Insulin resistance in type 1 diabetes managed with metformin (INTIMET): Study protocol of a double-blind placebo-controlled, randomised trial.

BACKGROUND: Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. METHODS: We will study 40 adults aged 20-55 years with Type 1 diabetes (HbA1c ≤ 80 mmol/mol [9.5%], fasting C-peptide <0.3 nmol/L) and 20 age-, gender- and body mass index (BMI)-matched controls. Insulin sensitivity will be determined by the two-step hyperinsulinaemic-euglycaemic clamp method with deuterated glucose to document liver, muscle and adipose insulin sensitivity. Subjects with Type 1 diabetes will be randomised to metformin extended-release 1500 mg daily or matched placebo for 26 weeks. The primary outcome is change in hepatic insulin sensitivity, assessed by change in basal rate of appearance (Ra) of glucose and suppression of endogenous glucose production (EGP) during the low-dose stage of the clamp. CONCLUSION: The INTIMET study is the first clinical trial to quantify the impact of metformin on liver, muscle and adipose insulin resistance in adults with Type 1 diabetes. This study may identify factors that predict an individual's response to metformin in Type 1 diabetes. TRIAL REGISTRATION: ACTRN12619001440112.

Nutritional and metabolic regulation of the metabolite dimethylguanidino valeric acid: an early marker of cardiometabolic disease.

Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.

Obesity and Insulin Resistance Are Inversely Associated with Serum and Adipose Tissue Carotenoid Concentrations in Adults.

BACKGROUND: Low tissue concentrations of carotenoids have been suggested to contribute to insulin resistance in obesity. OBJECTIVES: The objectives of the study were to 1) evaluate the relations of adipose tissue and serum carotenoids with body fat, abdominal fat distribution, muscle, adipose tissue and liver insulin resistance, and dietary intake; 2) evaluate the relations and distributions of carotenoids detected in adipose tissue and serum; and 3) compare serum carotenoids and retinol concentrations in subjects with and without obesity. METHODS: Post hoc analysis of serum and adipose tissue carotenoids in individuals [n = 80; 31 men, 49 women; age (mean ± SEM): 51.4 ± 1.1 y] who participated in 2 separate studies conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney) between 2008 and 2013. Retinol, α-carotene, ß-carotene, ζ-carotene, lutein, lycopene, phytoene, and phytofluene were measured using HPLC. Body composition was measured by dual-energy X-ray absorptiometry. Insulin resistance was measured by 2-step hyperinsulinemic-euglycemic clamps with deuterated glucose (n = 64), and subcutaneous and visceral abdominal volume and liver and pancreatic fat by MRI (n = 60). Periumbilical subcutaneous fat biopsy was performed and carotenoids and retinol measured in the tissue (n = 16). RESULTS: We found that ζ-carotene, phytoene, and phytofluene were stored in considerable amounts in adipose tissue (25% of adipose tissue carotenoids). Carotenoid concentrations in adipose tissue and serum correlated significantly, but they followed different distributions: ζ-carotene was 3-fold higher in adipose tissue compared with serum, while lutein and lycopene made up 20% and 21% of serum carotenoids compared with 2% and 12% of adipose tissue carotenoids, respectively. Liver (P ≤ 0.028) and adipose tissue (P = 0.023), but not muscle (P ≥ 0.16), insulin resistance correlated inversely with many of the serum carotenoids. CONCLUSIONS: Multiple serum and adipose tissue carotenoids are associated with favorable metabolic traits, including insulin sensitivity in liver and adipose tissue in humans.

Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes-cardiovascular and renal benefits in patients with chronic kidney disease.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have important cardiovascular and renal benefits in adults with type 2 diabetes who have or are at high risk of cardiovascular and renal disease. These benefits are seen in patients with impaired renal function where the glucose-lowering effects are not observed. Here, we review the pharmacokinetics and pharmacology of SGLT2 inhibitors in relation to cardiovascular and renal outcomes in patients with chronic kidney disease (CKD). METHODS: We searched PubMed and EMBASE for original research, meta-analyses and review articles relevant to the pharmacokinetics, and cardiac and renal outcomes of SGLT2 inhibitors published up until June 2019. Specialist society guidelines and publications were also consulted. RESULTS: Renal impairment is currently a contraindication to SGLT2 inhibitor use largely due to limited anti-hyperglycaemic efficacy. However, in cardiovascular outcome trials, and a dedicated renal outcome trial, cardiovascular and renal benefits were seen in participants with CKD suggesting that mechanisms underlying the cardiovascular and renal benefits of SGLT2 inhibitors are likely largely independent of the glucose-lowering action of these agents. CONCLUSIONS: Despite minimal glycaemic benefits in patients with type 2 diabetes and stage 3 CKD, the cardiovascular and renal benefits of these agents are preserved in this group of patients. Whether these agents have cardiovascular and renal benefits in patients with stage 4 CKD and patients with non-diabetic CKD needs further research.

Food Overconsumption in Healthy Adults Triggers Early and Sustained Increases in Serum Branched-Chain Amino Acids and Changes in Cysteine Linked to Fat Gain.

Background: Plasma concentrations of branched-chain amino acids (BCAAs) and the sulfur-containing amino acid cysteine are associated with obesity and insulin resistance. BCAAs predict future diabetes. Objective: We investigated amino acid changes during food overconsumption. Methods: Forty healthy men and women with a body mass index (mean ± SEM) of 25.6 ± 0.6 were overfed by 1250 kcal/d for 28 d, increasing consumption of all macronutrients. Insulin sensitivity and body composition were assessed at baseline (day 0) and day 28. Fasting serum amino acids were measured at days 0, 3, and 28. Linear mixed-effects models evaluated the effect of time in the total group and separately in those with low and high body fat gain (below compared with at or above median fat gain, 1.95 kg). At days 0 and 28, insulin-induced suppression of serum amino acids during a hyperinsulinemic-euglycemic clamp test and, in a subset (n = 20), adipose tissue mRNA expression of selected amino acid metabolizing enzymes were assessed. Results: Weight increased by 2.8 kg. High fat gainers gained 2.6 kg fat mass compared with 1.1 kg in low fat gainers. Valine and isoleucine increased at day 3 (+17% and +22%, respectively; P ≤ 0.002) and remained elevated at day 28, despite a decline in valine (P = 0.019) from day 3 values. Methionine, cystathionine, and taurine were unaffected. Serum total cysteine (tCys) transiently increased at day 3 (+11%; P = 0.022) only in high fat gainers (P-interaction = 0.043), in whom the cysteine catabolic enzyme cysteine dioxygenase (CDO1) was induced (+26%; P = 0.025) in adipose tissue (P-interaction = 0.045). Overconsumption did not alter adipose tissue mRNA expression of the BCAA-metabolizing enzymes branched-chain keto acid dehydrogenase E1α polypeptide (BCKDHA) or branched-chain amino transferase 1 (BCAT1). In the total population at day 0, insulin infusion decreased all serum amino acids (-11% to -47%; P < 0.01), except for homocysteine and tCys, which were unchanged, and glutathione, which was increased by 54%. At day 28, insulin increased tCys (+8%), and the insulin-induced suppression of taurine and phenylalanine observed at day 0, but not that of BCAAs, was significantly impaired. Conclusions: These findings highlight the role of nutrient oversupply in increasing fasting BCAA concentrations in healthy adults. The link between cysteine availability, CDO1 expression, and fat gain deserves investigation. This trial was registered at www.clinicaltrials.gov as NCT00562393.

Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4) - a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity.

Fibroblast growth factor-1 (FGF-1) promotes differentiation of human preadipocytes into mature adipocytes via modulation of a BMP and Activin Membrane-Bound Inhibitor (BAMBI)/Peroxisome proliferator-activated receptor (PPARγ)-dependent network. Here, we combined transcriptomic and functional investigations to identify novel downstream effectors aligned with complementary analyses of gene expression in human adipose tissue to explore relationships with insulin sensitivity. RNA-Seq and qRT-PCR analysis revealed significant down-regulation of carboxypeptidase A4 (CPA4) following FGF-1 treatment or induction of differentiation of human preadipocytes in a BAMBI/PPARγ-independent manner. siRNA-mediated knockdown of CPA4 resulted in enhanced differentiation of human preadipocytes. Furthermore, expression of CPA4 in subcutaneous adipose tissue correlated negatively with indices of local and systemic (liver and muscle) insulin sensitivity. These results identify CPA4 as a negative regulator of adipogenesis that is down-regulated by FGF-1 and a putative deleterious modulator of local and systemic insulin sensitivity. Further investigations are required to define the molecular mechanism(s) involved and potential therapeutic opportunities.

