Amino acid differences between diabetic older adults and non-diabetic older adults and their associations with cardiovascular function.

BACKGROUND: Ageing and insulin resistant states such as diabetes mellitus frequently coexist and increase the risk of cardiovascular disease development among older adults. Here we investigate metabolic differences in amino acid profiles between ageing and diabetes mellitus, and their associations with cardiovascular function. METHODS: In a group of community older adults we performed echocardiography, cardiac magnetic resonance imaging as well as cross sectional and longitudinal metabolomics profiling based on current and archived sera obtained fifteen years prior to examination. RESULTS: We studied a total of 515 participants (women 50%, n = 255) with a mean age 73 (SD = 4.3) years. Diabetics had higher alanine (562 vs 448, p < 0.0001), higher glutamate (107 vs 95, p = 0.016), higher proline (264 vs 231, p = 0.008) and lower arginine (107 vs 117, p = 0.043), lower citrulline (30 vs 38, p = 0.006) levels (µM) compared to non-diabetics. Over time, changes in amino acid profiles differentiated diabetic older adults from non-diabetic older adults, with greater accumulation of alanine (p = 0.002), proline (p = 0.008) and (non-significant) trend towards greater accumulation of glycine (p = 0.057) among the older diabetics compared to the older non-diabetics. However, independent of diabetes status, amino acids were associated with cardiovascular functions in ageing, [archived valine (p = 0.011), leucine (p = 0.011), archived isoleucine (p = 0.0006), archived serine (p = 0.008), archived glycine (p = 0.006) methionine (p = 0.003)] which were associated with impairments in E/A ratio. CONCLUSION: Markers of branched chain amino acids and one ­carbon metabolism pathways were associated with changes in cardiovascular function in older adults regardless of diabetes status. However, nitrogen handling pathways were specifically altered among older adults with diabetes. These findings broaden our understanding into specific amino acid pathways that may be altered between diabetic and non-diabetic older adults, and their relevance to cardiovascular function in ageing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.

Branched-Chain Amino Acid Oxidation Is Elevated in Adults with Morbid Obesity and Decreases Significantly after Sleeve Gastrectomy.

BACKGROUND: Plasma concentrations of branched-chain amino acids (BCAAs) are elevated in obese individuals with insulin resistance (IR) and decrease after bariatric surgery. However, the metabolic mechanisms are unclear. OBJECTIVES: Our objectives are to compare leucine kinetics between morbidly obese and healthy-weight individuals cross-sectionally, and to prospectively evaluate changes in the morbidly obese after sleeve gastrectomy. We hypothesized that leucine oxidation is slower in obese individuals and increases after surgery. METHODS: Ten morbidly obese [BMI (in kg/m2) ≥32.5, age 21-50 y] and 10 healthy-weight participants (BMI <25), matched for age (median ∼30 y) but not gender, were infused with [U-13C6] leucine and [2H5] glycerol to quantify leucine and glycerol kinetics. Morbidly obese participants were studied again 6 mo postsurgery. Primary outcomes were kinetic parameters related to BCAA metabolism. Data were analyzed by nonparametric methods and presented as median (IQR). RESULTS: Participants with obesity had IR with an HOMA-IR (4.89; 4.36-8.76) greater than that of healthy-weight participants (1.32; 0.99-1.49; P < 0.001) and had significantly faster leucine flux [218; 196-259 compared with 145; 138-149 µmol · kg fat-free mass (FFM)-1 · h-1], oxidation (24.0; 17.9-29.8 compared with 16.1; 14.3-18.5 µmol · kg FFM-1 · h-1), and nonoxidative disposal (204; 190-247 compared with 138; 129-140 µmol · kg FFM-1 · h-1) (P < 0.017 for all). After surgery, the morbidly obese had a marked improvement in IR (3.54; 3.06-6.08; P = 0.008) and significant reductions in BCAA concentrations (113; 95-157 µmol/L) and leucine oxidation (9.37; 6.85-15.2 µmol · kg FFM-1 · h-1) (P = 0.017 for both). Further, leucine flux in this group correlated significantly with IR (r = 0.78, P < 0.001). CONCLUSIONS: BCAA oxidation is not impaired but elevated in individuals with morbid obesity. Plasma BCAA concentrations are lowered after surgery owing to slower breakdown of body proteins as insulin's ability to suppress proteolysis is restored. These findings suggest that IR is the underlying cause and not the consequence of elevated BCAAs in obesity.

