Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression

The present study aimed at examining beneficial effects of intermittent hypoxia training (IHT) under prediabetic conditions. We investigate the effects of three-week IHT on blood glucose level, tolerance to acute hypoxia, and leukocyte mRNA expression of hypoxia inducible factor 1α (HIF-1α) and its target genes, i.e. insulin receptor, facilitated glucose transporter–solute carrier family-2, and potassium voltage-gated channel subfamily J. Seven healthy and 11 prediabetic men and women (44–70 years of age) were examined before, next day and one month after three-week IHT (3 sessions per week, each session consisting 4 cycles of 5-min 12% O2 and 5-min room air breathing). We found that IHT afforded beneficial effects on glucose homeostasis in patients with prediabetes reducing fasting glucose and during standard oral glucose tolerance test. The most pronounced positive effects were observed at one month after IHT termination. IHT also significantly increased the tolerance to acute hypoxia (i.e. SaO2 level at 20th min of breathing with 12% O2) and improved functional parameters of respiratory and cardiovascular systems. IHT stimulated HIF-1α mRNA expression in blood leukocytes in healthy and prediabetic subjects, but in prediabetes patients the maximum increase was lagged. The greatest changes in mRNA expression of HIF-1α target genes occurred a month after IHT and coincided with the largest decrease in blood glucose levels. The higher expression of HIF-1α was positively associated with higher tolerance to hypoxia and better glucose homeostasis. In conclusion, our results suggest that IHT may be useful for preventing the development of type 2 diabetes. Impact statement The present study investigated the beneficial effects of intermittent hypoxia training (IHT) in humans under prediabetic conditions. We found that three-week moderate IHT induced higher HIF-1α mRNA expressions as well as its target genes, which were positively correlated with higher tolerance to acute hypoxia and better glucose homeostasis in both middle-aged healthy and prediabetic subjects. This small clinical trial has provided new data suggesting a potential utility of IHT for management of prediabetes patients.

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The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00235.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. E397-E409

Author(s):

Maigen Bethea ◽

Yanping Liu ◽

Alexa K. Wade ◽

Rachel Mullen ◽

Rajesh Gupta ◽

...

Keyword(s):

Transcription Factor ◽

Glucose Homeostasis ◽

Target Genes ◽

Fasting Blood Glucose ◽

Oral Glucose ◽

Β Cell ◽

Knockout Mouse Model ◽

Glucose Levels ◽

Cell Extracts ◽

Islet 1

The LIM-homeodomain (LIM-HD) transcription factor Islet-1 (Isl1) interacts with the LIM domain-binding protein 1 (Ldb1) coregulator to control expression of key pancreatic β-cell genes. However, Ldb1 also has Isl1-independent effects, supporting that another LIM-HD factor interacts with Ldb1 to impact β-cell development and/or function. LIM homeobox 1 (Lhx1) is an Isl1-related LIM-HD transcription factor that appears to be expressed in the developing mouse pancreas and in adult islets. However, roles for this factor in the pancreas are unknown. This study aimed to determine Lhx1 interactions and elucidate gene regulatory and physiological roles in the pancreas. Co-immunoprecipitation using β-cell extracts demonstrated an interaction between Lhx1 and Isl1, and thus we hypothesized that Lhx1 and Isl1 regulate similar target genes. To test this, we employed siRNA-mediated Lhx1 knockdown in β-cell lines and discovered reduced Glp1R mRNA. Chromatin immunoprecipitation revealed Lhx1 occupancy at a domain also known to be occupied by Isl1 and Ldb1. Through development of a pancreas-wide knockout mouse model ( Lhx1∆Panc), we demonstrate that aged Lhx1∆Panc mice have elevated fasting blood glucose levels, altered intraperitoneal and oral glucose tolerance, and significantly upregulated glucagon, somatostatin, pancreatic polypeptide, MafB, and Arx islet mRNAs. Additionally, Lhx1∆Panc mice exhibit significantly reduced Glp1R, an mRNA encoding the insulinotropic receptor for glucagon-like peptide 1 along with a concomitant dampened Glp1 response and mild glucose intolerance in mice challenged with oral glucose. These data are the first to reveal that the Lhx1 transcription factor contributes to normal glucose homeostasis and Glp1 responses.