Effects of prednisolone on energy and fat metabolism in patients with rheumatoid arthritis: tissue-specific insulin resistance with commonly used prednisolone doses.

OBJECTIVE: Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low-dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism. DESIGN: An open interventional and cross-sectional study was undertaken. PATIENTS AND MEASUREMENTS: Eighteen patients who had not taken oral glucocorticoids for ≥6 months were studied before and after 7 days prednisolone (6 mg/day) to assess the acute effects of prednisolone. Baseline data from patients, not on glucocorticoids, were compared with 18 patients on long-term prednisolone (6·5 ± 1·8 mg/day for >6 months) to assess the chronic effects. Energy expenditure and substrate oxidation were measured using indirect calorimetry before and after a mixed meal. Adipocyte insulin resistance index and insulin-mediated suppression of NEFA were calculated from fasting and postprandial insulin and NEFA concentrations. RESULTS: There were no significant differences in resting energy expenditure or diet-induced thermogenesis with prednisolone. Acute (-2·1 ± 6·2 vs -16·3 ± 4·8 mg/min, P = 0·01) and chronic (-1·4 ± 2·8 vs -16·3 ± 4·8 mg/min, P = 0·01) prednisolone attenuated postprandial suppression of fat oxidation. Chronic (31·6 ± 3·8 vs 17·0 ± 3·3, P = 0·007), but not acute, prednisolone increased adipocyte insulin resistance index. However, insulin-mediated suppression of NEFA was not significantly different after acute or chronic prednisolone. CONCLUSIONS: Prednisolone does not alter energy expenditure. However, even at low doses, prednisolone exerts adverse effects on fat metabolism, which could exacerbate insulin resistance and increase cardiovascular risk. Attenuated postprandial suppression of fat oxidation, but not lipolysis, suggests that prednisolone causes greater insulin resistance in skeletal muscle than in adipocytes.

Effect of acute and chronic glucocorticoid therapy on insulin sensitivity and postprandial vascular function.

OBJECTIVE: Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low-dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis. DESIGN: An open interventional and cross-sectional study was undertaken. PATIENTS AND MEASUREMENTS: Eighteen subjects with rheumatoid arthritis who had not taken oral glucocorticoids for ≥6 months were studied before and after prednisolone 6 mg/day for 7 days to determine the acute effects of prednisolone. Pre-prednisolone data were compared to 18 subjects with rheumatoid arthritis taking long-term (>6 months) prednisolone (6·5 ± 1·8 mg/day) to assess the chronic effects of prednisolone. Augmentation index (by applanation tonometry) and reactive hyperaemia index (by peripheral artery tonometry) were measured before and after a mixed-meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). Insulin sensitivity was estimated by the Matsuda index and sympathetic nervous system activity from urinary noradrenaline excretion. RESULTS: Matsuda index was lower after acute (2·0 ± 1·0 vs 3·6 ± 1·1, P = 0·01) and chronic (1·9 ± 1·0 vs 3·6 ± 1·1, P = 0·04) prednisolone. Postprandial augmentation index was lower after acute prednisolone (2551 ± 197 vs 2690 ± 272%*min, P ≤ 0·001), but not chronic prednisolone. There were no significant differences in reactive hyperaemia index with acute or chronic prednisolone. Noradrenaline excretion was lower after acute (54 ± 8 vs 93 ± 23 nmol/6 h, P = 0·02), but not chronic, prednisolone. CONCLUSIONS: Prednisolone-induced insulin resistance is not associated with postprandial vascular dysfunction in patients with rheumatoid arthritis. Reduced sympathetic activity may contribute to the reduction in postprandial arterial stiffness with acute prednisolone.

Dietary Determinants of Metabolic and Gut Microbial Health in Patients with Inflammatory Bowel Disease.

