Table 1.

The potential health benefit effect of RS interventions on diabetic biomarkers.

References	Objective (s)	Methods	Findings	Conclusion
Bodinham et al. (26)	To further explore the effects of RS on insulin secretion.	• A subject-blind, randomized crossover study. • 12 overweight individuals (37 ± 4.0 yrs) consumed either 40 g RS2 or energy and carbohydrate (CHO)-matched placebo daily, for 4 wks. • Assessment of insulin secretion, plasma insulin and C-peptide concentrations.	• Significantly higher plasma insulin and C-peptide concentrations with RS (p < 0.05). • Significantly improved 1st phase insulin secretion with RS (p < 0.05). • No changes on body weight or habitual food intake.	• RS intake significantly increased the 1st -phase insulin secretion in individuals at risk of developing T2DM. • Further studies exploring this effect in individuals with T2DM are required.
Bodinham et al. (27)	To determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM.	• A single-blind, randomized dietary intervention crossover study. • 17 individuals (mean age 55 yrs) with well-controlled T2DM consumed either 40 g of HAM-RS2 or placebo for 12 wks. • Three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. • Determination of plasma glucose, insulin, triglycerides (TG), non-esterified fatty acids (NEFA), total cholesterol (TC) and high-density lipoprotein (HDL). • Determination of fasting tumor necrosis factor-α (TNF-α) and interleukin (IL) 6, C-peptide and total glucagon-like peptide-1 (GLP1).	• Significantly lower postprandial glucose concentrations (p = 0.045). • No effect of HAM-RS2 on hepatic, peripheral insulin sensitivity, or HbA1c. • No significant difference in C-peptide, HOMA, TC, HDL and IL6 between the HAM-RS2 and placebo. • Significant difference in NEFA, TG and TNF-α. • Fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (p = 0.049). • Significantly greater postprandial GLP1 excursions during the MTT (p = 0.009).	• HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1.
Dainty et al. (28)	To examine the chronic effects of consuming bagels high in HAM-RS2 on fasting and postprandial glycemic markers in adults at increased risk of T2DM.	• A randomized, double-blind crossover design. • 24 men and women (mean age of 55.3 ± 1.59 yrs and body mass index (BMI) of 30.2 ± 0.57 kg/m2) consumed 1 bagel containing 25 g/d HAM-RS2 or one control wheat bagel for 56 d each, separated by a 4 wks washout. • Fasting and postprandial OGTT glucose and insulin.	• Significantly lower fasting, 2 h and 3 h insulin incremental area under the curve (iAUC) and fasting insulin resistance (IR) than control (p < 0.05). • No difference in fasting and postprandial OGTT glucose concentrations.	• Consumption of a high-HAM-RS2 bagel improves glycemic efficiency and fasting insulin sensitivity in adults at increased risk of T2DM.
Peterson et al. (29)	To test whether RS2 can improve cardiometabolic health among pre-diabetic adults.	• A randomized, double-blind, placebo-controlled, parallel-arm trial. • 68 overweight adults (35–75 yrs) with pre-diabetes were randomized to consume 45 g/d of HAM-RS2 or an isocaloric amount of the RDS amylopectin (control) for 12 wks. • HbA1c, insulin sensitivity, insulin secretion, ectopic fat, and markers of inflammation.	• RS2 lowered HbA1c by a clinically insignificant (p > 0.05). • RS2 also did not affect insulin sensitivity, TG, TC, FFA, high-sensitive (hs)-CRP, iAUC relative to baseline (p > 0.05). • Significant reduction in TNF-α, and heart rate (p < 0.05).	• RS supplementation reduced the inflammatory marker TNF-α and heart rate, but it did not significantly improve glycemic control and other cardiovascular disease risk factors among pre-diabetic adults.