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The Beneficial Effects of SesaVitaTM on Lipid Profiles and Blood Glucose Levels in Subjects With Prediabetes and Mild-To-Moderate Hyperlipidemia in India

Journal of Food Research ◽

10.5539/jfr.v2n5p104 ◽

2013 ◽

Vol 2 (5) ◽

pp. 104 ◽

Cited By ~ 1

Author(s):

H. N. Shivaprasad ◽

M. Bhanumathy ◽

Ceyhun Tamer ◽

G. Sushma ◽

K. R. Raveendra ◽

...

Keyword(s):

Blood Glucose ◽

Lipid Profile ◽

Lifestyle Changes ◽

Secondary Outcome ◽

Oral Glucose ◽

Double Blind Study ◽

Beneficial Effects ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Normal Ranges

Individuals suffering from Type 2 diabetes develop prediabetes before progression of diabetes. In case of prediabetes people, the blood glucose levels are higher than normal but not sufficient to be diagnosed as diabetes. On the basis of existing reports on Sesame extract, SesaVitaTM which is an herbal food supplement containing Sesame seeds (Sesamum indicum L.) extract may provide an option for management of prediabetes. The objective of this study was to determine the beneficial effects of SesaVitaTM in prediabetes and mild to moderate hyperlipidemia subjects. This randomized, placebo-controlled, double-blind study comprised of 13 female and 07 male patients with prediabetes and mild to moderate hyperlipidemia, aged between 18 and 65 years. Twenty subjects were randomized to receive SesaVitaTM (500 mg/day) or placebo along with therapeutic lifestyle changes for 6 weeks. The primary outcome was the measure of efficacy in terms of change in serum lipid profile and glycaemic levels on week 3 and 6. Secondary outcome measures include safety and tolerability evaluated by physical examination and clinical laboratory evaluations. Improvements in lipid profile and glycaemic levels were observed in SesaVitaTM treated group when compared with placebo and baseline. A statistical significant reduction was observed in low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), oral glucose tolerance test (OGTT) and fasting blood sugar (FBS) levels during week 3 and 6 when treated with SesaVitaTM extract. No adverse events occurred and all safety parameters were within normal ranges during the study. This study revealed that the treatment with SesaVitaTM was safe and well tolerated; may be beneficial in the management of prediabetes and mild-to-moderate hyperlipidemia.

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Blackthorn Flower Extract Impact on Glycaemic Homeostasis in Normoglycemic and Alloxan-Induced Hyperglycaemic C57BL/6 Mice

Food Technology and Biotechnology ◽

10.17113/ftb.59.03.21.7057 ◽

2021 ◽

Vol 59 (3) ◽

Author(s):

Irena Crnić ◽

Tajana Frančić ◽

Petar Dragičević ◽

Vedran Balta ◽

Verica Dragović-Uzelac ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

Serum Insulin ◽

Sugar Content ◽

Tolerance Test ◽

Oral Glucose ◽

Mice Model ◽

Flower Extract ◽

Prunus Spinosa

Research background. The use of plants and their extracts in treatments of chronic diseases is widely known in traditional medicine. The aim of this study is to determine the effects of 10-day consumption of Prunus spinosa L. flower extract on blood glucose, glycaemic load, serum α-amlyase and serum insulin, in normoglycaemic and hypergycaemic (alloxan) mice model. Experimental approach. Normoglycemic and hyperglycemic (alloxan treated, 150 mg/kg body mass) C57BL/6 mice were treated daily, during 10 days, with Prunus spinosa L. flower extract by gavage. The sugar content within extract was determined by HPLC analysis. In mice, blood and serum blood glucose level and OGTT-test were determined by blood glucometer. Serum insulin was determined by ELISA assay and α-amlyase by colourimetric assay. Results and conclusions. The Prunus spinosa L. flower extract increased glucose in normoglycaemic mice by 30 % after 1st and 5th day and by 17 % after 10th day of consumption in normoglycaemic mice. It is a consequence of released sugars because sugar analysis revealed 59.8 mg/L monosaccharides, mainly fructose (55.7 mg/L) and glucose (24.3 mg/L) within the extract. On the opposite, the extract consumption, reduced serum blood glucose in alloxan-induced hyperglycaemic mice by 29 % after 10 days of treatment. Oral glucose tolerance test also confirmed that that in the hyperglycaemic group treated with Prunus spinosa L. flower extract glucose homeostasis was improved and showed decrease in blood glucose, since the blood glucose over the period of 120 min, glucose homeostasis is faster achieved after treatment with shows that in Prunus spinosa L. flower extract. Serum insulin increased by 49 % and serum alpha amylase by 46 % after 10 days of treatment with Prunus spinosa L. flower extract in hyperglycaemic group. Thus, it can be concluded that Prunus spinosa L. flower extract improved glucose tolerance, enhanced insulin secretion and lowered serum α-amylase activity. Novelty and scientific contribution. The results examined for the first time the potential of Prunus spinosa L. flower extract in hyperglycaemia management.