Background: Diet has been linked to gut dysbiosis and the onset, course, and response to treatment of patients with IBD and metabolic disease. Methods: This single-centre prospective case-control study investigated the relationship between dietary intake, metabolic profile, and stool microbial composition in 57 individuals with IBD in clinical remission and 24 healthy individuals (HC). Participants' baseline anthropometric measurements, serum metabolic parameters, lipid profiles, and oral and stool samples for microbiota testing were collected. Their dietary intake and physical activity were documented. A partially corrected correlation was performed to examine the associations between variables and p-values adjusted for multiple comparisons using the Benjamini-Hochberg equation (adj-p). Results: In participants with IBD, the intake of saturated fat correlated positively, and the intake of dietary fibre correlated negatively with anthropometric indices (saturated fat and BMI: r = 0.37, adj-p = 0.04, fibre and BMI: r = -0.45, adj-p = 0.01). Higher anthropometric indices were associated with poorer glucose control and a less favourable serum lipid profile (BMI and insulin: r = 0.48, p < 0.01, WHR and triglycerides: r = 0.57, p < 0.01). The stool microbiota of participants in the IBD group was less diverse and more similar to their oral microbiota than was observed in the HC group (Mann-Whitney U test p = 0.03). Within the IBD group, a higher intake of added sugar and processed meat and a higher serum insulin level was associated with lower stool microbial alpha diversity (processed meat intake and Shannon's diversity: r = -0.43, adj-p = 0.02; added sugar and Shannon's diversity: r = -0.39, adj-p = 0.03; insulin and Shannon's diversity: r = -0.45, adj-p = 0.02). Neither the dietary intake nor stool microbial composition correlated with the risk of disease flaring. Conclusions: Our findings suggest that dietary intake is associated with the metabolic health and gut microbial composition of IBD patients.

Dietary Emulsifier Exposure in People With Inflammatory Bowel Disease Compared With Healthy Controls: Is There a Cause for Concern?

BACKGROUND: Emulsifiers are implicated in the pathogenesis of inflammatory bowel disease (IBD). Few studies have examined emulsifier intake in people with existing IBD. We aimed to describe the frequency of exposure to 6 selected emulsifiers in a contemporary cohort of people with IBD and compare intake with healthy controls (HCs). METHODS: Baseline food records from participants in an Australian prospective cohort study examining the microbiome of IBD patients and HCs were analyzed. Exposure to inflammatory emulsifiers polysorbate-80 (P80); carboxymethylcellulose (CMC); carrageenan; xanthan gum (XG); lecithin (soy and sunflower) and mono- and diglycerides of fatty acids (MDGs) were determined by examining ingredient lists. Frequency of emulsifier exposure between groups (IBD vs HC, Crohn's disease [CD] vs ulcerative colitis [UC], IBD children vs adults, active disease vs remission) was examined after controlling for confounders. RESULTS: Records from 367 participants were analyzed (n = 176 IBD, of which there were 101 CD, 75 UC, and 191 HC patients). In total, 5022 unique food items were examined, with 18% containing 1 or more emulsifier of interest. Inflammatory bowel disease participants had significantly higher total daily emulsifier exposure compared with HCs (2.7 ±â€…1.8 vs 2.3 ±â€…1.6, P = .02). In IBD participants, emulsifiers with the highest daily exposure were MDGs (1.2 ±â€…0.93), lecithin (0.85 ±â€…0.93), and XG (0.38 ±â€…0.42). There were no recorded exposures to P80. CONCLUSIONS: Inflammatory bowel disease participants were exposed to more emulsifiers than HCs. Intake of inflammatory emulsifiers were low or nonexistent, suggesting their presence in the food supply are not as common as frequently stated.

The Role of the Gastrointestinal Microbiome in Liver Disease.

Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.

Metabolomics and Lipidomics Signatures of Insulin Resistance and Abdominal Fat Depots in People Living with Obesity.