Mother's pre-pregnancy BMI is an important determinant of adverse cardiometabolic risk in childhood.

OBJECTIVE: Maternal adiposity is associated with poor offspring cardiometabolic health. We aimed to evaluate the relationship of maternal pre-pregnancy body mass index (BMI) on the BMI, body composition and cardiometabolic characteristics of the offspring. METHODS: Forty offspring of overweight/obese mothers (O-OW) and 28 offspring of normal weight mothers (O-NW) underwent evaluation of body composition, abdominal fat distribution, blood pressure measurement, fasting lipids and an oral glucose tolerance test. The anthropometric and cardiometabolic characteristics of O-OW were compared with those of O-NW, and the relationship to maternal BMI was evaluated. RESULTS: Subjects (mean age: 12.6 ± 0.4, female: 52.9%) had similar gestational age, birth weight, age, gender, and Tanner stage. However, O-OW had a significantly higher BMI (24.4 ± 1.2 vs. 19.7 ± 0.8 kg/m(2) , p = 0.001), % body fat (31.7 ± 1.6 vs. 24.6 ± 1.1%, p < 0.001), visceral fat (41.9 ± 4.7 vs. 26.1 ± 3.9 cm(2) , p = 0.012) with no difference in lean body mass compared with O-NW. O-OW had lower whole body insulin sensitivity index (WBISI) with an adverse cardiovascular disease risk profile [higher blood pressure (BP), triglycerides to high-density lipoprotein (HDL) ratio, hs-C-reactive protein (CRP) and lower HDL]. In addition to offspring's %body fat (ß = -0.60, p < 0.001), maternal pre-pregnancy BMI (ß = -0.19, p = 0.046) contributed significantly and independently to the offspring's WBISI (R(2) =0.55, p < 0.001). CONCLUSIONS: High pre-pregnancy BMI is an important contributor to excess adiposity, insulin resistance, and cardiometabolic disease risk in the offspring during childhood.

The impact of obesity-associated glycine deficiency on the elimination of endogenous and exogenous metabolites via the glycine conjugation pathway.

Background: Glycine is an integral component of the human detoxification system as it reacts with potentially toxic exogenous and endogenously produced compounds and metabolites via the glycine conjugation pathway for urinary excretion. Because individuals with obesity have reduced glycine availability, this detoxification pathway may be compromised. However, it should be restored after bariatric surgery because of increased glycine production. Objective: To examine the impact of obesity-associated glycine deficiency on the glycine conjugation pathway. We hypothesize that the synthesis rates of acylglycines from endogenous and exogenous sources are significantly reduced in individuals with obesity but increase after bariatric surgery. Methods: We recruited 21 participants with class III obesity and 21 with healthy weight as controls. At baseline, [1,2-13C2] glycine was infused to study the glycine conjugation pathway by quantifying the synthesis rates of several acylglycines. The same measurements were repeated in participants with obesity six months after bariatric surgery. Data are presented as mean ± standard deviation, and p-value< 0.05 is considered statistically significant. Results: Baseline data of 20 participants with obesity were first compared to controls. Participants with obesity were significantly heavier than controls (mean BMI 40.5 ± 7.1 vs. 20.8 ± 2.1 kg/m2). They had significantly lower plasma glycine concentration (168 ± 30 vs. 209 ± 50 µmol/L) and slower absolute synthesis rates of acetylglycine, isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine. Pre- and post-surgery data were available for 16 participants with obesity. Post-surgery BMI decreased from 40.9 ± 7.3 to 31.6 ± 6.0 kg/m2. Plasma glycine concentration increased from 164 ± 26 to 212 ± 38 µmol/L) and was associated with significantly higher rates of excretion of acetylglycine, isobutyrylglycine, tigylglycine, isovalerylglycine, and hexanoylglycine. Benzoic acid (a xenobiotic dicarboxylic acid) is excreted as benzoylglycine; its synthesis rate was significantly slower in participants with obesity but increased after bariatric surgery. Conclusion: Obesity-associated glycine deficiency impairs the human body's ability to eliminate endogenous and exogenous metabolites/compounds via the glycine conjugation pathway. This impairment is ameliorated when glycine supply is restored after bariatric surgery. These findings imply that dietary glycine supplementation could treat obesity-associated metabolic complications due to the accumulation of intramitochondrial toxic metabolites. Clinical trial registration: https://clinicaltrials.gov/study/NCT04660513, identifier NCT04660513.