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Case Report: A Novel ABCC8 Variant in a Chinese Pedigree of Maturity-Onset Diabetes of the Young

Frontiers in Endocrinology ◽

10.3389/fendo.2021.758723 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chaoyan Tang ◽

Liheng Meng ◽

Ping Zhang ◽

Xinghuan Liang ◽

Chaozhi Dang ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Homeostasis ◽

Fasting Blood Glucose ◽

Family Members ◽

Missense Variant ◽

Postprandial Blood Glucose ◽

Chinese Family ◽

Oral Glucose ◽

Maturity Onset Diabetes ◽

Onset Diabetes

BackgroundWe aimed to analyze a novel ABCC8 variant of a Chinese patient with suspected maturity-onset diabetes of the young (MODY) and to provide evidence for precise diagnosis and appropriate treatment.MethodA Chinese family with suspected MODY was recruited in this study, which included a 15-year-old female patient with diabetes. Clinical data and blood samples were collected from the proband and other family members. All of the living relatives were given an oral glucose tolerance test. Next-generation sequencing was performed to identify the mutated genes in the proband. Sanger sequencing was utilized to confirm the location of the pathogenic variant in all subjects. Further treatment was referred to targeted family members according to genetic testing.ResultsThe proband was found to have a random blood glucose level of 244.8 mg/dl and an HbA1c level of 9.2%. Before this investigation, her grandparents had been diagnosed with diabetes. The second uncle, two aunts, mother, and cousin of the proband were diagnosed with diabetes by abnormal HbA1C (6.5–12.1%) and fasting blood glucose (FBG, 91.4–189.7 mg/dl). The second aunt of the proband had impaired glucose homeostasis (HbA1C = 6.4% and FBG = 88.0 mg/dl). One novel missense variant c.1432G>A (p.A478T) in exon 9 of the ABCC8 gene was detected in the proband with suspected MODY. The variant was also found in six family members with diabetes or impaired glucose homeostasis, including her second uncle, two aunts, mother, and cousin. After the treatment was switched to glimepiride, the fasting blood glucose was adjusted to 99.54 mg/dl, the 2-h postprandial blood glucose was 153.54 mg/dl, serum fructosamine was 259 μmol/l, and HbA1c was 5.8%. The glycemic control remained optimal, and no hypoglycemic episodes were observed in the living relatives.ConclusionThis study revealed one novel missense variant of the ABCC8 gene in Chinese families. The present findings indicated that the members of this family responded to treatment with sulfonylureas as previously seen in ABCC8 MODY.

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Transcription Factor HMG Box-Containing Protein 1 (HBP1) Regulates Glycemic Homeostasis Through Modulation of Gluconeogenesis

Current Developments in Nutrition ◽

10.1093/cdn/nzaa058_005 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1247-1247

Author(s):

Chin-Ming Chang ◽

Chun-Yin Huang

Keyword(s):