The liver, skeletal muscle, and adipose tissue are major insulin target tissues and key players in glucose homeostasis. We and others have described diverse insulin resistance (IR) phenotypes in people at risk of developing type 2 diabetes. It is postulated that identifying the IR phenotype in a patient may guide the treatment or the prevention strategy for better health outcomes in populations at risk. Here, we performed plasma metabolomics and lipidomics in a cohort of men and women living with obesity not complicated by diabetes (mean [SD] BMI 36.0 [4.5] kg/m2, n = 62) to identify plasma signatures of metabolites and lipids that align with phenotypes of IR (muscle, liver, or adipose tissue) and abdominal fat depots. We used 2-step hyperinsulinemic-euglycemic clamp with deuterated glucose, oral glucose tolerance test, dual-energy X-ray absorptiometry and abdominal magnetic resonance imaging to assess muscle-, liver- and adipose tissue- IR, beta cell function, body composition, abdominal fat distribution and liver fat, respectively. Spearman's rank correlation analyses that passed the Benjamini−Hochberg statistical correction revealed that cytidine, gamma-aminobutyric acid, anandamide, and citrate corresponded uniquely with muscle IR, tryptophan, cAMP and phosphocholine corresponded uniquely with liver IR and phenylpyruvate and hydroxy-isocaproic acid corresponded uniquely with adipose tissue IR (p < 7.2 × 10−4). Plasma cholesteryl sulfate (p = 0.00029) and guanidinoacetic acid (p = 0.0001) differentiated between visceral and subcutaneous adiposity, while homogentisate correlated uniquely with liver fat (p = 0.00035). Our findings may help identify diverse insulin resistance and adiposity phenotypes and enable targeted treatments in people living with obesity.

Glutamine reduces postprandial glycemia and augments the glucagon-like peptide-1 response in type 2 diabetes patients.

Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes. The conditionally essential amino acid glutamine stimulates GLP-1 secretion in vitro and in vivo. In a randomized, crossover study, we evaluated the effect of oral glutamine, with or without sitagliptin (SIT), on postprandial glycemia and GLP-1 concentration in 15 type 2 diabetes patients (glycated hemoglobin 6.5 ± 0.6%). Participants ingested a low-fat meal (5% fat) after receiving either water (control), 30 g l-glutamine (Gln-30), 15 g L-glutamine (Gln-15), 100 mg SIT, or 100 mg SIT and 15 g L-glutamine (SIT+Gln-15). Studies were conducted 1-2 wk apart. Blood was collected at baseline and postprandially for 180 min for measurement of circulating glucose, insulin, C-peptide, glucagon, and total and active GLP-1. Gln-30 and SIT+Gln-15 reduced the early (t = 0-60 min) postprandial glycemic response compared with control. All Gln treatments enhanced the postprandial insulin response from t = 60-180 min but had no effect on the C-peptide response compared with control. The postprandial glucagon concentration was increased by Gln-30 and Gln-15 compared with control, but the insulin:glucagon ratio was not affected by any treatment. In contrast to Gln-30, which tended to increase the total GLP-1 AUC, SIT tended to decrease the total GLP-1 AUC relative to control (both P = 0.03). Gln-30 and SIT increased the active GLP-1 AUC compared with control (P = 0.008 and P = 0.01, respectively). In summary, Gln-30 decreased the early postprandial glucose response, enhanced late postprandial insulinemia, and augmented postprandial active GLP-1 responses compared with control. These findings suggest that glutamine may be a novel agent for stimulating GLP-1 concentration and limiting postprandial glycemia in type 2 diabetes.

Diabetes mellitus and hearing loss: A review.

Diabetes (type 2) and sensorineural hearing loss are common health problems manifested with ageing. While both type 1 and type 2 diabetes have been associated with hearing loss, a causal link has been difficult to establish. Individuals with diabetes have twice the incidence of hearing loss compared to those without diabetes and those with prediabetes have a 30% higher rate of hearing loss. Whether hearing loss is associated with diabetes independent of glycemic control remains to be determined. Hearing loss has its own set of risk factors and shares others with diabetes. This review will summarize the complex relationship between diabetes and sensorineural hearing loss.

Systematic review with meta-analysis: dietary intake in adults with inflammatory bowel disease.

