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Objective:This study aimed to explore the facilitators and barriers to healthy dietary behaviour in adults with type 2 diabetes mellitus (T2DM) in Kenya.Design:A qualitative descriptive design using telephone interviews was applied. An interview guide was developed through a modified theoretical framework.Setting:This study was conducted in selected hospitals in Nakuru County, located in west-central Kenya.Participants:A two-step sampling strategy was used to select hospitals and study participants. Adult participants aged 30 to 85 years, with T2DM from six hospitals were selected based on their ability to openly elaborate on the theme of dietary behaviour.Results:Thirty respondents were interviewed (mean age 62 years; 43·3 % females). The average duration of the interviews was 32:02 min (sd 17·07). The highest-ranking internal facilitators of healthy dietary behaviour were knowledge of healthy food choices, gardening, self-efficacy, food preparation skills and eating at home. External facilitators included inaccurate beliefs and information on food and diet, education by healthcare workers, food availability, proximity to food selling points and family support. Internal barriers included tastes and preferences, health conditions barring intake of certain foods, and random eating of unhealthy foods. External barriers included socio-economic factors, seasonal unavailability of fruits and food safety concerns.Conclusions:Facilitators and barriers to healthy dietary behaviour among Kenyan adults with T2DM are related to food literacy and include selection, preparation and eating. Interventions to enhance healthy dietary behaviour should target context-specific knowledge, skills and self-efficacy.

Background and Objectives Rebaudioside A, a steviol glycoside, is deglycosylated by intestinal microflora prior to the absorption of steviol and conjugation to steviol glucuronide. While glucose-lowering properties are observed for rebaudioside A in mice, they have been attributed to the metabolites steviol and steviol glucuronide. We aimed to characterize the pharmacokinetic and pharmacodynamic properties of rebaudioside A and its metabolites in patients with early-onset type 2 diabetes mellitus (T2DM). Methods This randomized, placebo-controlled, open-label, two-way crossover trial was performed in subjects with T2DM on metformin or no therapy at the University Hospitals Leuven, Belgium. Following oral rebaudioside A (3 g), plasma concentrations of rebaudioside A, steviol and steviol glucuronide were determined. The effect on glucose homeostasis was examined by an oral glucose tolerance test (OGTT) performed 19 h following rebaudioside A administration, i.e. the presumed time of maximal steviol and steviol glucuronide concentrations. The primary pharmacodynamic endpoint was the difference in area under the blood glucose concentration–time curve during the first 2 h of the OGTT (AUC Glucose(0–2h)) for rebaudioside A vs. placebo. Results In total, 30 subjects [63.5 (57.8–69.0) years of age, 86.7% male] completed the trial. Rebaudioside A was detected as early as 1 h after administration in nearly all subjects. As expected, steviol and steviol glucuronide reached their maximal concentrations at 19.5 h following rebaudioside A administration. Rebaudioside A did not lower the AUC Glucose(0–2h) compared to placebo (− 0.7 (95% CI − 22.3; 20.9) h·mg/dL, P = 0.95). Insulin and C-peptide concentrations were also comparable between both conditions (P > 0.05). Conclusion Rebaudioside A is readily absorbed after oral administration and metabolized to steviol and steviol glucuronide. However, no effect on glucose nor insulin or C-peptide excursion was observed during the OGTT at the time of maximal metabolite concentrations. Thus, no antidiabetic properties of rebaudioside A could be observed in patients with T2DM after single oral use. ispartof: European Journal Of Drug Metabolism And Pharmacokinetics vol:47 issue:6 pages:1-13 ispartof: location:France status: Published online

BACKGROUND The global prevalence of type 2 diabetes has risen alarmingly in the past decade in sub-Saharan Africa. At the same time, mobile phone use has increased in Africa, providing a potential for innovative mobile health (mHealth) interventions to support diabetes care. OBJECTIVE This study aimed to apply the Behaviour Change Wheel (BCW) to design and develop a mHealth intervention to optimize glycaemic control in adults with type 2 diabetes in urban Kenya METHODS The three stages of the BCW that include understanding the behaviour identifying the intervention options and identifying content and implementations options guided the development of this mHealth intervention. Recent preparatory studies from low- and middle-income countries (LMICs) provided information that was used to contextualize the three stages of intervention development. RESULTS Stage 1 revealed unhealthy eating patterns, characterized by low intake of fruits and vegetables and larger portion sizes of carbohydrates, as the key behaviour problem. In stage 2, target options to optimize glycaemic control were identified and related to food literacy components, including nutrition information, food selection, meal preparation and eating. In stage 3, text messages were selected as the delivery mode. A total of 36 mobile text messages were developed based on nine behaviour change techniques. CONCLUSIONS We developed a mHealth guided by the step-by-step BCW framework while using evidence from the target population. We, therefore, created contextualized intervention components and applied behaviour change techniques that were used to design mobile text messages to optimize glycaemic control for adults with type 2 diabetes in LMICs. The effectiveness of this intervention will be tested in a proof-of-concept study in the target population

This document contains supplemental figures 1-7 and detailed supplemental methods

Supplemental tables 1-10.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC.Significance:With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

This scoping review summarizes current evidence with regard to the impact of bariatric surgery on psychological health in adults with obesity. While a large body of evidence reports major metabolic benefit and improved quality of life, there is also ample evidence suggesting an increased incidence of self-harming behavior, a greater likelihood of developing an alcohol problem and higher rates of completed suicide among bariatric patients. Being able to identify the "at risk" patient population requires more longitudinal research into the risk factors for psychological complications after bariatric surgery. Bariatric surgery remains an extremely valuable long-term treatment option for managing obesity; however, there is a need to invest in mitigating psychological complications after the surgery, such as depression, alcohol consumption, and other self-harming behaviors. ispartof: OBESITY SURGERY vol:31 issue:12 pages:5409-5417 ispartof: location:United States status: published