Transcription Factor ◽

Blood Glucose ◽

Glucose Homeostasis ◽

Molecular Mechanisms ◽

Ectopic Expression ◽

Tolerance Test ◽

Public Health Issue ◽

Oral Glucose ◽

Hmg Box ◽

Blood Glucose Homeostasis

Abstract Objectives Glycemic dysregulation is one of the major metabolic disorders, which has long been a significant public health issue. The liver plays a pivotal role in the maintenance of blood glucose homeostasis. Previous studies indicate that upon refeeding a high carbohydrate diet, the expression of transcription factor HMG box-containing protein 1 (HBP1) was elevated in mice livers, suggesting a role of HBP1 in carbohydrate metabolism. Therefore, the objective of the current study was to understand the molecular mechanisms through which HBP1 regulates glucose generation in the liver. Methods Both in vivo HBP1 knockdown mice and in vitro HepG2 cell line were employed as the experimental models. Results First, we observed that overnight fasting led to increased PEPCK but decreased HBP1 expression in mice livers, and subsequent addition of insulin reversed the expression pattern. More importantly, HBP1 knockout (KO) mice displayed a significantly higher blood glucose level (173 mg/dL) than that of the controls (98 mg/dL). Also, HBP1 KO led to impaired OGTT (oral glucose tolerance test) and ITT (insulin tolerance test). These data suggest that HBP1 might have a role in the regulation of gluconeogenesis in the liver. To unveil the molecular mechanism by which HBP1 regulates glucose homeostasis, we examined its role in gluconeogenesis. Administration of gluconeogenic stimulators glucagon (100 nM) and cAMP (0.5 ng/mL) resulted in increased expression of Phosphoenolpyruvate carboxykinase (PEPCK; encoded by the PCK1 gene), a key enzyme in gluconeogenesis, but decreased HBP1 expression in HepG2 cells. Last, HBP1 siRNA-mediated mRNA disruption led to elevated PEPCK expression, whereas ectopic expression of HBP1 (pcDNA3-HBP1-Flag) significantly suppressed it. Conclusions In conclusion, our data indicate that HBP1 might negatively regulate glucose production and support HBP1 as a novel biological regulator of blood glucose homeostasis. Funding Sources This work was supported by the grant to MOST 108–2320-B-039–051-MY3 C-Y Huang.

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Effects of age on ACTH, corticosterone, glucose, insulin, and mRNA levels during intermittent hypoxia in the neonatal rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00073.2013 ◽

2013 ◽

Vol 304 (9) ◽

pp. R782-R789 ◽

Cited By ~ 21

Author(s):

Kathan Chintamaneni ◽

Eric D. Bruder ◽

Hershel Raff

Keyword(s):

Mrna Expression ◽

Glucose Homeostasis ◽

Intermittent Hypoxia ◽

Neonatal Rat ◽

Mrna Levels ◽

Plasma Acth ◽

Tissue Samples ◽

Rat Pups ◽

Developmental Age ◽

Adrenal Response

Apnea, the temporary cessation of respiratory airflow, is a common cause of intermittent hypoxia (IH) in premature infants. We hypothesized that IH elicits a stress response and alters glucose homeostasis in the neonatal rat. Rat pups were studied on postnatal day (PD) 2, 8, 10, 12, and 14. Pups were exposed to normoxia (control) or six cycles consisting of 30-s exposures to hypoxia (FiO2 = 3%) over a 60-min period. Blood samples were obtained at baseline, after the third cycle (∼30 min), and after the sixth cycle (∼60 min). Tissue samples were collected following the sixth cycle. Plasma ACTH, corticosterone, glucose, and insulin were analyzed at all ages. Hypothalamic, pituitary, and adrenal mRNA expression was evaluated by quantitative PCR in PD2, PD8, and PD12 pups. Exposure to IH elicited significant increases in plasma ACTH and corticosterone at all ages studied. The largest increase in corticosterone occurred in PD2 pups, despite only a very small increase in plasma ACTH. This ACTH-independent increase in corticosterone in PD2 pups was associated with increases in adrenal Ldlr and Star mRNA expression. Additionally, IH caused hyperglycemia and hyperinsulinemia at all ages. We conclude that IH elicits a significant pituitary-adrenal response and significantly alters glucose homeostasis. Furthermore, the quantitative and qualitative characteristics of these responses depend on developmental age.

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Effect of Quercetin on the Expression of NOXs and P-Smad3C in TGF-Β-Activated Hepatic Stellate Cell Line LX-2

Hepatitis Monthly ◽

10.5812/hepatmon.116875 ◽

2021 ◽

Vol 21 (6) ◽

Author(s):

Narges Mohammadtaghvaei ◽

Reza Afarin ◽

Fatemeh Mavalizadeh ◽

Elham Shakerian ◽

Samaneh Salehipour Bavarsad ◽

...