BACKGROUND: Poor dietary intake is associated with the development of malnutrition, micronutrient deficiencies, anaemia and osteoporosis in individuals with inflammatory bowel disease. While trials are underway to manipulate the diet of people with IBD, there has been no comprehensive systematic review of the dietary intake of adults with IBD. AIMS: To conduct a systematic evaluation and meta-analysis of the dietary intake of adults with IBD, including macronutrients, micronutrients and food group data. METHODS: CINAHL, Embase, Medline and Scopus were searched from 1 January 2000 to 25 September 2020 for cohort, case-control or cross-sectional studies that reported usual dietary intake in adults. Data were pooled and reported as weighted mean intake for: all adults with IBD; Crohn's disease; ulcerative colitis; active disease; remission; males; females. A random-effects meta-analysis model compared intake with healthy individuals. RESULTS: Forty studies were identified and 19 were included in the meta-analysis. All subgroups of adults with IBD consumed inadequate energy (mean intake in adults with IBD 1980 ± 130 kcal), fibre (14 ± 4 g), folate (246 ± 33 mg) and calcium (529 ± 114 mg) per day. Intake of breads and cereals, legumes, fruit, vegetables and dairy were inadequate. Compared to healthy individuals, adults with IBD consume significantly less dietary fibre (SMD -0.59; 95% CI: -0.73, -0.46). CONCLUSIONS: This review provides improved clarity about the dietary intake of adults with IBD. Future attention is required to improve diet quality and increase understanding of factors influencing dietary intake in IBD.

Plasma Bile Acids More Closely Align With Insulin Resistance, Visceral and Hepatic Adiposity Than Total Adiposity.

CONTEXT: The etiological mechanism of bile acid (BA) effects on insulin resistance and obesity is unknown. OBJECTIVE: This work aimed to determine whether plasma BAs are elevated in human obesity and/or insulin resistance. METHODS: This observational study was conducted at an academic research center. Seventy-one adult volunteers formed 4 groups: lean insulin-sensitive (body mass index [BMI] ≤ 25 kg/m2, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR] < 2.0, n = 19), overweight/obese nondiabetic who were either insulin sensitive (Obsensitive, BMI > 25 kg/m2, HOMA-IR < 1.5, n = 11) or insulin resistant (Obresistant, BMI > 25 kg/m2, HOMA-IR > 3.0, n = 20), and type 2 diabetes (T2D, n = 21). Main outcome measures included insulin sensitivity by hyperinsulinemic-euglycemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution, and liver density by computed tomography and plasma BA. RESULTS: In the Obresistant group, glucose infusion rate/fat-free mass (GIR/FFM, an inverse measure of insulin resistance) was significantly lower, and visceral and liver fat higher, compared to lean and Obsensitive individuals, despite similar total adiposity in Obresistant and Obsensitive. Total BA concentrations were higher in Obresistant (2.62 ±â€…0.333 mmol/L, P = .03) and T2D (3.36 ±â€…0.582 mmol/L, P < .001) vs Obsensitive (1.16 ±â€…0.143 mmol/L), but were similar between Obsensitive and lean (2.31 ±â€…0.329 mmol/L) individuals. Total BAs were positively associated with waist circumference (R = 0.245, P = .041), visceral fat (R = 0.360, P = .002), and fibroblast growth factor 21 (R = 0.341, P = .004) and negatively associated with insulin sensitivity (R = -0.395, P = .001), abdominal subcutaneous fat (R = -0.352, P = .003), adiponectin (R = -0.375, P = .001), and liver fat (Hounsfield units, an inverse marker of liver fat, R = -0.245, P = .04). Conjugated BAs were additionally elevated in T2D individuals (P < .001). CONCLUSIONS: BA concentrations correlated with abdominal, visceral, and liver fat in humans, though an etiological role in insulin resistance remains to be verified.

Australia IBD Microbiome (AIM) Study: protocol for a multicentre longitudinal prospective cohort study.