Despite the increasing prevalence and medical burden of obesity, the understanding of gastrointestinal physiology in obesity is scarce, which hampers drug development.To investigate the effect of obesity and food intake on gastrointestinal transit, pressure and pH.An exploratory cross-sectional study using a wireless motility capsule (SmartPill©) was performed in 11 participants with obesity and 11 age- and gender-matched participants with normal weight (group) in fasted and fed state (visit). During the first visit, the capsule was ingested after an overnight fast. During a second visit, the capsule was ingested after a nutritional drink to simulate fed state. Linear mixed models were constructed to compare segmental gastrointestinal transit, pressure and pH between groups (obesity or control) and within every group (fasted or fed).Food intake slowed gastric emptying in both groups (both P 0.0001), though food-induced gastric contractility was higher in participants with obesity compared to controls (P = 0.02). In the small intestine, a higher contractility (P = 0.001), shorter transit (P = 0.04) and lower median pH (P = 0.002) was observed in participants with obesity compared to controls. No differences were observed for colonic measurements.Obesity has a profound impact on gastrointestinal physiology, which should be taken into account for drug development.

BACKGROUND: The reported prevalences and effects of nutritional risk vary widely in the literature because of both methodological differences (e.g., screening tools and statistical analyses) and different patient populations. OBJECTIVE: In this study the authors analyzed in-hospital mortality, 30-d mortality, readmission within 4 mo, and justified length of stay (jLoS) (determined by governmental assessment to justify financial compensation) in hospitalized patients nutritionally at risk compared with hospitalized patients not at risk. DESIGN: This was a multicenter retrospective cohort study in 6 Belgian hospitals among inpatients in 2018. Propensity score matching was applied, including comorbidity score and exact matching for hospital, age group, sex, type of admission, living situation, and medical specialty. RESULTS: In total, 73,843 of 85,677 patients were screened at admission, with 16,141 found to have nutritional risk (prevalence of 21.9%). Oncology patients had the highest risk prevalence of 38.3%, whereas patients receiving plastic or reconstructive surgery had a prevalence of 5.2%. Patients nutritionally at risk had higher odds of dying in the hospital (5.1% compared with 3.3%; OR: 1.56; 95% CI: 1.37, 1.76), dying within 30 d of admission (6.8% compared with 4.3%; OR: 1.62; 95% CI: 1.45, 1.81) and being readmitted within 4 mo after discharge (35.5% compared with 32.9%; OR: 1.12; 95% CI: 1.07, 1.18). These differences were consistent across hospitals. The association between being nutritionally at risk and jLoS was ambiguous. CONCLUSIONS: One out of 5 patients included in this study was nutritionally at risk. Using propensity score matching, higher odds of in-hospital mortality, readmission, and 30-d mortality were observed. In contrast to oft-reported increased length of stay with poor nutrition, propensity matched data for jLoS suggested that this association was less pronounced in this cohort. ispartof: AMERICAN JOURNAL OF CLINICAL NUTRITION vol:114 issue:3 pages:1123-1130 ispartof: location:United States status: published

Knowledge regarding the gastrointestinal physiology after sleeve gastrectomy and Roux-en-Y gastric bypass is urgently needed to understand, prevent and treat the nutritional and pharmacological complications of bariatric surgery.To investigate the effect of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal motility (e.g., transit and pressure), pH, and intestinal bile acid concentration.An exploratory cross-sectional study was performed in six participants living with obesity, six participants who underwent sleeve gastrectomy, and six participants who underwent Roux-en-Y gastric bypass. During the first visit, a wireless motility capsule (SmartPill©) was ingested after an overnight fast to measure gastrointestinal transit, pH, and pressure. During the second visit, a gastric emptying scintigraphy test of a nutritional drink labeled withImmediate pouch emptying (P=0.0007) and a trend for faster GETThe anatomical alterations of sleeve gastrectomy and Roux-en-Y gastric bypass have an important impact on gastrointestinal physiology. This data confirms changes in transit and pH and provides the first evidence for altered intraluminal bile acid concentration.

INTRODUCTION: Aside from an impact on health, obesity is also associated with higher social and economic costs such as impaired productivity, increased work absenteeism, and higher rates of unemployment. The aim of this study was to assess the effect of bariatric surgery on employment status in a large nationwide database, using data from all patients that underwent bariatric surgery in Belgium. METHODS: This is a retrospective analysis of all Belgian patients that underwent bariatric surgery between 2014 and 2015. The work status of these patients was examined yearly: 4 years before and 3 years after surgery. Increased employment after surgery was defined (1) as a reduction in days of unemployment and incapacity and (2) as the resumption of work among the unemployed. RESULTS: In total, 16,276 patients were included. The number of working people rose from 49.7% before to 61.2% 3 years after bariatric surgery, i.e., an increase of 11.5% between pre- and post-surgery. The largest improvement in reduction in unemployment was found in individuals who were absent from work for more than 9 months, namely, a reduction from 13.4 to 7.2%. In the population of unemployed patients, 20.9% became employed after bariatric surgery. CONCLUSION: We found an increase in employment rate and a decrease in work incapacity and unemployment after bariatric surgery. Higher rates of employment after bariatric surgery may also contribute to an increased cost-effectiveness of bariatric surgery. It would be interesting to research possible targeting strategies to increase the employment rate even more after bariatric surgery. ispartof: OBESITY SURGERY vol:32 issue:8 pages:2625-2631 ispartof: location:United States status: published