Kwak et al. (30)	To evaluate whether 4 wks of dietary treatment with rice containing RS reduces blood glucose and oxidative stress as well as improves endothelial function.	• Patients with IFG, IGT or newly diagnosed T2DM (n = 90) were randomly assigned to either rice containing 6.51 g RS/d or a control rice group for 4 wks. • Fasting and postprandial levels of glucose and insulin, oxidative stress markers and endothelial function.	• Significant reduction on fasting insulin and IR, postprandial glucose (p < 0.010) and insulin levels at 30 min, and glucose and iAUC after the standard meal. • Decreased urinary 8-epi-PGF2α and plasma malondialdehyde (MDA) and increased the RH-PAT index (p < 0.001) and total nitric oxide (NO). • Postprandial changes in glucose at 60 and 120 min and areas under the glucose response curve, MDA, RH-PAT, and total NO of the test group differed significantly from control.	• In patients with IFG, IGT or newly diagnosed T2DM, rice containing RS was associated with improved endothelial function reduction of postprandial glucose and oxidative stress compared with control.
Lotfollahi et al. (31)	To investigate the effects of 6 mths consumption of green-banana biomass on the LDL particle functionality in subjects with T2DM.	• Subjects (n = 39, mean age 65 yrs) of both sexes with diabetes (HbA1c ≥ 6.5%) were randomized to receive nutritional support plus green-banana biomass (40 g) (n = 21) or diet alone (n = 18) for 6 months. • Non-linear optical responses of LDL solutions from these participants were studied by Z-scan technique. • Measurement absorbance structural changes in LDL samples and determination of LDL sub-fractions.	• Significant reduction on total- and non-HDL-cholesterol, glucose, HbA1c and improved the protection of the LDL particle against oxidation, by increasing carotenoids content in the particles (p < 0.05).	• Higher protection against modifications may decrease the risk of developing cardiovascular disease. • Benefits of the green-banana biomass encourage the RS usage with potential clinical applications among pre-diabetic and diabetic individuals.
Gargari et al. (32)	To determine effects of RS2 on metabolic parameters and inflammation in women with T2DM.	• A randomized controlled clinical trial. • 60 females (30–65 yrs) with T2DMreceived 10 g/d RS2 or placebo for 8 wks. • FPG, HbA1c, lipid profile, hs-CRP, IL-6 and TNF-α.	• RS2 significantly decreased HbA1c (−0.3%, −3.6%), TNF-α (−3.4 pg/mL, −18.9%) compared with placebo (p < 0.05). • Changes in FBS, hs-CRP and IL-6 were not significant.	• RS2 can improve glycemic status, inflammatory markers and lipid profile in women with T2DM. • More studies are needed to confirm efficacy of RS2 as an adjunct therapy in diabetes.
Alfa et al. (33)	To determine the tolerability as well as the glucose and insulin modulating ability of MSPrebiotic® digestion RS in healthy mid-age (MID) and elderly (ELD) adults.	• A prospective, blinded, placebo-controlled study. • ELD (>70 yrs) and MID (30–50 yrs) consumed either 30 g/d MSPrebiotic® or placebo for 12 wks. • Blood glucose, lipid profile, C-reactive protein (CRP), lipid particles, TNF-α, IL-10, insulin and IR.	• A significant difference in blood glucose (p = 0.0301) and insulin levels (p = 0.009), as well as IR (HOMA-IR; p = 0.009) in ELD adults who consumed MSPrebiotic®. • MSPrebiotic® consumption for 12 wks was not sufficient to reduce the elevated CRP and TNF-α levels in the ELD group. • No significant changes in MID adults.	• Dietary supplementation with prebiotics such as MSPrebiotic® may be part of an effective strategy to reduce IR, in the ELD.