INTRODUCTION: Crohn's disease and ulcerative colitis are common chronic idiopathic inflammatory bowel diseases (IBD), which cause considerable morbidity. Although the precise mechanisms of disease remain unclear, evidence implicates a strong multidirectional interplay between diet, environmental factors, genetic determinants/immune perturbations and the gut microbiota. IBD can be brought into remission using a number of medications, which act by suppressing the immune response. However, none of the available medications address any of the underlying potential mechanisms. As we understand more about how the microbiota drives inflammation, much interest has focused on identifying microbial signals/triggers in the search for effective therapeutic targets. We describe the establishment of the Australian IBD Microbiota (AIM) Study, Australia's first longitudinal IBD bioresource, which will identify and correlate longitudinal microbial and metagenomics signals to disease activity as evaluated by validated clinical instruments, patient-reported surveys, as well as biomarkers. The AIM Study will also gather extensive demographic, clinical, lifestyle and dietary data known to influence microbial composition in order to generate a more complete understanding of the interplay between patients with IBD and their microbiota. METHODS: The AIM Study is an Australian multicentre longitudinal prospective cohort study, which will enrol 1000 participants; 500 patients with IBD and 500 healthy controls over a 5-year period. Assessment occurs at 3 monthly intervals over a 24-month period. At each assessment oral and faecal samples are self-collected along with patient-reported outcome measures, with clinical data also collected at baseline, 12 and 24 months. Intestinal tissue will be sampled whenever a colonoscopy is performed. Dietary intake, general health and psychological state will be assessed using validated self-report questionnaires. Samples will undergo metagenomic, transcriptomic, proteomic, metabolomic and culturomic analyses. Omics data will be integrated with clinical data to identify predictive biomarkers of response to therapy, disease behaviour and environmental factors in patients with IBD. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the South Eastern Sydney Local Health District Research Ethics Committee (HREC 2019/ETH11443). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12619000911190.

The effect of body acid-base state and manipulations on body glucose regulation in human.

Long-term exposure to high dietary acid load has been associated with insulin resistance and type 2 diabetes in epidemiological studies. However, it remains unclear whether the acid load of the diet translates to mild metabolic acidosis and whether it is responsible for the impairment in glucose regulation in humans. Previously, in a cross-sectional study we have reported that dietary acid load was not different between healthy individuals with normal weight and those with overweight/obesity, irrespective of insulin sensitivity. However, 4-week high acid load diet increased plasma lactate (a small component of the anion gap) and increased insulin resistance in healthy participants. The change in plasma lactate correlated significantly with the change in insulin resistance. Because cause-and-effect could not be evaluated in these settings, we sought to directly test the effect of an alkalizing treatment preload on postprandial glucose regulation. In a randomized placebo-controlled study with a crossover design, we administered sodium bicarbonate (NaHCO3, 1.68 g) prior to high acid load meal to healthy individuals. We found that while the bicarbonate preload attenuated the post meal decrease in pH observed with placebo, no effect on postprandial glucose regulation (glucose, insulin, and C-peptide) was observed. Following 3-month treatment of nondiabetic individuals with bicarbonate, others have reported no change in insulin resistance markers, consistent with our findings. Together, studies in human suggest that insulin resistance associated with longstanding obesogenic diet may be mediated by mild metabolic acidosis. However, buffering the Western diet with bicarbonate and increasing body pH does not change glucose homeostasis in nondiabetic individuals. Further studies are required to shed light on the role of body acid-base balance and glucose homeostasis in health and disease.

The Role of Diet in the Pathogenesis and Management of Inflammatory Bowel Disease: A Review.

Inflammatory bowel diseases, which include ulcerative colitis and Crohn's disease, are chronic relapsing and remitting inflammatory diseases of the gastrointestinal tract that are increasing in prevalence and incidence globally. They are associated with significant morbidity, reduced quality of life to individual sufferers and are an increasing burden on society through direct and indirect costs. Current treatment strategies rely on immunosuppression, which, while effective, is associated with adverse events. Epidemiological evidence suggests that diet impacts the risk of developing IBD and modulates disease activity. Using diet as a therapeutic option is attractive to patients and clinicians alike due to its availability, low cost and few side effects. Diet may influence IBD risk and disease behaviour through several mechanisms. Firstly, some components of the diet influence microbiota structure and function with downstream effects on immune activity. Secondly, dietary components act to alter the structure and permeability of the mucosal barrier, and lastly dietary elements may have direct interactions with components of the immune response. This review will summarise the mechanisms of diet-microbial-immune system interaction, outline key studies examining associations between diet and IBD and evidence demonstrating the impact of diet on disease control. Finally, this review will outline current prescribed dietary therapies for active CD.