Purpose: Patients with prior bariatric surgery (BS) are at risk to develop alcohol use disorder (AUD) and alcohol-related liver disease (ALD). Severe alcoholic hepatitis (sAH) is one of the most severe manifestations of ALD with a 28-day mortality of 20-50%. The impact of prior BS on patients presenting with sAH was assessed. Methods: From 01/2008 to 04/2021, consecutive patients admitted to a tertiary referral center with biopsy-proven sAH were included in a database. Results: One hundred fifty-eight sAH patients of which 28 patients had a history of BS (BS group) were identified. Of this BS group, 24 patients underwent a Roux-en-Y gastric bypass (RYGB), 3 a biliopancreatic diversion, 1 an adjustable gastric band, and no patients a sleeve gastrectomy. The proportion of patients with BS increased threefold over time during the study period. Patients in the BS group were significantly younger at diagnosis of sAH (44.3 years vs 52.4 years), were more frequently female, and had a higher body mass index and a higher grade of steatosis on liver biopsy. The correlation between BS and a younger age at diagnosis remained significant in a multivariate regression analysis. There were no differences in disease severity between both groups. Furthermore, there were no differences in corticosteroid response, 28-day, 90-day, or 1-year survival. Conclusion: Prior BS is independently associated with a younger age of presentation with sAH, but is not independently associated with a different disease severity or outcome. These findings support the need for early detection of AUD in patients who underwent BS, in particular RYGB.

Background and objectives: To investigate the effect of carbohydrate intake before laparoscopic Roux-en-Y gastric bypass (LRYGB) on body weight, body composition and glycaemic status after surgery. Methods: In a tertiary centre cohort study, dietary habits, body composition and glycaemic status were evaluated before and 3, 6 and 12 months after LRYGB. Detailed dietary food records were processed by specialized dietitians on the basis of a standard protocol. The study population was subdivided according to relative carbohydrate intake before surgery. Results: Before surgery, 30 patients had a moderate relative carbohydrate intake (26%–45%, M-CHO), a mean body mass index (BMI) of 40.4 ± 3.9 kg/m² and a mean glycated haemoglobin A1c (A1C) of 6.5 ± 1.2% compared to 20 patients with a high relative carbohydrate intake (> 45%, H-CHO), mean BMI of 40.9 ± 3.7 kg/m² (non-significant, NS) and a mean A1C of 6.2% (NS). One year after surgery, body weight, body composition and glycaemic status were similar in the M-CHO (n = 25) and H-CHO groups (n = 16), despite less caloric intake in the H-CHO group (1317 ± 285 g vs. 1646 ± 345 g in M-CHO, p

BACKGROUND: Metabolic surgery has beneficial metabolic effects, including remission of type 2 diabetes. We hypothesized that duodenojejunal bypass (DJB) surgery can protect against development of type 1 diabetes (T1D) by enhancing regulation of cellular and molecular pathways that control glucose homeostasis. METHODS: BBDP/Wor rats, which are prone to develop spontaneous autoimmune T1D, underwent loop DJB (n=15) or sham (n=15) surgery at a median age of 41 days, before development of diabetes. At T1D diagnosis, a subcutaneous insulin pellet was implanted, oral glucose tolerance test was performed 21 days later, and tissues were collected 25 days after onset of T1D. Pancreas and liver tissues were assessed by histology and RT-qPCR. Fecal microbiota composition was analyzed by 16S V4 sequencing. RESULTS: Postoperatively, DJB rats weighed less than sham rats (287.8 vs 329.9 g, P=0.04). In both groups, 14 of 15 rats developed T1D, at similar age of onset (87 days in DJB vs 81 days in sham, P=0.17). There was no difference in oral glucose tolerance, fasting and stimulated plasma insulin and c-peptide levels, and immunohistochemical analysis of insulin positive cells in the pancreas. DJB rats needed 1.3±0.4 insulin implants vs 1.9±0.5 in sham rats (P=0.002). Fasting and glucose stimulated glucagon-like peptide 1 (GLP-1) secretion was elevated after DJB surgery. DJB rats had reduced markers of metabolic stress in liver. After DJB, the fecal microbiome changed significantly, including increases in Akkermansia and Ruminococcus, while the changes were minimal in sham rats. CONCLUSION: DJB does not protect against autoimmune T1D in BBDP/Wor rats, but reduces the need for exogenous insulin and facilitates other metabolic benefits including weight loss, increased GLP-1 secretion, reduced hepatic stress, and altered gut microbiome.

Gastrectomy and gastric bypass improve type 2 diabetes (T2DM), potentially through alterations in intestinal hormones and the microbiome. The aim of this study was to analyze whether colorectal resections result in improvement of T2DM. A total of 171 patients with T2DM who underwent colectomy for benign diseases were studied with a median postoperative follow-up of 3 years (interquartile range [IQR] 1–5). The median BMI and glycated hemoglobin (HbA1c) at baseline and post-colectomy were 30.3 kg/m2 (IQR 26.6–34.6) versus 30.4 kg/m2 (IQR 26.2–35) (p = 0.1), and 6.7% (IQR 6.2–7.5) versus 6.5% (IQR 6.5–7.1) (p = 0.5), respectively. The proportion of patients taking diabetes medications at baseline versus post-colectomy did not differ significantly. Changes in BMI, HbA1c, and status of diabetes medications were not statistically different between the subtypes of colorectal resection. Our experience suggests that colectomy for benign colorectal diseases is not associated with long-term changes in body weight or glycemic control.