Giles et al. (34)	To determine the in vivo net energy content of RS and examine its effect on macronutrient oxidation.	• A randomized, double-blind cross-over study. • 18 healthy adults aged 25–45 yrs. • Measurement of total energy expenditure (TEE), substrate oxidation, and postprandial metabolites in response to three diets: (a) digestible starch (DS), (b) RS (33% dietary fiber), (c) RS with high fiber (RSF, 56% fiber).	• The in vivo net energy content of RS and RSF are 2.74 ± 0.41 and 3.16 ± 0.27 kcal/g, respectively. • No difference in TEE or protein oxidation between DS, RS, and RSF. • RS and RSF consumption caused a 32% increase in fat oxidation (p = 0.04) with a concomitant 18% decrease in CHO oxidation (p = 0.03) vs. DS. • Insulin responses were unaltered after breakfast but lower in RS and RSF after lunch, at equivalent glucose concentrations.	• RS and RSF consumption increase fat and decrease CHO oxidation with postprandial insulin responses lowered after lunch.
Belobrajdic et al. (35)	To determine if bread made from HAW and enriched in RS dampens postprandial glycemia compared with bread made from conventional low-amylose wheat (LAW).	• A single-center, randomized, double-blinded, crossover- controlled study. • 20 healthy non-diabetic men and women (mean age 30 ± 3 yrs; BMI 23 ± 0.7 kg/m2) consumed a glucose beverage or 4 different breads (LAW-R (refined), LAW-W (wholemeal), HAW-R, or HAW-W) for 7 wks. • Plasma glucose, insulin, ghrelin, incretin hormone concentrations and iAUC.	• HAW breads: iAUC: 39% < conventional wheat breads (HAW 39 ± 5 mmol/L × 3 h; LAW 64 ± 5 mmol/L × 3 h; p < 0.0001). • Insulinemic and incretin: 24–30% less for HAW breads than for LAW breads (p < 0.05). • Flour processing did not affect the glycemic, insulinemic, or incretin response. • The HAW breads did not influence plasma ghrelin.	• Replacing LAW with HAW flour may be an effective strategy for lowering postprandial glycemic and insulinemic responses to bread in healthy men and women, but further research is warranted.
Hallström et al. (36)	To evaluate the postprandial glucose and insulin responses in vivo to bread products based on a novel wheat genotype with elevated amylose content (EAW) of 38%.	• A randomized cross-over trial. • Healthy 7 females and 7 males (20–35 yrs; BMI: 22.2 ± 1.91) were served test meals on 4 occasions. • RS content (in vitro), postprandial glucose and insulin responses.	• Significantly higher RS content in EAW bread than in whole grain wheat bread (WGW) (p < 0.001). • EAW induced lower postprandial glucose response than white wheat flour (REF) during the first 120 min (p < 0.05), but no significant differences in insulin responses. • Increased RS content per test portion was correlated to a reduced GI (r = −0.571, p < 0.001).	• Wheat with EAW may be preferable to other wheat genotypes considering RS formation, however further research is required.
Poquette et al. (37)	To measure the contents of functional starch fractions, SDS and RS, and to investigate the effects of grain sorghum on postprandial plasma glucose and insulin levels.	• A randomized-crossover design. • 10 healthy males (25.1 ± 4 yrs) consumed grain sorghum and whole wheat flour (control) muffins containing 50 g total starch with a 1 wk washout period. • Measurement of glucose and insulin levels at 15 min before and 0, 15, 30, 45, 60, 75, 90, 120, 180 min after consumption.	• Mean glucose and insulin responses reduced at 45–120 min and 15†90 min with grain sorghum, compared to control (p < 0.05). • The iAUC was significantly lowered for plasma glucose responses (p < 0.05). • Significant reduction with insulin responses with sorghum (p < 0.05).	• Grain sorghum is a good functional ingredient to assist in managing glucose and insulin levels in healthy individuals.