The Impact of Bariatric Surgery on Nitrogen Balance at Six months Post-surgery.

PURPOSE: Obesity, defined as abnormal or excessive fat accumulation that presents a risk to health, rose from 8.6 to 10.5% in Singapore's residents. Bariatric surgery, the primary treatment for severe obesity, induces fat and muscle loss. Adequate protein intake is vital for preventing muscle loss. This study examines nitrogen balance in individuals with obesity pre- and post-surgery. MATERIALS AND METHODS: Sixteen participants with severe obesity (BMI ≥ 32.5 kg/m2) undergoing bariatric surgery (14 sleeve gastrectomy, 2 Roux-en-Y gastric bypass) and 20 normal-weight controls (BMI < 25 kg/m2) were recruited. Nitrogen balance, calculated from dietary protein intake and urine nitrogen excretion, was assessed. Participants with obesity were re-evaluated 6 months post-surgery. Data were analyzed using parametric methods. RESULTS: At baseline, controls had a BMI of 20.8 ± 2.1 kg/m2; those with obesity had 40.9 ± 7.3. Daily calorie and protein intake for participants with obesity were not statistically significantly different from controls (calorie intake at 1467 ± 430 vs. 1462 ± 391 kcal, p = 0.9701, protein intake 74.2 ± 28.7 vs. 64.6 ± 18.3 g, p = 0.2289). Post-surgery, BMI, fat-free mass, fat mass, total energy intake, carbohydrate, and protein intake decreased significantly (p < 0.01). Protein oxidation and urine nitrogen excretion did not change after bariatric surgery. However, nitrogen balance significantly reduced from 2.62 ± 5.07 to - 1.69 ± 5.07 g/day (p = 0.025). CONCLUSION: Dietary protein intake is inadequate in individuals with obesity at 6 months post-bariatric surgery and contributes to a state of negative nitrogen balance.

Topical and oral peroxisome proliferator-activated receptor-α agonist ameliorates diabetic corneal neuropathy.

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal ß-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased ß-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.

Assessing the Utility, Impact, and Adoption Challenges of an Artificial Intelligence-Enabled Prescription Advisory Tool for Type 2 Diabetes Management: Qualitative Study.

BACKGROUND: The clinical management of type 2 diabetes mellitus (T2DM) presents a significant challenge due to the constantly evolving clinical practice guidelines and growing array of drug classes available. Evidence suggests that artificial intelligence (AI)-enabled clinical decision support systems (CDSSs) have proven to be effective in assisting clinicians with informed decision-making. Despite the merits of AI-driven CDSSs, a significant research gap exists concerning the early-stage implementation and adoption of AI-enabled CDSSs in T2DM management. OBJECTIVE: This study aimed to explore the perspectives of clinicians on the use and impact of the AI-enabled Prescription Advisory (APA) tool, developed using a multi-institution diabetes registry and implemented in specialist endocrinology clinics, and the challenges to its adoption and application. METHODS: We conducted focus group discussions using a semistructured interview guide with purposively selected endocrinologists from a tertiary hospital. The focus group discussions were audio-recorded and transcribed verbatim. Data were thematically analyzed. RESULTS: A total of 13 clinicians participated in 4 focus group discussions. Our findings suggest that the APA tool offered several useful features to assist clinicians in effectively managing T2DM. Specifically, clinicians viewed the AI-generated medication alterations as a good knowledge resource in supporting the clinician's decision-making on drug modifications at the point of care, particularly for patients with comorbidities. The complication risk prediction was seen as positively impacting patient care by facilitating early doctor-patient communication and initiating prompt clinical responses. However, the interpretability of the risk scores, concerns about overreliance and automation bias, and issues surrounding accountability and liability hindered the adoption of the APA tool in clinical practice. CONCLUSIONS: Although the APA tool holds great potential as a valuable resource for improving patient care, further efforts are required to address clinicians' concerns and improve the tool's acceptance and applicability in relevant contexts.