Introduction: Obesity is a global health challenge, and pharmacologic options are emerging. Once daily subcutaneous administration of 3 mg liraglutide, a glucagon like peptide-1 analogue, has been shown to induce weight loss in clinical trials, but real-world effectiveness data are scarce. Methods: It is a single-centre retrospective cohort study of patients who were prescribed liraglutide on top of lifestyle adaptations after multidisciplinary evaluation. In Belgium, liraglutide is only indicated for weight management if the BMI is >30 kg/m2 or ≥27 kg/m2 with comorbidities such as dysglycaemia, dyslipidaemia, hypertension, or obstructive sleep apnoea. No indication is covered by the compulsory health care insurance. Liraglutide was started at 0.6 mg/day and uptitrated weekly until 3 mg/day or the maximum tolerated dose. Treatment status and body weight were evaluated at the 4-month routine visit. Results: Between June 2016 and January 2020, liraglutide was prescribed to 115 patients (77% female), with a median age of 47 (IQR 37.7–54.0) years, a median body weight of 98.4 (IQR 90.0–112.2) kg, a BMI of 34.8 (IQR 32.2–37.4) kg/m2, and an HbA1c level of 5.6%. Five (4%) patients did not actually initiate treatment, 9 (8%) stopped treatment, and 8 (7%) were lost to follow-up. At the 4-month visit, the median body weight had decreased significantly by 9.2% to 90.8 (IQR 82.0–103.5) kg (p < 0.001). Patients using 3.0 mg/day (n = 60) had lost 8.0 (IQR 5.8–10.4) kg. The weight loss was similar (p = 0.9622) in patients that used a lower daily dose because of intolerance: 7.4 (IQR 6.2–9.6) kg for 1.2 mg (n = 3), 7.8 (IQR 4.1–7.8) kg for 1.8 mg (n = 16), and 9.0 (IQR 4.8–10.7) kg for 2.4 mg/day (n = 14). Weight loss was minimal if liraglutide treatment was not started or stopped prematurely (median 3.0 [IQR 0.3–4.8] kg, p < 0.001, vs. on treatment). Further analysis showed an additional weight reduction of 1.8 kg in the patients that had started metformin p < 0.001). The main reasons for liraglutide discontinuation were gastrointestinal complaints (n = 5/9) and drug cost (n = 2/9). Conclusion: In this selected group of patients, the majority complied with liraglutide treatment over the initial 4-month period and achieved a significant weight loss, irrespective of the maximally tolerated maintenance dose. Addition of metformin induced a small but significant additional weight loss.

BACKGROUND: As lipid targets became more stringent in the latest ESC/EAS guidelines, many patients on statin monotherapy are left above their risk-based target, increasing the need for lipid-lowering therapies. The results of the ODYSSEY APPRISE study were recently published by Gaudet et al In this trial, alirocumab (a PCSK9 inhibitor) was investigated in high cardiovascular risk patients in a real-life setting. OBJECTIVE: We aim at analysing the characteristics, safety and efficacy of alirocumab in the Belgian population of the ODYSSEY APPRISE trial and, based on literature research, we aim to evaluate the importance and the need for the add-on, non-statin lipid-lowering therapy in clinical practice. METHODS AND RESULTS: ODYSSEY APPRISE is a multicentric, prospective, single-arm, Phase 3b open-label trial. A total of 68 Belgian patients were enrolled, 63 patients had heterozygous familial hypercholesterolaemia (HeFH). Baseline mean LDL-c was 188.7 mg/dL (SD ± 51.8). At week 12, 65 patients had an evaluable efficacy end point with a mean LDL-c reduction of 59.9% from baseline. The overall incidence of treatment-emergent adverse events (TEAEs) was 75.0%. The most frequent TEAE was back pain (10.3%), nasopharyngitis (10.3%) and injection site erythema (8.8%). Based on the literature, a majority of patients do not reach their risk-based lipid target despite statin therapy alone. CONCLUSION: In a real-life setting, alirocumab is both well-tolerated, safe and very effective in reducing LDL-c in this Belgian cohort. In clinical practice, more patients should be initiated on the add-on, non-statin lipid-lowering therapy in order to reach their risk-based lipid target. ispartof: INTERNATIONAL JOURNAL OF CLINICAL PRACTICE vol:75 issue:12 ispartof: location:India status: published

At the time of its first clinical application 100 years ago, insulin was presented as the cure for people with diabetes mellitus. That transpired to be an overstatement, yet insulin has proven to be the lifesaver for people with type 1 diabetes mellitus and an essential therapy for many with type 2 diabetes mellitus or other forms of diabetes mellitus. Since its discovery, insulin (a molecule of only 51 amino acids) has been the subject of pharmaceutical research and development that has paved the way for other protein-based therapies. From purified animal-extracted insulin and human insulin produced by genetically modified organisms to a spectrum of insulin analogues, pharmaceutical laboratories have strived to tailor the preparations to the needs of patients. Nonetheless, overall glycaemic control often remains poor as exogenous insulin is still not able to mimic the physiological insulin profile. Circumventing subcutaneous administration and the design of analogues with profiles that mimic that of physiological insulin are ongoing areas of research. Novel concepts, such as once-weekly insulins or glucose-dependent and oral insulins, are on the horizon but their real-world effectiveness still needs to be proven. Until a true cure for type 1 diabetes mellitus is found and the therapeutic arsenal for other forms of diabetes mellitus is expanded, insulin will remain central in the treatment of many people living with diabetes mellitus.

