alter the free fatty acid and glycerol that are released by adipocytes, regulate the bile acid metabolism 
or alter the intestinal microbiota profile 
2. Resisting Digestion
It has been shown that RS could regulate the levels of glucose and insulin in vivo and be beneficial to maintain the homeostasis of glucose. Due to its metabolic characteristics of slow absorption, RS plays a significant role in controlling and intervening in the condition of diabetes by reducing fasting and the postprandial blood glucose, as well as increasing the IS 
Bindels et al. 
have shown that the increase of the insulin level mediated by RS also occurred in the absence of the relevant microbiota, through parallel experiments on RS fed conventional mice and sterile mice. The cecal concentrations of several bile acids (BAs) were changed, and the gene expression of the macrophage markers was reduced in the adipose tissue, of which the polarization phenotypes was implicated in the control of IS in both mice groups. The result showed that both the IS and the glucose homeostasis could be regulated by the BAs via the nuclear farnesoid X receptor (FXR) and the membrane-bound TGR5 signaling.
Wang et al. 
found that the average blood glucose and the postprandial blood glucose could be reduced significantly in T2DM patients, with the blood glucose fluctuations decreasing after the RS diet treatment and the oral administration of glucose. The results were preliminarily inferred to be related to the anti-digestion characteristics of RS. Strozyk et al. 
found that, compared with the fresh rice (NR) group, the peak of the postprandial blood glucose in type 1 diabetes was lower in the cooling and reheated rice (CR) group. A shorter time of the glycemic peak has also been observed in the CR group, suggesting a beneficial effect to the glycemic control, as the delayed glycemic peak could improve the activity of the short-acting insulin analogues. Yadav et al. 
] have also found that the content of RS was increased in starch products with multiple heating/cooling cycles, while the content of digestible carbohydrates was reduced. Haini et al. 
found that, compared with the control group, the 2-h postprandial glucose of healthy female subjects was lower in the high-amylose maize starch 30 (HM30) group. In the HM group, 30% wheat flour has been replaced by HM in a Chinese steamed bun (CSB), which decreased the content of the digestible starch and the digestion speed of the starch. Therefore, the glycemic response and the increase in the postprandial blood glucose of healthy adult subjects have been delayed. Djurle et al. 
found similar results, a slower rise of the postprandial glucose in healthy adult subjects was observed in the RS bread group. In this group, the breads were made with refined flour containing RS. Maki et al. 
. have assessed the effects of the two doses of HAM-RS2 intake on the IS participants with different waist circumferences. The participants were randomized to receive 0 (control starch), 15, or 30 g/d (double-blind) of HAM-RS2 for four weeks with washout intervals of three weeks. At the end of each period, the minimal model IS had been evaluated by using an insulin-modified intravenous glucose tolerance test. The present results suggested that the intake of HAM-RS2 at 15–30 g/d could improve IS in obese men whereas no significant change in IS was observed in women for reasons that remain to be determined. Zeng et al. 
. found that the type 3 resistant starch (RS3) couldn’t be degraded into glucose by the digestive enzymes in the human intestine, which could reduce the amount of the glucose conversion by the human body. The RS3 could also reduce the glycemic index that helped to reduce the postprandial blood glucose. At the same time, Wang’s study 
has shown that RS3 could stabilize the human blood glucose by repairing the pancreas β cell function, as well as improving the IS and IR of the peripheral tissues. Gourineni et al. 
have completed a study on type 4 resistant starch (RS4). In this research, a nutritional bar containing a control (2 g), medium (21 g) and high (30 g) fiber, were consumed by healthy adults (n
= 38). Venous glucose, insulin, and the capillary glucose were measured at the end. They found that the concentrations of the capillary glucose and venous insulin in the two fiber groups were significantly lower than those in the control group. At the same time, they found that the postprandial glucose and insulin responses were significantly reduced in the generally healthy adults who consumed the bar containing the potato RS4 fiber.
There are also several other studies about RS4. Stewart et al. 
have proved that substituting RS4 for a digestible carbohydrate in scones significantly lowered the blood glucose levels in healthy adults. Likewise, Mah et al. 
have replaced the digestible starch with cassava RS4, to reduce the available carbohydrates and they found that the postprandial blood glucose and insulin concentrations decreased significantly in the healthy subjects. Other studies also found similar results by using RS4 (25 g of VERSAFIBE™ 1490 (Ingredion Incorporated, Bridgewater, NJ, USA)) to replace the normal starch in cookies 
. In general, there was a study that showed that glycemia could be reduced by replacing the rapidly digestible starch with RS4. This result might be caused by the incomplete release of glucose and the anti-digestibility of the starch 
. Wang et al. 
have postulated that the diabetes-related liver glycogen fragility could also be attenuated by RS. They found that both the diabetic group and the non-diabetic group of mice, fed with two types of high-amylose RS, contained less hepatic glycogen than those fed with normal corn starch (NCS). In addition, the molecular size and the chain-length distributions of the liver glycogen were characterized to detect the fragility of the liver glycogen before and after the dimethyl sulfoxide (DMSO) treatment. The result showed that the high-amylose RS diet could prevent the fragility of the liver-glycogen α particles, which were consistent with the hypothesis that hyperglycemia was related to the glycogen fragility. They postulated the reason was that the high-amylose RS was eventually fermented in the large intestine rather than in the small intestine, which elicited beneficial effects on the glycemic response and T2DM.