Relationship between CGM-derived nocturnal hypoglycemia and subjective sleep quality in people with type 1 diabetes.

This pilot study explores the relationship between nocturnal hypoglycemia (NH) and subjective sleep quality in people with type 1 diabetes (T1D). Twenty-seven adults with T1D wore a Freestyle Libre Pro CGM and recorded subjective sleep quality daily, as assessed by a single Likert scale question. Frequency, duration, area under the curve (AUC) of NH (00:00-06:00) defined as sensor glucose below threshold (< 3.9 mmol/L; < 3 mmol/L) for ≥ 15 min, nocturnal mean glucose, Time in Range (3.9-10 mmol/L), and coefficient of variation were calculated. Twenty-seven adults, 18 (66.7%) women, with median (IQR) age of 27 (26, 32) years and HbA1c of 7.6 (7.1, 8.1) participated. Nights with NH < 3.9 mmol/L resulted in a lower (worse) sleep score than nights without NH [Mean (SD): 3.3 (1.2) vs 3.5 (1.0), p = 0.03). A higher frequency and longer duration but not AUC [adjusted OR (95% CI) 0.52 (0.38, 0.72), 0.961 (0.932, 0.991), 0.999 (0.998, 1.001) respectively)], of NH < 3.9 mmol/L, were associated with a lower sleep score. NH < 3.0 mmol/L metrics were not associated with sleep quality. Recurrent NH < 3.9 mmol/L, rather than prolonged NH < 3.0 mmol/L, seems associated with subjective sleep quality, implying that those with the highest burden of NH are likely unaware of it.

Association of Smartphone-Based Activity Tracking and Nocturnal Hypoglycemia in People With Type 1 Diabetes.

BACKGROUND: Nocturnal hypoglycemia (NH) remains a major burden for people with type 1 diabetes (T1D). Daytime physical activity (PA) increases the risk of NH. This pilot study tested whether cumulative daytime PA measured using a smartphone-based step tracker was associated with NH. METHODS: Adults with T1D for ≥ 5 years (y) on multiple daily insulin or continuous insulin infusion, not using continuous glucose monitoring and HbA1c 6 to 10% wore blinded Freestyle Libre Pro sensors and recorded total daily carbohydrate (TDC) and total daily dose (TDD) of insulin. During this time, daily step count (DSC) was tracked using the smartphone-based Fitbit MobileTrack application. Mixed effects logistic regression was used to estimate the effect of DSC on NH (sensor glucose <70, <54 mg/dl for ≥15 minutes), while adjusting for TDC and TDD of insulin, and treating participants as a random effect. RESULTS: Twenty-six adults, with 65.4% females, median age 27 years (interquartile range: 26-32) mean body mass index 23.9 kg/m2, median HbA1c 7.6% (7.1-8.1) and mean Gold Score 2.1 (standard deviation 1.0) formed the study population. The median DSC for the whole group was 2867 (1820-4807). There was a significant effect of DSC on NH episodes <70 mg/dl. (odds ratio 1.11 [95% CI: 1.01-1.23, P = .04]. There was no significant effect on NH <54 mg/dl. CONCLUSION: Daily PA measured by a smartphone-based step tracker was associated with the risk of NH in people with type 1 diabetes.

Telemonitoring With a Connected Glucose Meter Improves Glycemia Among People With Insulin-Treated Type 2 Diabetes.