Keyword(s):

Mrna Expression ◽

Cell Line ◽

Hepatic Fibrosis ◽

Target Genes ◽

Stellate Cell ◽

Primary Role ◽

Cytotoxic Effects ◽

Beneficial Effects ◽

Smad3 Phosphorylation ◽

Liver Fibrogenesis

Background: Hepatic stellate cells (HSCs) play a primary role in liver fibrogenesis. NOXs are the main origin of reactive oxygen species (ROS) in the liver. Among them, NOX1, NOX2, and NOX4 are expressed more in HSCs and are involved in the development of liver fibrosis. Quercetin, an abundant citrus flavonoid, is known to have beneficial effects on liver injury and hepatic fibrosis. Objectives: In this study, the effect of quercetin on NOX1, NOX2, and NOX4 expression and Smad3 phosphorylation induced by TGF-β in the human hepatic LX2 cell line was investigated. Methods: The cytotoxic effects of quercetin on the cells were determined by MTT assay. The cells were activated with 2 ng/mL of TGF-β for 24 h and then treated with different concentrations of Quercetin. The mRNA expression rates of NOX1, NOX2, NOX4, and phosphorylated Smad 3C (p-Smad3C) were analyzed using real-time polymerase chain reaction (PCR) and western blot assays. Results: TGF-β increased the mRNA expression of NOX1, NOX2, and NOX4 and the protein level of p-Smad3C in the LX2 cell line. Quercetin significantly decreased the mRNA expression of NOX1, NOX2, and NOX4 in the LX-2 cells. Moreover, quercetin significantly diminished the p-Smad3C level in the LX-2 cell line activated with TGF-β. Conclusions: Quercetin may be effective in improving hepatic fibrosis via the reduction of NOX1, NOX2, and NOX4 expression in activated HSCs. The main mechanism through which quercetin reduces the expression of these target genes may be related to the reduction of the p-Smad3C level.

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Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

10.21203/rs.3.rs-104995/v1 ◽

2020 ◽

Author(s):

Gang Shu ◽

Yexian Yuan ◽

Jia Sun ◽

Canjun Zhu ◽

Jinlong Feng ◽

...

Keyword(s):

Body Weight ◽

Blood Glucose ◽

Mouse Model ◽

Resistance Exercise ◽

Glucose Homeostasis ◽

Metabolic Function ◽

Inhibitory Effects ◽

Hepatic Gluconeogenesis ◽

Beneficial Effects

Abstract While resistance exercise effectively improves overall health in diabetic patients, the underlying biological mechanism by which resistance exercise improves metabolic function and glucose homeostasis remain mostly unknown. Previously, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial effects of resistance exercise on metabolic function. We found that resistance exercise-induced α-ketoglutaric acid (AKG) stimulates muscle hypertrophy and fat loss through 2-oxoglutarate receptor 1 (OXGR1)-dependent adrenal activation. Here, we provided evidence for the beneficial effects of AKG on glucose homeostasis in a diet-induced obesity (DIO) mouse model, which are independent of OXGR1. We showed that circulating AKG levels are negatively correlated with the fraction of blood glycated hemoglobin (HbA1c) in both humans and mice and significantly decreased in DIO mice. Consistently, pharmacological elevation of AKG effectively decreased body weight, blood glucose, and hepatic gluconeogenesis without changing insulin sensitivity and glucose tolerance in DIO mice. Notably, OXGR1KO blocked the inhibitory effects of AKG on body weight but failed to affect AKG’s suppression on blood glucose and hepatic gluconeogenesis, indicating distinct mechanisms for AKG’s regulation on energy balance and glucose homeostasis. In supporting this view, we showed that serpina1e, a member of protease inhibitor serpins superfamily, mediates the direct inhibitory effects of AKG on gluconeogenesis in both in vitro hepatocytes and liver slice. By using a liver-specific serpina1e deletion mouse model, we further demonstrated that liver serpina1e is required for the inhibitory effects of AKG on hepatic gluconeogenesis and hyperglycemia in DIO mice. Finally, we provided in vitro evidence to support a model in which AKG decreases hepatic gluconeogenesis by targeting trimethylation of lysine 27 on histone 3 (H3K27me3) in seprina1e promoter region. Our studies established an important role of AKG in glucose homeostasis, and identified the AKG-serpina1e pathway as potential therapeutic targets to attenuate hyperglycemia.