Non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome. Our aim was to study the long-term effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on NAFLD/NASH. Between 2008 and 2015, 3813 patients had an intraoperative liver biopsy performed at the time of primary RYGB and SG at a single academic center. Utilizing strict inclusion criteria, 487 patients with biopsy-proven NAFLD who had abnormal alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values (≥ 40 IU/L) at baseline were identified. Matching of SG to RYGB patients (1:4) was performed via logistic regression and propensity scores adjusting for clinical and liver histological characteristics. Changes in liver function tests (LFTs) at least 1 year after surgery were compared to baseline values and between the surgical groups. A total of 310 (weighted) patients (SG n = 62, and RYGB n = 248) with a median follow-up time of 4 years (range, 1–10) were included in the analysis. The distribution of covariates was well-balanced after propensity matching. In 84% of patients, LFT values normalized after bariatric surgery at the last follow-up time. The proportions of patients having normalized LFT values did not differ significantly between the SG and RYGB groups (82% vs. 84%, p = 0.66). The AST decreased from (SG: 49.1 ± 21.5 vs. RYGB: 49.3 ± 22.0, p = 0.93) at baseline to (SG: 28.0 ± 16.5 vs. RYGB: 26.5 ± 15.5, p = 0.33) at the last follow-up. Similarly, a significant reduction in ALT values from (SG: 61.7 ± 30.0 vs. RYGB 59.4 ± 24.9, p = 0.75) at baseline to (SG: 27.2 ± 21.5 vs. RYGB: 26.1 ± 19.2, p = 0.52) at the last follow-up was observed. In patients with biopsy-proven NAFLD/NASH, abnormal LFTs are normalized in most SG and RYGB patients by the end of the first postoperative year and remain normal until the last follow-up. This study also suggests that both bariatric procedures are similarly effective in improving liver function.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC. Significance: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

Testosterone (T) reduces male fat mass, but the underlying mechanisms remain elusive, limiting its clinical relevance in hypogonadism-associated obesity. Here, we subjected chemically castrated high-fat diet-induced adult obese male mice to supplementation with T or the nonaromatizable androgen dihydrotestosterone (DHT) for 20 weeks. Both hormones increased lean mass, thereby indirectly increasing oxygen consumption and energy expenditure. In addition, T but not DHT decreased fat mass and increased ambulatory activity, indicating a role for aromatization into estrogens. Investigation of the pattern of aromatase expression in various murine tissues revealed the absence of Cyp19a1 expression in adipose tissue while high levels were observed in brain and gonads. In obese hypogonadal male mice with extrahypothalamic neuronal estrogen receptor alpha deletion (N-ERαKO), T still increased lean mass but was unable to decrease fat mass. The stimulatory effect of T on ambulatory activity was also abolished in N-ERαKO males. In conclusion, our work demonstrates that the fat-burning action of T is dependent on aromatization into estrogens and is at least partially mediated by the stimulation of physical activity via extrahypothalamic ERα signaling. In contrast, the increase in lean mass upon T supplementation is mediated through the androgen receptor and indirectly leads to an increase in energy expenditure, which might also contribute to the fat-burning effects of T. ispartof: ENDOCRINOLOGY vol:162 issue:6 ispartof: location:United States status: published

Objective: Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and beta-cell dysfunction. Ectopic fat accumulation in liver and muscle causes IR. Since bariatric and metabolic surgery significantly improves fatty liver disease, we hypothesized that coexistence of liver steatosis (i.e., when hepatic IR contributes in T2DM) would be associated with greater diabetes improvement after surgery. Research design and methods: A total of 519 patients with T2DM who underwent Roux-en-Y gastric bypass and simultaneous liver biopsy and had a minimum 5-year follow-up were analyzed to assess the independent association between biopsy-proven liver steatosis and postoperative long-term diabetes remission (glycated hemoglobin < 6.5% off medications). Results: Of the 407 patients with biopsy-proven liver steatosis, long-term diabetes remission was achieved in 211 (52%) patients, compared with 44/112 (39%) remission in patients without steatosis (P=0.027). In multivariable analysis, presence of liver steatosis was an independent predictor of long-term diabetes remission (odds ratio 1.96, [95% confidence interval 1.04 – 3.72], P=0.038). Hepatocyte ballooning, lobular inflammation, or fibrosis at baseline did not predict diabetes remission. Conclusion: This study, for the first time, suggests that in patients with T2DM who are considering bariatric and metabolic surgery, coexistence of liver steatosis is associated with better long-term glycemic outcomes. Furthermore, our data suggest that there are different variants of T2DM wherein metabolic responses to surgical weight loss are different. A subgroup of patients whose T2DM is characterized by the presence of hepatic steatosis (presumably associated with worse IR) experience better postoperative metabolic outcomes.

Roux-en-Y gastric bypass (RYGB) is thought to reduce calcium absorption from the gut. Here, we report the case of a patient with a RYGB, who developed primary hypoparathyroidism after a total thyroidectomy, leading to recalcitrant hypocalcaemia. Despite aggressive oral calcium and calcitriol supplementation, she remained hypocalcaemic and required intravenous (IV) calcium supplementation to control her symptoms, and to keep calcium serum levels within an acceptable range. Teriparatide treatment improved calcium levels marginally. This treatment, however, was poorly tolerated and ultimately stopped by the patient. As a last resort, reversal of RYGB was performed to improve calcium absorption from the gut. Unfortunately, IV calcium supplementation remained necessary. This case illustrates that the reversal of RYGB is not always a guarantee for success in managing recalcitrant hypocalcaemia. ispartof: OBESITY SURGERY vol:30 issue:12 pages:5150-5152 ispartof: location:United States status: published