BACKGROUND: Delayed initiation and inadequate titration remain critical challenges to optimizing insulin therapy in type 2 diabetes (T2D). We aimed to study whether hemoglobin A1c (HbA1c) can be lowered in people with insulin-treated T2D using telemonitoring. METHODS: This single-center study recruited adults with greater than or equal to six months of diabetes, greater than or equal to three months of insulin therapy, HbA1c ≥8.5% and ≤12.5%, and body mass index (BMI) ≤40 kg/m2. All participants received a connected glucose meter and the accompanying smartphone application. Participants sent weekly blood glucose (BG) diary to their primary endocrinologist via email. Adjustments in insulin doses were communicated to the participants. HbA1c, proportion of BG readings in range (70-180 mg/dL, PIR), below range (<70 mg/dL, PBR) and above range (>180 mg/dL, PAR), and glycemic variability as the coefficient of variation (% CV) were measured at baseline, week 12, and week 24 and compared using repeated-measures analysis of variance (ANOVA) or Friedman's ANOVA. RESULTS: We recruited 40 people (55% women). Mean age was 57.9 years, BMI 27.8 kg/m2, and baseline HbA1c 9.8% (83.7 mmol/mol). Mean HbA1c improved by 1.7%, % CV reduced from 32.9% to 30.7%, PIR increased from 58.8% to 67.1% (all P <.01) by week 24, without any change in PBR. This was achieved with a 0.04 U/kg/d median increase in total daily dose of insulin and 0.9 kg weight gain over 24 weeks. CONCLUSION: Telemonitoring and titration of insulin using a connected glucose meter resulted in significant improvements in glycemia, characterized by a reduction in HbA1c, increase in PIR, and reduction in glycemic variability without any increase in hypoglycemia.

Comparison of existing methods of low-density lipoprotein cholesterol estimation in patients with type 2 diabetes mellitus.

Introduction: Elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor for atherosclerotic cardiovascular disease (ASCVD). Direct LDL-C measurement is not widely performed. LDL-C is routinely calculated using the Friedewald equation (FLDL), which is inaccurate at high triglyceride (TG) or low LDL-C levels. We aimed to compare this routine method with other estimation methods in patients with type 2 diabetes mellitus (T2DM), who typically have elevated TG levels and ASCVD risk. Method: We performed a retrospective cohort study on T2DM patients from a multi-institutional diabetes registry in Singapore from 2013 to 2020. LDL-C values estimated by the equations: FLDL, Martin/Hopkins (MLDL) and Sampson (SLDL) were compared using measures of agreement and correlation. Subgroup analysis comparing estimated LDL-C with directly measured LDL-C (DLDL) was conducted in patients from a single institution. Estimated LDL-C was considered discordant if LDL-C was <1.8mmol/L for the index equation and ≥1.8mmol/L for the comparator. Results: A total of 154,877 patients were included in the final analysis, and 11,475 patients in the subgroup analysis. All 3 equations demonstrated strong overall correlation and goodness-of-fit. Discordance was 4.21% for FLDL-SLDL and 6.55% for FLDL-MLDL. In the subgroup analysis, discordance was 21.57% for DLDL-FLDL, 17.31% for DLDL-SLDL and 14.44% for DLDL-MLDL. All discordance rates increased at TG levels >4.5mmol/L. Conclusion: We demonstrated strong correlations between newer methods of LDL-C estimation, FLDL, and DLDL. At higher TG concentrations, no equation performed well. The Martin/Hopkins equation had the least discordance with DLDL, and may minimise misclassification compared with the FLDL and SLDL.

Expanding the use of salivary cortisol as a non-invasive outpatient test in the dynamic evaluation of suspected adrenal insufficiency.

Background: Adrenal insufficiency (AI) is potentially life-threatening, and accurate diagnosis is crucial. The first-line diagnostic test, the adrenocorticotrophic hormone (ACTH) stimulation test, measures serum total cortisol. However, this is affected in states of altered albumin or cortisol-binding globulin levels, limiting reliability. Salivary cortisol reflects free bioactive cortisol levels and is a promising alternative. However, few studies are available, and heterogenous methodologies limit applicability. Methods: This study prospectively recruited 42 outpatients undergoing evaluation for AI, excluding participants with altered cortisol-binding states. Serum (immunoassay) and salivary (liquid chromatography tandem mass spectrometry) cortisol levels were sampled at baseline, 30 min, and 60 min following 250 µg synacthen administration. AI was defined as a peak serum cortisol level <500 nmol/L in accordance with guidelines. Results: The study recruited 21 (50%) participants with AI and 21 without AI. There were no significant differences in baseline characteristics, blood pressure, or sodium levels between groups. Following synacthen stimulation, serum and salivary cortisol levels showed good correlation at all timepoints (R2 = 0.74, P < 0.001), at peak levels (R2 = 0.72, P < 0.001), and at 60 min (R2 = 0.72, P < 0.001). A salivary cortisol cut-off of 16.0 nmol/L had a sensitivity of 90.5% and a specificity of 76.2% for the diagnosis of AI. Conclusion: This study demonstrates a good correlation between serum and salivary cortisol levels during the 250 µg synacthen test. A peak salivary cortisol cut-off of 16.0 nmol/L can be used for the diagnosis of AI. It is a less invasive alternative to evaluate patients with suspected AI. Its potential utility in the diagnosis of AI in patients with altered cortisol-binding states should be further studied.