Gu (38)	To investigate the effects of sorghum starch on postprandial blood glucose and insulin levels in pre-diabetic men	• Grain sorghum and wheat (control) muffins containing 50 g total starch were consumed by 15 pre-diabetic males on two mornings with a 1 wk washout period. • Measurement of glucose and insulin levels at −15 (baseline), 0, 15, 30, 45, 60, 75, 90, 120, and 180 min after each treatment.	• The functional starch content [combined SDS and RS] of grain sorghum muffin was higher than control. • Postprandial blood glucose and insulin responses were both significantly reduced at 45–120 min intervals (p < 0.05). • The mean iAUC of glucose and insulin was significantly reduced by 35 and 36.7%, respectively (p < 0.05).	• Grain sorghum is a good candidate in controlling blood glucose and insulin levels in pre-diabetic population for the prevention of T2DM.
Lin et al. (39)	To evaluate the effects of the new RS formula, PPB-R-203, on glucose homeostasis in healthy subjects and subjects with T2DM.	• A cohort consisting of 40 healthy participants (20–65 yrs) received test and control diets. • A randomized, 2-regimen, cross-over, comparative study was conducted in 44 subjects (20–65 yrs) with T2DM and glycemic control was assessed with a continuous glucose monitoring system. • Determination of blood glucose and iAUC	• Serum glucose values and iAUC were significantly lower in the PPB-R-203 than the control group, for healthy subjects (p < 0.05). • In patients with T2DM, mean blood glucose concentrations for control regimen were higher than the PPB-R-203-based regimen (p = 0.023). • AUCs for total blood glucose and hyperglycemia were also reduced for subjects on the PPB-R-203- compared to control (total blood glucose: p < 0.001; hyperglycemia: p = 0.021).	• A PPB-R-203-based diet reduced postprandial hyperglycemia in patients with T2DM without increasing the risk of hypoglycemia or glucose excursion.
Sanders et al. (40)	To evaluate the effect of consuming cooked, then chilled potatoes, compared to isoenergetic, CHO-containing control foods.	• A pilot cross-over randomized controlled trial. • 19 adults (18–74 yrs;BMI 27.0–39.9)consumed 300 g/day RS-enriched potatoes, over a 24 h period. • Assessment of insulin sensitivity, fasting plasma glucose and fasting insulin	• No significant difference for insulin sensitivity between potato and control. • Lower fasting plasma glucose (p = 0.043) with potato compared to control. • Lower fasting insulin (p = 0.077) in the potato vs. control.	• RS-enriched potatoes may have a favorable impact on CHO metabolism and support the view that additional research in a larger study sample is warranted.
Mohan et al. (41)	To compare the GI of a newly developed high fiber white rice (HFWR) with that of commercial white rice (WR)	• A randomized controlled crossover study design. • 30 healthy adults age 18–45 yrs were recruited for the GI study of HFWR in 2013 • In 2014, GI testing of the second harvest HFWR was done in a subsample of 15 healthy volunteers. • HFWR and WR diets providing 50 g of available CHO (63.6 g of uncooked rice) were given as test foods	• Dietary fiber content of HFWR was 5-fold higher. • RS content of HFWR was 6.5-fold higher (p < 0.001) • Amylose content of HFWR was significantly higher (p < 0.001) compared with WR • HFWR had 23% lower GI compared with WR (p = 0.002).	• HFWR has lower GI excellent sensory and other characteristics compared with WR. • Switching from the current high GI WR to HFWR could help to reduce overall dietary GI and the glycemic load.
Nomura et al. (42)	To evaluate the postprandial glycemic response for boiled BARLEYmax® and determined its GI in a Japanese population.	• 11 healthy subjects (20–50 yrs) were administered a 50 g/150 mL glucose drink twice and boiled BARLEYmax® containing 50 g available CHO after a wash-out period. • Determination of blood glucose, postprandial blood glucose, glucose iAUC and GI of BARLEYmax®.	• Postprandial blood glucose, its change from baseline over 90 min, and the iAUC for BARLEYmax® were statistically lower than those for the glucose drink. • The GI of the BARLEYmax® was 24.3.	• Boiled BARLEYmax® contributes to improving the postprandial glycemic response.