OBJECTIVE Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and β-cell dysfunction. Ectopic fat accumulation in liver and muscle causes IR. Since bariatric and metabolic surgery significantly improves fatty liver disease, we hypothesized that coexistence of liver steatosis (i.e., when hepatic IR contributes in T2DM) would be associated with greater diabetes improvement after surgery. RESEARCH DESIGN AND METHODS A total of 519 patients with T2DM who underwent Roux-en-Y gastric bypass and simultaneous liver biopsy and had a minimum 5-year follow-up were analyzed to assess the independent association between biopsy-proven liver steatosis and postoperative long-term diabetes remission (glycated hemoglobin RESULTS Of the 407 patients with biopsy-proven liver steatosis, long-term diabetes remission was achieved in 211 (52%) patients compared with remission in 44 out of 112 (39%) patients without steatosis (P = 0.027). In multivariable analysis, presence of liver steatosis was an independent predictor of long-term diabetes remission (odds ratio 1.96 [95% CI 1.04–3.72]; P = 0.038). Hepatocyte ballooning, lobular inflammation, or fibrosis at baseline did not predict diabetes remission. CONCLUSIONS This study, for the first time, suggests that in patients with T2DM who are considering bariatric and metabolic surgery, coexistence of liver steatosis is associated with better long-term glycemic outcomes. Furthermore, our data suggest that there are distinct variants of T2DM in which metabolic responses to surgical weight loss are different. A subgroup of patients whose T2DM is characterized by the presence of hepatic steatosis (presumably associated with worse IR) experience better postoperative metabolic outcomes.

Gastrectomy and gastric bypass improve type 2 diabetes (T2DM), potentially through alterations in intestinal hormones and the microbiome. The aim of this study was to analyze whether colorectal resections result in improvement of T2DM. A total of 171 patients with T2DM who underwent colectomy for benign diseases were studied with a median postoperative follow-up of 3 years (interquartile range [IQR] 1-5). The median BMI and glycated hemoglobin (HbA

Background Bone loss and increased fracture risk following bariatric surgery has been reported. We investigated whether the two most commonly performed surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), lead to bone loss. In addition, we examined whether fortification of the diet with calcium citrate prevents bone loss. Methods We used mouse models for SG and RYGB and compared bone loss with a group of sham mice with similar weight loss. All groups were switched at the time of surgery to a low-fat diet (LFD). We also examined whether fortification of the diet with calcium citrate and vitamin D was able to prevent bone loss. Results At 2 weeks we observed no major bone effects. However, at 8 weeks, both trabecular and cortical bone were lost to the same extent after SG and RYGB, despite increased calcium absorption and adequate serum levels of calcium, vitamin D, and parathyroid hormone (PTH). Diet fortification with calcium citrate and vitamin D was able to partially prevent bone loss. Conclusions Both SG and RYGB lead to excess bone loss, despite intestinal adaptations to increase calcium absorption. Fortifying the diet with calcium citrate and vitamin D partly prevented the observed bone loss. This finding emphasizes the importance of nutritional support strategies after bariatric surgery, but also affirms that the exact mechanisms leading to bone loss after bariatric surgery remain elusive and thus warrant further research. ispartof: International Journal Of Obesity vol:44 issue:10 ispartof: location:England status: Published online

Summary The hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that regulates the body’s response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), Zinc finger and BTB domain containing 32 (ZBTB32) is a transcription factor with poorly described functional relevance in physiology. This study shows that ZBTB32 is essential for the production of glucocorticoids (GCs) in response to starvation, since ZBTB32−/− mice fail to increase their GC production in the absence of nutrients. In terms of mechanism, GR-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32−/− mice, implicating defective cholesterol import as the cause of the poor GC synthesis. These lower GC levels are further associated with aberrations in the metabolic adaptation to starvation, which could explain the progressive weight gain of ZBTB32−/− mice. In conclusion, ZBTB32 performs a crosstalk with the GR in the metabolic adaptation to starvation via regulation of adrenal GC production., Graphical abstract Nutrient shortage is sensed by the brain and causes the activation of the HPA axis. The synthesis and release of corticosterone by the adrenal glands is stimulated via the release of ACTH. Cholesterol, the precursor of corticosterone, is imported into the adrenal cortex cells via high-density lipoproteins (HDLs) which are internalized via the SR-B1 (Scarb1) receptor. ZBTB32 acts as a GR co-activator by enhancing the GR-induced upregulation of Scarb1 gene expression and thereby controlling the cholesterol import into the adrenal glands during food deprivation. The expression of Scarb1 is positively regulated by corticosterone and the GR agonist dexamethasone. Furthermore, corticosterone is also responsible for the metabolic adaptations of mice during starvation, by inducing lipolysis in the white adipose tissue (WAT) thereby releasing glycerol and free fatty acids into the bloodstream. Glycerol will then be used as a precursor for gluconeogenesis in the liver, while the FFAs will induce PPARα signaling in the liver. Lower corticosterone levels in ZBTB32−/− mice are associated with disturbances in the metabolic adaptation to starvation, including lower lipolytic activity of WAT and aberrant PPARα signaling in the liver, which could result in weight gain and fat mass accumulation in ZBTB32−/− mice over time., Highlights • ZBTB32 is involved in the glucocorticoid production in response to starvation • GR-mediated upregulation of adrenal Scarb1 regulates cholesterol import • The weight gain of ZBTB32−/− mice is associated with aberrant metabolic adaptations, Biological sciences; physiology; animal physiology; Endocrinology

Evidence on the association between diabetes and adverse outcomes for the novel coronavirus disease 2019 (COVID-19) is emerging, but most studies start from observations in hospitalized patients (1–3). Uncertainty remains as to whether the predisposing factor for COVID-19 severity is the multimorbid profile of these patients or dysglycemia itself. In particular, it is unclear whether people living with type 1 diabetes (T1D) are at high risk for adverse COVID-19 outcomes. Here, we report the hospitalization rate in community-dwelling people living with T1D during the first 3 months of the COVID-19 pandemic in Belgium. We retrospectively analyzed medical records of all adults with T1D that have their diabetes care contract in either of two diabetes specialist centers. All data were retrieved through data queries from the electronic patient record and were checked manually for validity. Hospitalization in other Belgian hospitals was checked using the national electronic patient record. Patients were selected on the basis of their clinical diagnosis. For the study period of 1 February to 30 April, we retrieved hospital admission date, location, and primary indication as well as BMI, glycemic control (HbA1c), blood pressure, history of macroangiopathy, nephropathy, and hypertension, and angiotensin-converting enzyme (ACE) inhibitor or angiotensin …