Oral Peroxisome Proliferator-Activated Receptor-α Agonist Enhances Corneal Nerve Regeneration in Patients With Type 2 Diabetes.

Diabetic corneal neuropathy (DCN) is a common complication of diabetes. However, there are very limited therapeutic options. We investigated the effects of a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, fenofibrate, on 30 patients (60 eyes) with type 2 diabetes. On in vivo confocal microscopy evaluation, there was significant stimulation of corneal nerve regeneration and a reduction in nerve edema after 30 days of oral fenofibrate treatment, as evidenced by significant improvement in corneal nerve fiber density (CNFD) and corneal nerve fiber width, respectively. Corneal epithelial cell morphology also significantly improved in cell circularity. Upon clinical examination, fenofibrate significantly improved patients' neuropathic ocular surface status by increasing tear breakup time along with a reduction of corneal and conjunctival punctate keratopathy. Tear substance P (SP) concentrations significantly increased after treatment, suggesting an amelioration of ocular surface neuroinflammation. The changes in tear SP concentrations was also significantly associated with improvement in CNFD. Quantitative proteomic analysis demonstrated that fenofibrate significantly upregulated and modulated the neurotrophin signaling pathway and linolenic acid, cholesterol, and fat metabolism. Complement cascades, neutrophil reactions, and platelet activation were also significantly suppressed. Our results showed that fenofibrate could potentially be a novel treatment for patients with DCN.

Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Elastography to Evaluate the Early Effects of Bariatric Surgery on Nonalcoholic Fatty Liver Disease.

Background: Bariatric surgery is the most effective treatment for morbid obesity and reduces the severity of nonalcoholic fatty liver disease (NAFLD) in the long term. Less is known about the effects of bariatric surgery on liver fat, inflammation, and fibrosis during the early stages following bariatric surgery. Aims: This exploratory study utilises advanced imaging methods to investigate NAFLD and fibrosis changes during the early metabolic transitional period following bariatric surgery. Methods: Nine participants with morbid obesity underwent sleeve gastrectomy. Multiparametric MRI (mpMRI) and magnetic resonance elastography (MRE) were performed at baseline, during the immediate (1 month), and late (6 months) postsurgery period. Liver fat was measured using proton density fat fraction (PDFF), disease activity using iron-correct T1 (cT1), and liver stiffness using MRE. Repeated measured ANOVA was used to assess longitudinal changes and Dunnett's method for multiple comparisons. Results: All participants (Age 45.1 ± 9.0 years, BMI 39.7 ± 5.3 kg/m2) had elevated hepatic steatosis at baseline (PDFF >5%). In the immediate postsurgery period, PDFF decreased significantly from 14.1 ± 7.4% to 8.9 ± 4.4% (p = 0.016) and cT1 from 826.9 ± 80.6 ms to 768.4 ± 50.9 ms (p = 0.047). These improvements continued to the later postsurgery period. Bariatric surgery did not reduce liver stiffness measurements. Conclusion: Our findings support using MRI as a noninvasive tool to monitor NAFLD in patient with morbid obesity during the early stages following bariatric surgery.

De Novo Glycine Synthesis Is Reduced in Adults With Morbid Obesity and Increases Following Bariatric Surgery.