Zhu et al. (43)	To examine the possibility of integrating domestically cooked non-cereal starchy foods into glycemic management diet, and compare their glycemic characteristics with those of waxy and non-waxy whole grains and starchy beans.	• An undouble-blind, randomized crossover design. • 10 healthy subjects (18–26 yrs) consumed dried lily bulb (LB), lotus seed (LS), adlay (AD), waxy black rice (BR), millet (MI), and adzuki bean (AB), pre-soaked. • In vitro CHO digestion for each test food.	• Both the LS and AB meals achieved low GI (21–51), while the other starchy foods failed to show significant difference with rice GI (83–109). • The hydrolysis indexes of LS and AB were 37.7–61.1%, significantly lower than other test foods. • The in vitro tests indicated that pre-soaking resulted in high RDS and low RS.	• Careful choice of whole grain materials, minimized pre-soaking, and moderate cooking may be critical factors for successful postprandial glycemic management for diabetic and pre-diabetic.
Yulianto et al. (44)	To evaluate content of RS, and GI of Cr—fortified—parboiled rice (Cr-PR) coated with herbal extracts.	• 18 non-diabetic volunteers were recruited to test on GI of the cooked Cr-PR coated with herbal extract. • Unhulled rice and forticant used (Ciherang and CrCl3). Three herbal extracts used were cinnamon bark powder, pandan leaf and bay leaf. • Determination of RS content by enzymatic process.	• RS content of Cr-PR coated with herbal extracts ranged between 8.27 and 8.84%. • Cr-PR coated with herbal extract of 3% had higher RS levels than herbal extracts of 6% and 9% (p < 0.05). • Rice coated with 3% cinnamon extract showed the highest RS content (8.84%). • The lowest GI (29–30) was attained by the Cr-PR coated with cinnamon extract of 6–9%.	• The low GI of Cr-PR may be more influenced by the potential of polyphenolic compounds in the herbal extract than its RS levels.
Sandberg et al. (45)	To investigate the effect of WG rye-based products on glucose- and appetite regulation.	• A crossover overnight study design. • 21 healthy subjects (25.3 ± 3.9 yrs) were provided four rye-based evening test meals of either WG rye flour bread (RFB) or a 1:1 ratio of WG rye flour and rye kernels bread (RFB/RKB), with or without added RS. • Determination of blood glucose, insulin, peptide YY (PYY), FFA, IL-6, ad libitum energy intake as well as breath H2 and subjective rating of appetite.	• The evening meal with RFB/RKB + RS decreased postprandial glucose- and iAUC (p < 0.05). • All rye-based evening meals decreased or tended to decrease fasting FFA (p < 0.05, RFB/RKB: p = 0.057). • The evening meal comprising RFB/RKB + RS resulted in an increased p-PYY concentration at fasting (+17%, p < 0.05). • No effects on energy intake or IL-6 compared to WWB. • All rye-based evening meals resulted in increased breath H2 levels at fasting, that remained increased after the standardized breakfast (p < 0.001).	• WG rye bread has the potential to improve cardiometabolic variables in an 11–14.5 h perspective in healthy humans. • The combination RFB/RKB + RS positively affected biomarkers of glucose- and appetite regulation in a semi-acute perspective. Meanwhile, RFB and RFB/RKB improved subjective appetite ratings.
Sandberg et al. (46)	To investigate the effects of short-term intervention with WG rye on cognitive functions, mood and cardiometabolic risk markers in MID test subjects.	• Crossover study • 38 healthy MID subjects consumed rye-based breads made up of WG rye kernel/flour (1:1) supplemented with RS2 (RB + RS2) for three consecutive days, with white wheat flour bread as reference. • Cognitive function, mood and cardiometabolic risk markers were determined the following morning, 11 – 14 h post intake.	• RB + RS2 increased insulin sensitivity (p < 0.05), (PYY, p < 0.05; GLP-2, p < 0.01) and fasting concentrations of plasma acetate, butyrate and total SCFA (p < 0.001). • Fasting levels of IL – 1β were decreased (p < 0.05). • No significant difference for other inflammatory markers (CRP, IL-6, IL-18 and LBP) and blood lipids (FFA and TG). • Insulin sensitivity was positively correlated with working memory test performance (p < 0.05).	• This study displays novel findings regarding effects of WG rye products on mood, and glucose and appetite regulation in MID subjects, indicating anti-diabetic properties of WG rye. • The beneficial effects are suggested to be mediated through gut fermentation of dietary fiber in the RB + RS2 product.