Bariatric surgery induces weight loss and restores glucose metabolism in patients with obesity and type 2 diabetes (T2D) (1). In patients with autoimmune diabetes that eventually results in β-cell failure, the glycemic effects of bariatric surgery are limited (2). Adult patients with latent autoimmune diabetes in adults (LADA) have a slower decline in β-cell function and lower requirement for insulin therapy than patients with classical young-onset type 1 diabetes (T1D) (3). They are often misdiagnosed as having T2D and might have unrealistic expectations of diabetes remission after bariatric surgery with additional risk for development of postoperative diabetic ketoacidosis (DKA) (4). The safety and efficacy of bariatric surgery in patients with obesity and LADA have not been characterized. We retrospectively analyzed medical records of patients with obesity and LADA who underwent bariatric surgery at the Cleveland Clinic Health System in the U.S. LADA status was defined as adult-onset diabetes with presence of GAD antibodies. We compared pre- and postsurgery BMI, glycemic control (HbA1c), daily insulin dose, and blood pressure and lipid profile using a paired Student t test, with a P value of 0.05 considered significant. Between October 2006 and March 2018, nine female patients underwent laparoscopic bariatric surgery (five Roux-en-Y gastric bypass and four sleeve gastrectomy) and one male patient underwent sleeve gastrectomy. The median age at …

Vitamin D deficiency is associated with beta-cell dysfunction and a higher risk of diabetes, but mice and humans with an absence of the vitamin D receptor (VDR) display normal glucose tolerance. Here, we investigated the direct effects of absence of VDR or absence of ligand activation of VDR on beta-cell function. For this purpose, we generated mice, with a mutation in the AF2 domain of Vdr (VDRΔAF2), preventing ligand-driven transcriptional activation of vitamin D responsive genes. VDRΔAF2 mice were compared to Vdr full knockout (VDR-/-) and wild type (WT) mice. In order to avoid hypocalcemia, which has a direct effect on beta-cell function, mice were fed a high calcium, high lactose diet yielding comparable serum calcium in all mice. While VDR-/- mice developed extensive alopecia by the age of 24 weeks, the fur of VDRΔAF2 remained normal. All VDRΔAF2 mice weighed significantly less than WT, while male but not female VDR-/- mice had a lower body weight than WT mice. Dual-energy X-ray absorptiometry showed that both VDRΔAF2 (17.2% (females) and 16.6% (males)) and VDR-/- (15.7% and 14.8%) mice have a lower percentage of body fat (vs 19.3% and 22.2% in WT). Serum 25(OH)D3 concentrations were lower for both VDRΔAF2 (-4.55 fold, P

Diabetic nephropathy is the leading cause of chronic kidney disease. Observational studies suggest Roux-en-Y gastric bypass (RYGB) reduces progression of diabetic nephropathy.To unravel the mechanisms by which RYGB is beneficial and protective for diabetic nephropathy.Academic laboratories.Forty-eight Zucker diabetic fatty rats were randomized to RYGB, sham surgery (SHAM), or pair-fed (PF) groups. An oral glucose tolerance test was performed at 25 days post intervention and kidneys were harvested at 30 days. Primary outcome measures included expression of key genes and proteins in the glucose transport, oxidative stress, inflammation, and fibrosis pathways.Thirty days post intervention, RYGB rats weighed 349 ± 8 g, which was lower than SHAM (436 ± 14 g, P.001), but not PF (374 ± 18 g) rats. RYGB rats had lower fasting glucose than PF animals and improved homeostatic model assessment of insulin resistance compared with PF and SHAM groups. These enhanced metabolic outcomes were accompanied by reduced sodium-glucose co-transporter 1 (Sglt1) gene expression (-23% versus PF, P = .01) in the kidney of RYGB rats. Expression of Sglt2, Glut1, or Glut2 mRNA, or oxidative stress and inflammation markers did not differ significantly. However, RYGB surgery induced a 19% lower expression of transforming growth factor (Tgfβ) mRNA (P = .004) compared with SHAM treated animals. Notably, adenosine monophosphate-activated protein kinase phosphorylation was increased (P = .04) in kidneys of the RYGB surgery animals.Improvement of hyperglycemia after RYGB may reduce the glucose load on the kidney leading to a downregulation of specific glucose transporters. RYGB surgery may also attenuate kidney fibrosis through the adenosine monophosphate-activated protein kinase/TGFβ pathway.