Background: Glycine is a dietary non-essential amino acid that is low in obesity and increases following bariatric surgery. However, the exact mechanism responsible remains unclear and it is unknown whether hypoglycinemia is a cause or consequence of insulin resistance. Objective: Using multiple isotopically labeled tracers, we aimed to determine the underlying kinetic changes responsible for hypoglycinemia in obesity by: 1) Comparing glycine kinetics between participants with morbid obesity (BMI ≥ 32.5 kg/m2) to those with healthy weight (BMI < 25 kg/m2), and 2) Comparing glycine kinetic changes in participants with morbid obesity after bariatric surgery. Methods: [1,2-13C2] glycine, [2,3,3-2H3] serine, and [2H5] phenylalanine were infused to compare the glycine kinetic parameters between 21 participants with morbid obesity and 21 controls with healthy weight. Participants with morbid obesity then underwent bariatric surgery and 17 were re-studied 6 months later. Data were analyzed by non-parametric methods and presented as median (interquartile range). Results: Compared to controls, participants with morbid obesity had significantly lower plasma glycine concentrations at 163 (153-171) vs. 201 (172-227) µmol/L and significantly reduced de novo glycine synthesis rate at 86.2 (64.5-111) vs.124 (103-159) µmol·kg LBM-1·h1, p < 0.001. Following surgery, body weight and insulin resistance decreased and this was accompanied by significant increases in plasma glycine concentration to 210 (191-243) µmol/L as well as the de novo glycine synthesis rate to 127 (98.3-133) µmol·kg LBM-1·h-1, p < 0.001 vs. baseline. Conclusion: Hypoglycinemia in participants with morbid obesity was associated with impaired de novo glycine synthesis. The increase in plasma glycine concentration and de novo glycine synthesis plus the marked improvement in insulin resistance after bariatric surgery suggest that hypoglycinemia may be secondary to impaired glycine synthesis because of obesity-induced insulin resistance. Clinical Trial Registration: [https://tinyurl.com/6wfj7yss], identifier [NCT04660513].

Diabetic corneal neuropathy as a surrogate marker for diabetic peripheral neuropathy.

Diabetic neuropathy is a prevalent microvascular complication of diabetes mellitus, affecting nerves in all parts of the body including corneal nerves and peripheral nervous system, leading to diabetic corneal neuropathy and diabetic peripheral neuropathy, respectively. Diabetic peripheral neuropathy is diagnosed in clinical practice using electrophysiological nerve conduction studies, clinical scoring, and skin biopsies. However, these diagnostic methods have limited sensitivity in detecting small-fiber disease, hence they do not accurately reflect the status of diabetic neuropathy. More recently, analysis of alterations in the corneal nerves has emerged as a promising surrogate marker for diabetic peripheral neuropathy. In this review, we will discuss the relationship between diabetic corneal neuropathy and diabetic peripheral neuropathy, elaborating on the foundational aspects of each: pathogenesis, clinical presentation, evaluation, and management. We will further discuss the relevance of diabetic corneal neuropathy in detecting the presence of diabetic peripheral neuropathy, particularly early diabetic peripheral neuropathy; the correlation between the severity of diabetic corneal neuropathy and that of diabetic peripheral neuropathy; and the role of diabetic corneal neuropathy in the stratification of complications of diabetic peripheral neuropathy.

Revisional Surgery or Pharmacotherapy for Insufficient Weight Loss and Weight Regain After Primary Bariatric Procedure: a Descriptive Study.

PURPOSE: Bariatric surgery is the most effective and durable treatment option for clinically severe obesity. Unfortunately, some degree of weight regain (WR) is common after nadir weight is achieved. Pharmacotherapy and revision surgery are potential options to treat this phenomenon. We aim to determine the efficacy of both approaches in patients with WR versus insufficient weight loss (IWL). MATERIALS AND METHODS: We retrospectively reviewed a prospectively collected database of patients who underwent bariatric surgery from 2008 to 2018 with IWL or WR. RESULTS: Of 422 patients with WR or IWL after bariatric surgery, 150 patients were placed on pharmacotherapy and 27 underwent revisional surgeries. Mean age of patients was 41.4 years and mean BMI was 42.1 kg/m2. The most common conversion surgery was LSG to RYGB. % Total weight loss (TWL) was higher in IWL group (23.8% ± 11.0) compared to WR group (17.2% ± 7.9) in revisional surgery (p = 0.02). The converse was observed for pharmacotherapy, with %TWL 1.9% in the WR group compared to 0.7% in the IWL group (p = 0.0067). CONCLUSION: Patients with IWL or WR had modest weight loss with adjunctive use of pharmacotherapy after primary bariatric surgery. Conversely, revisional surgery is an effective treatment for both IWL and WR.