Nichenametla et al. (47)	To examine the effects of a blinded exchange of RS4-enriched flour (30% v/v) with regular/control flour (CF) diet on multiple metabolic syndrome (MetS) comorbidities.	• A double blind, placebo-controlled, cluster cross-over intervention. • 86 male and female subjects (≥ 18 yrs) consumed RS4-enriched flour (30% v/v) and regular flour as control with 2 wks washout period • Determination of glucose profile (FPG, post-prandial glucose, and HbA1C).	• RS4 consumption resulted in 7.2% (p = 0.002) lower mean TC, 5.5% (p = 0.04) lower non-HDL, and a 12.8% (p < 0.001) lower HDL in the MetS group. • No significant effect of RS4 was observed for glycemic variables (FPG, postprandial glucose, and HbA1C) and blood pressures.	• RS4 consumption improved dyslipidemia and body composition.
García et al. (48)	To evaluate the glycemic control and cardiovascular risk biomarkers in fragile, ELD T2DM patients after the intake of a new fructose-free diabetes-specific formula enriched with RS4 and high in monounsaturated FAs.	• An experimental, prospective, intention-to-treat clinical trial. • 41 patients with T2DM (78.9 ± 2.8 yrs) were fed exclusively with an enteral diabetes-specific formula for 6 wks. • Data were collected at baseline and after 6 wks of feeding. • CHO and lipid metabolism, inflammatory and cardiovascular risk biomarkers were measured.	• Blood HbA1c significantly decreased after the intervention (p < 0.05), as well as monocyte chemotactic protein-1 (MCP-1) and soluble E-selectin (p < 0.05). • Soluble vascular cell adhesion molecule-1 (sVCAM-1) and plasminogen activator inhibitor-1 (PAI-1) tended to decrease from baseline to 6 wks (p = 0.084 and p = 0.05, respectively).	• The new product improves glycemic control and cardiovascular risk without altering lipid metabolism, which is useful for the prevention of diabetic complications. • Longer intervention studies are needed.
Rahat-Rozenbloom et al. (49)	To compare the effects of two fermentable fibers on postprandial SCFA and second-meal glycemic response in healthy overweight or obese (OWO) vs. lean (LN) participants.	• Randomized crossover design. • Male and non-pregnant, non-lactating females aged 18–65 yrs. • 13 OWO and 12 LN overnight fasted participants were studied for 6 h on three separate days after consuming 300 mL water containing 75 g glucose as control or with 24 g IN or 28 g RS. • Determination of blood and serum glucose, insulin, C-peptide and FFA.	• IN significantly increased serum SCFA (p < 0.001) but had no effect on FFA or second-meal glucose and insulin responses compared to control. • RS had no significant effect on SCFA but reduced FFA rebound (p < 0.001) and second-meal glucose (p = 0.002) and insulin responses (p = 0.024). • OWO had similar postprandial serum SCFA and glucose concentrations but significantly greater insulin and FFA than LN. • The effects of IN and RS on SCFA, glucose, insulin and FFA responses were similar in LN and OWO.	• RS has favorable second-meal effects, likely related to changes in FFA rather than SCFA concentrations. However, a longer study may be needed to demonstrate RS effects on SCFA. • No evidence that acute increases in SCFA after IN reduce glycemic responses. • No significant differences detected in SCFA responses between OWO vs. LN subjects.