The aim of this pilot study was to evaluate long-term effects of Roux-en-Y gastric bypass (RYGB) on physical and psychosocial health as well as eating behavior of obese patients.We compared 23 patients 7 years after RYGB to 23 body mass index (BMI), sex, and age matched obese control patients by means of self-reporting questionnaires: Hospital Anxiety and Depression Scale (HADS), Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q SF), Dutch Eating Behavior Questionnaire (DEBQ), and Alcohol Use Disorders Identification Test (AUDIT). Data are presented as median ± interquartile rage.Physical health had improved and body image (80 ± 25% vs. 20 ± 49%, p 0.001) was better in post-RYGB patients when compared to controls. HADS-depression score (4 ± 8 vs. 11 ± 9; p = 0.005) was lower post-RYGB. Satisfaction with physical health (2 ± 2 vs. 2 ± 1, p = 0.037), daily life functioning (4 ± 2 vs. 2 ± 2, p = 0.050), and hobbies (4 ± 1 vs. 2 ± 2, p = 0.011) was higher post-RYGB, but social relationships and sexual performance were not perceived as superior. In addition, post-RYGB patients were more prone to eat on external cues (13 ± 7 vs. 19 ± 13; p = 0.007).Seven years post-RYGB, patients reported a significant improvement of physical health and higher satisfaction with daily life, but not with social relationships or sexual performance. Eating behavior post-RYGB was more influenced by external cues.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with obesity and hyperglycemia. Roux-en-Y gastric bypass (RYGB) surgery is a common treatment for severely obese patients and T2DM. Both RYGB and T2DM are linked to increased skeletal fragility, though the exact mechanisms are poorly understood. Our aim was to characterize the structural, mechanical and compositional properties of bones from diet-induced obese and RYGB-treated obese (bypass) mice to elucidate which the exact factors are contributing to the increased skeletal fragility. To achieve this, a combinatory approach including microfocus X-ray computed tomography, 3-point bending, finite element modeling and Raman spectroscopy, was used. Compared to aged-matched lean controls, the obese mice displayed decreased cortical thickness, trabecular bone loss, decreased stiffness and increased Young’s modulus. For the bypass mice, these alterations were even more pronounced, and additionally they showed low mineral-to-matrix ratio in the cortical endosteal area. Accumulation of the advanced glycation end-product (AGE) pentosidine was found in the cortex of obese and bypass groups and this accumulation was correlated with an increased Young’s modulus. In conclusion, we found that the increased fracture risk in T2DM- and post-RYGB bones is mainly driven by accumulation of AGEs and macro-structural alterations, generating biomechanical dysfunctionality. ispartof: Scientific Reports vol:8 issue:1 pages:5881-1 ispartof: location:England status: published

The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel-Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin. In vitro and in vivo data indicated that Vhl-deficient osteoblasts displayed massively increased glucose uptake and glycolysis associated with upregulated HIF-target gene expression, resembling the Warburg effect that typifies cancer cells. Overall, the glucose consumption by the skeleton was increased in the mutant mice, as revealed by 18F-FDG radioactive tracer experiments. Moreover, the glycemia levels correlated inversely with the level of skeletal glucose uptake, and pharmacological treatment with the glycolysis inhibitor dichloroacetate (DCA), which restored glucose metabolism in Vhl-deficient osteogenic cells in vitro, prevented the development of the systemic metabolic phenotype in the mutant mice. Altogether, these findings reveal a novel link between cellular glucose metabolism in osteoblasts and whole-body glucose homeostasis, controlled by local hypoxia signaling in the skeleton. ispartof: Journal of Clinical Investigation vol:128 issue:3 pages:1087-1105 ispartof: location:United States status: published

BACKGROUND: Achieving weight loss is the cornerstone of the treatment of the metabolic consequences of obesity, in particular of glucose intolerance. OBJECTIVE: To determine whether improvement in glucose control depends on dietary macronutrient composition of the diet at identical weight loss. MATERIALS AND METHODS: Twenty-two weeks old diet-induced obese C57BL/6 mice lost weight through caloric restriction on normal chow (R-NC) or high fat diet (R-HF). Control mice were fed normal chow (LEAN) or high fat diet (OBESE) ad libitum. Body weight and composition were assessed after 8 weeks of dietary intervention. Glucose homeostasis was evaluated by intraperitoneal glucose tolerance tests (IPGTT). Epididymal white adipose (eWAT) and hepatic tissues were analyzed by immunohistochemistry and RT-qPCR. RESULTS: By 30 weeks of age, the body weight of the mice on R-NC (31.6±1.7g, mean±SEM) and R-HF (32.3±0.9g) was similar to LEAN mice (31.9±1.4g), while OBESE mice weighed 51.7±2.4g. Glucose tolerance in R-NC was better than in LEAN mice (69% AUC IPGTT, P 0.0168) whereas R-HF mice remained significantly less glucose tolerant (125% AUC IPGTT, P 0.0279 vs LEAN), despite identical weight loss. The eWAT pads and adipocyte size were similar in LEAN and R-NC mice, while the eWAT pad size of R-HF was 180% of R-NC (P < 0.0001) and the average adipocyte size of R-HF mice was 134% of R-NC fed mice (P 0.0285). No LEAN or R-NC mice had hepatic steatosis, in contrast to 28.6% of R-HF mice. Compared to OBESE mice, inflammatory markers were lower in eWAT and liver tissue of R-NC, but not in R-HF mice. Measures of visceral adiposity correlated well with glucose tolerance parameters. CONCLUSIONS: In mice, caloric restriction on a normal chow diet improved glucose tolerance significantly more when identical weight loss was achieved on a high fat diet. ispartof: PLOS ONE vol:13 issue:7 ispartof: location:United States status: published

The incidence of both type 1 and type 2 diabetes is increasing and although environmental pollutants are believed to be potential culprits, the extent to which they can be held responsible remains uncertain. Some bacterial strains of the Bacillus cereus produce a toxin, cereulide, which is frequently found in starchy meals and which is difficult to eradicate from the food chain as it is highly resistant to heat, acidity and proteolysis. While cereulide is well known to cause acute emetic toxicity when ingested at high doses, several in vitro studies have shown that also extremely low doses of cereulide can be toxic, with beta cells being particularly sensitive. Mechanistically, such low doses impair the mitochondrial activity of the beta cells thereby leading to hampered insulin secretion and cell death, both key traits in the pathophysiology of diabetes. In vivo studies of chronic or repeated low dose exposure to cereulide are currently lacking, but should be performed to further clarify the true relevance of cereulide as a potential environmental contributor to the ongoing diabetes epidemic.