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Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice

Endocrinology ◽

10.1210/en.2018-00853 ◽

2019 ◽

Vol 160 (5) ◽

pp. 1333-1347 ◽

Cited By ~ 5

Author(s):

Kebin Zhang ◽

Xiaoqin Guo ◽

Hui Yan ◽

Yuxin Wu ◽

Quan Pan ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Homeostasis ◽

Target Genes ◽

Cell Function ◽

Hepatic Glucose Production ◽

Fasting Blood Glucose ◽

Phosphorylation Site ◽

Glucose Production ◽

Β Cell Function

Abstract The transcription factor forkhead box O1 (FoxO1) is a key mediator in the insulin signaling pathway and controls multiple physiological functions, including hepatic glucose production (HGP) and pancreatic β-cell function. We previously demonstrated that S256 in human FOXO1 (FOXO1-S256), equivalent to S253 in mouse FoxO1 (FoxO1-S253), is a key phosphorylation site mediating the effect of insulin as a target of protein kinase B on suppression of FOXO1 activity and expression of target genes responsible for gluconeogenesis. Here, we investigated the role of FoxO1-S253 phosphorylation in control of glucose homeostasis in vivo by generating global FoxO1-S253A/A knockin mice, in which FoxO1-S253 alleles were replaced with alanine (A substitution) blocking FoxO1-S253 phosphorylation. FoxO1-S253A/A mice displayed mild increases in feeding blood glucose and insulin levels but decreases in fasting blood glucose and glucagon concentrations, as well as a reduction in the ratio of pancreatic α-cells/β-cells per islet. FoxO1-S253A/A mice exhibited a slight increase in energy expenditure but barely altered food intake and glucose uptake among tissues. Further analyses revealed that FoxO1-S253A/A enhances FoxO1 nuclear localization and promotes the effect of glucagon on HGP. We conclude that dephosphorylation of S253 in FoxO1 may reflect a molecular basis of pancreatic plasticity during the development of insulin resistance.

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Assessment of the mechanisms exerting glucose-lowering effects of dried peas in glucose-intolerant rats

British Journal Of Nutrition ◽

10.1017/s0007114512000736 ◽

2012 ◽

Vol 108 (S1) ◽

pp. S91-S102 ◽

Cited By ~ 9

Author(s):

Kevin A. Whitlock ◽

Lisa Kozicky ◽

Alena Jin ◽

Homun Yee ◽

Christine Ha ◽

...

Keyword(s):

Glucose Tolerance ◽

Glucose Homeostasis ◽

Seed Coat ◽

Cell Mass ◽

Oral Glucose ◽

High Fat ◽

Beneficial Effects ◽

Glucose Stimulated Insulin Secretion ◽

Seed Coats ◽

Pea Seed

The present study compared the effects of feeding uncooked pea fractions (embryov.seed coat) on glucose homeostasis in glucose-intolerant rats and examined potential mechanisms influencing glucose homeostasis. Rats were made glucose intolerant by high-fat feeding, after which diets containing both high-fat and pea fractions were fed for 4 weeks. Rats fed diets containing uncooked pea seed coats low (non-coloured seed coat; NSC) or high (coloured seed coat; CSC) in proanthocyanidins but not embryos had improved oral glucose tolerance (P < 0·05). NSC also lowered fasting and glucose-stimulated insulin secretion (P < 0·05), decreased β-cell mass by 50 % (P < 0·05) and lowered levels of malondialdehyde, a marker of oxidative stress. Furthermore, NSC decreased the mucosal thickness of the colon by 25 % (P < 0·05), which might affect fibre fermentation and other gut functions. Small but statistically significant (P < 0·05) effects consistent with enhanced glucose transport or metabolism were observed in the skeletal muscle of rats fed NSC or CSC, for example, increased levels of AMP-dependent kinase or akt. We conclude that pea seed coats are the fraction exerting beneficial effects on glucose tolerance. Most of the changes were small in amplitude, suggesting that additive effects on multiple tissues may be important. NSC content appeared to have the most beneficial effects in improving glucose homeostasis but our ability to detect the effect of flavonoids may have been limited by their low concentration in the diet.

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