Satisfaction of patients with diabetic kidney disease with traditional chinese medicine physician visits.

Background: Patient-centred care is an important part of quality healthcare and patient satisfaction has been shown to be associated with improved clinical outcomes. We aim to explore the satisfaction of patients with diabetic kidney disease (DKD) with their visits to the TCM physician and its association with patients' socio-economic characteristics. Methods: A questionnaire survey was conducted among patients aged >21 years with DKD. Participants' demographic, socioeconomic characteristics and satisfaction scores measured with the self-administered Medical Interview Satisfaction Scale (MISS) were collected after they visited the TCM physician. MISS is a 26-item questionnaire consisting of three domains - cognitive, affective and behavioural which was developed to assess patient satisfaction with medical consultation. Independent samples t-test and one-way analysis of variance (ANOVA) were used to analyse the data. Results: 137 participants completed the questionnaires and were included in the analysis. The mean satisfaction score was 3.1 out of 5, with the cognitive domain being significantly higher compared to the affective and behavioural domains. The mean satisfaction score of the cognitive domain differed significantly among participants staying in different types of housing and those with previous TCM encounters. The mean satisfaction score of the behavioural domain differed significantly among participants of different ethnicities. The mean satisfaction scores of all the domains were also significantly different among participants with different duration of follow-up with their TCM physicians. Conclusion: We found that ethnicity, types of housing, previous TCM experience and the duration of follow-up with the TCM physician may affect the satisfaction scores of patients with DKD.

Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans.

BACKGROUNDCytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.METHODSTo determine whether reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays.RESULTSMutation carriers had lower plasma 12α-hydroxylated/non-12α-hydroxylated BA and cholic acid (CA)/chenodeoxycholic acid (CDCA) ratios compared with age-, sex-, and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to mutation-carrier CA/CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We found that reduced CYP8B1 activity associates with increased insulin sensitivity in humans.CONCLUSIONOur findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.FUNDINGBiomedical Research Council/National Medical Research Council of Singapore.

The Impact of Bariatric Surgery Compared to Medical Therapy on Health-Related Quality of Life in Subjects with Obesity and Type 2 Diabetes Mellitus.

INTRODUCTION: The adverse implications of obesity extend beyond physical health to include negative impact on quality of life (QoL), mood, and eating habits. While bariatric surgery provides successful weight loss and metabolic benefits, studies describe conflicting results on QoL and mood-related outcomes. METHODS: Patients (n = 140) with class II/III obesity and T2DM were recruited from 2015 to 2019, and stratified based on medical or surgical treatment. Questionnaires including the Hospital Anxiety and Depression Scale, Euro QoL visual analogue scale (EQ-VAS), and Revised 21-item Three-Factor Eating Questionnaire (TFEQ-R21) were recorded at baseline, 6 months, and 12 months after treatment. RESULTS: At baseline, the surgical group (n = 55) and medical group (n = 85) had no significant difference in questionnaire outcomes. At 6 and 12 months, EQ-VAS was higher in the surgical group (12 months surgical 82.00 ± 12.64, medical 72.81 ± 16.56, p = 0.001), with greater improvement from baseline. HADS-D scores at 12 months were lower in the surgical group (surgical 2.60 ± 2.88, medical 3.90 ± 3.58, p = 0.025). At 12 months, the surgical group also had better TFEQ-R21 scores, with higher cognitive restraint scores (surgical 19.09 ± 3.00, medical 16.69 ± 3.61, p < 0.001), and lower scores for uncontrolled eating (surgical 14.96 ± 3.87, medical 17.89 ± 5.34, p = 0.001). CONCLUSION: In the treatment of patients with obesity and T2DM, bariatric surgery resulted in improved QoL outcomes at 12 months compared to medical therapy. This could be related to improvement in weight and metabolic outcomes, and altered gut-brain axis communication. This is the first prospective study assessing the impact of bariatric surgery on health-related QoL in Asia compared against a control group who received medical therapy.