Through the above studies, it is not hard to find that the IS could be affected by RS through the reducing gene expression of the macrophage markers in the adipose tissue, regulating the membrane-bound TGR5 signaling, repairing the pancreas β cell function and preventing the fragility of the liver-glycogen α particles. Meanwhile, the RS shows less effect on the blood glucose, since it cannot be degraded by the digestive enzymes in the small intestine but only be fermented in the large intestine that reduces the absorption of glucose.
3. Reducing Inflammation
Studies have shown that the damaged pancreatic β cells could be repaired, while the expression of the binding genes, such as the C-reactive protein (CRP), TNF-α and interleukin, could be down-regulated by the RS to show the hypoglycemic effect 
Gargari et al. 
found that the glycated hemoglobin (HbA1c) (−0.3%, −3.2%) and TNF-α (−3.4 pg/mL, −18.8%) could be decreased by the RS2, compared with the placebo groups. In this research, 28 females with diabetes took RS (intervention group) and 32 took a placebo (placebo group) at 10 g/d for 8 weeks. The fasting blood sugar (FBS), HbA1c, lipid profile, high-sensitive CRP (HS-CRP), IL-6 and TNF-α were measured at the end of the trial. The results suggested that the glycemic status and the inflammatory markers in the women with T2DM could be improved. Based on the results, they speculated that the improvement in the glycemic status was due to the reduction of the TNF-α levels. And Tayebi Khosroshahi et al. 
came to similar conclusions through their research. They found that the IR level and the body’s IS could be improved by RS. In the research, a 20–25 g high linear chain RS and wheat flour, daily, were used to treat hemodialysis patients for 8 weeks, respectively. The results showed that the serum IL-6 and TNF-α levels in the RS group were significantly decreased.
Xu et al. 
found that the blood glucose of obese mice could be reduced efficiently by RS. The obese mice were placed into four groups: NC, HF, URS (intervention group with RS from untreated lentil starch) and ARS (intervention group with RS from autoclaved lentil starch). The mice in the ARS and URS groups were administrated intragastrically with the ARS and URS (400 mg/kg·BW) suspension, once daily. Furthermore, the histological analysis and the gut microbiota analysis suggested the results above might be achieved, based on the improvement of the inflammatory state and the changes of the microbial components related to vagal signals. Yuan et al. 
have reported the similar results. Compared with the normal rice (NR)-treated diabetes mice, the levels of the related inflammation factor, such as the serum CRP, TNF-α, IL-6, nuclear factor-k-gene binding (NF-κB) and leptin (LEP), were lower while the Adiponutrin (ADPN) level was higher in the selenium-enriched rice with a high RS content (SRRS) treated mice and the normal rice with the high RS content (NRRS) treated mice. The results suggested that the hypoglycemic effects might be achieved by the high RS rice treatment because of the improvement of the chronic inflammation.
It is not hard to see that the levels of the related inflammatory factors, such as CRP, IL-6, TNF-α and NF-κB, were lowered by the RS. The reduction of glomerular damage and the enhancement of the glomerular reabsorption alleviated the development of diabetes.
4. Regulating Hypoglycemic Related Enzymes
The level of the blood glucose could be regulated by some metabolic enzymes, such as glycogen synthase (GS), phosphoenolpyruvate carboxy kinase (PEPCK) and α-glucosidase. The activity of these enzymes could be regulated by the RS to achieve a hypoglycemic effect.
Zhou et al. 
found that the blood glucose level in the RS administration group diabetic mice was lower than that in the control group. Moreover, the expression of the insulin-induced genes Insig-1 and Insig-2, that were related to the glycolipid metabolism, were also significantly up-regulated after the RS administration in mice. The blood glucose level in the diabetic mice fed with RS was regulated by promoting glycogen synthesis and the inhibiting gluconeogenesis. Further studies suggested that the expression level of isoform 1 of the glucose-6-phosphatase (G6PC1) catalytic subunit, was lower in the RS group than it was in the MC group. In addition, this research found that the expression of the glycogen synthesis genes, the GS and glycogenin1 (GYG1) increased more than twofold after the RS intake, which suggested a progressive stimulation of the hepatic glycogen synthesis in the liver. These results suggested that the inhibition of the gluconeogenesis and the promotion of the glycogen synthesis may be one of the main ways for RS to decrease the blood glucose. This research demonstrated that the mRNA encoding enzymes involved in the gluconeogenesis could be reduced by the RS to alleviate the glucose metabolic disorders in diabetic mice. Zhu et al. 
found that after the intervention with a kind of RS in banana powder, the glucose uptake in the liver, the glycogen synthesis, the IS and IR of the db/db diabetes mice, were improved, while the mRNA expression of the key enzyme PEPCK, the carbohydrate response element binding protein (ChREBP) of the gluconeogenesis and the GSK-3 of the glycogen synthesis, were all significantly down regulated by the RS. Hao et al. 
found that the green banana powder was rich in RS2 and made biscuits from it, which verified its feasibility. Xiao et al. 
found that the blood glucose of T2DM Kunming (KM) mice was increased by 10.9% in the control group, while it was decreased by 14.7% in the RS group. The inhibition rate of α-glucosidase that related to the blood glucose peak in the T2DM mice, was measured. In RS group, the inhibition rate was 23.13%, showing a certain inhibitory effect. Since the activity of α-glucosidase could be inhibited by the RS, the consumption of the liver glycogen would be reduced and the trend of weight loss would be alleviated as well.
Above of all, it’s not difficult to find that the present studies of the related enzymes were all carried out in mice. In addition, to reduce the blood glucose, the expression level of the key enzymes, such as GS, G6PC1, PEPCK, ChREBP, GK and α-glucosidase, could be lowered by the RS treatment, leading to the reduction of IS and IR.