Abdominal fat distribution modulates the metabolic effects of exogenous ketones in individuals with new-onset prediabetes after acute pancreatitis: Results from a randomized placebo-controlled trial.

BACKGROUND AND AIMS: Exogenous ketone supplementation is emerging as a nutritional intervention that beneficially affects blood glucose control. We hypothesized that varying abdominal fat phenotypes play a role in the effect of exogenously induced ketosis. The aim was to investigate whether intra-abdominal fat distribution modulates the effect of exogenous ketones on glucoregulatory peptides in new-onset prediabetes. METHODS: Eighteen individuals with new-onset prediabetes after acute pancreatitis were randomized to receive a ketone monoester supplement or placebo in a crossover fashion. All participants underwent magnetic resonance imaging on a 3T scanner to determine their abdominal fat phenotypes. They were non-exclusively categorized as low adiposity or high adiposity phenotypes based on their abdominal and ectopic fat distribution (regardless of body mass index and waist circumference). Blood samples were analyzed for glucoregulatory peptides. Total area under the curve (AUC) over 150 min was calculated for each analyte. RESULTS: The total AUCs for insulin and C-peptide were significantly higher after ketone supplementation in individuals with high intra-pancreatic fat deposition, skeletal muscle fat deposition, and subcutaneous fat volume; and low visceral fat volume and intra-hepatic fat deposition. The total AUC for glucose-dependent insulinotropic peptide was significantly higher after ketone supplementation in individuals with high intra-pancreatic fat deposition, skeletal muscle fat deposition, subcutaneous fat volume, and visceral fat volume. The total AUC for glucagon-like peptide-1 was not associated with any adiposity phenotype. CONCLUSIONS: Individuals with high depositions of intra-pancreatic fat, skeletal muscle fat, subcutaneous fat may not achieve favorable outcomes of blood glucose control following ketone supplementation. Abdominal fat distribution is an important factor in the pathogenesis of new-onset prediabetes and it may influence the effectiveness of nutritional strategies designed for these individuals. REGISTERED UNDER CLINICALTRIALS. GOV IDENTIFIER NO: NCT03889210.

Acute Nutritional Ketosis and Its Implications for Plasma Glucose and Glucoregulatory Peptides in Adults with Prediabetes: A Crossover Placebo-Controlled Randomized Trial.

BACKGROUND: The potential of a ketone monoester (ß-hydroxybutyrate; KEßHB) supplement to rapidly mimic a state of nutritional ketosis offers a new therapeutic possibility for diabetes prevention and management. While KEßHB supplementation has a glucose-lowering effect in adults with obesity, its impact on glucose control in other insulin-resistant states is unknown. OBJECTIVES: The primary objective was to investigate the effect of KEßHB-supplemented drink on plasma glucose in adults with prediabetes. The secondary objective was to determine its impact on plasma glucoregulatory peptides. METHODS: This randomized controlled trial [called CETUS (Cross-over randomizEd Trial of ß-hydroxybUtyrate in prediabeteS)] included 18 adults [67% men, mean age = 55 y, mean BMI (kg/m2) = 28.4] with prediabetes (glycated hemoglobin between 5.7% and 6.4% and/or fasting plasma glucose between 100 and 125 mg/dL). Participants were randomly assigned to receive KEßHB-supplemented and placebo drinks in a crossover sequence (washout period of 7-10 d between the drinks). Blood samples were collected from 0 to 150 min, at intervals of 30 min. Paired-samples t tests were used to investigate the change in the outcome variables [ß-hydroxybutyrate (ßHB), glucose, and glucoregulatory peptides] after both drinks. Repeated measures analyses were conducted to determine the change in concentrations of the prespecified outcomes over time. RESULTS: Blood ßHB concentrations increased to 3.5 mmol/L within 30 minutes after KEßHB supplementation. Plasma glucose AUC was significantly lower after KEßHB supplementation than after the placebo [mean difference (95% CI): -59 (-85.3, -32.3) mmol/L × min]. Compared with the placebo, KEßHB supplementation led to significantly greater AUCs for plasma insulin [0.237 (0.044, 0.429) nmol/L × min], C-peptide [0.259 (0.114, 0.403) nmol/L × min], and glucose-dependent insulinotropic peptide [0.243 (0.085, 0.401) nmol/L × min], with no significant differences in the AUCs for amylin, glucagon, and glucagon-like peptide 1. CONCLUSIONS: Ingestion of the KEßHB-supplemented drink acutely increased the blood ßHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes. Further research is needed to investigate the dynamics of repeated ingestions of a KEßHB supplement by individuals with prediabetes, with a view to preventing new-onset diabetes. This trial was registered at www.clinicaltrials.gov as NCT03889210.

Implications of Tobacco Smoking and Alcohol Consumption on Ectopic Fat Deposition in Individuals After Pancreatitis.

OBJECTIVES: Tobacco smoking and alcohol consumption are established risk factors for pancreatitis. This study investigated the associations between tobacco smoking/alcohol consumption in people after an attack of pancreatitis and intrapancreatic fat deposition (IPFD), intrahepatic fat deposition (IHFD), and skeletal muscle (SMFD) fat deposition. METHODS: In this cross-sectional study, magnetic resonance imaging was used to quantify IPFD, IHFD, and SMFD by 2 independent raters. A validated questionnaire was used to determine tobacco smoking and alcohol consumption. RESULTS: A total of 119 individuals after an attack of pancreatitis were included. Average tobacco smoking contributed most to variance in IPFD (R = 6.5%) and least to variance in SMFD (R = 0.4%). Average alcohol consumption contributed most to variance in variance in IPFD (R = 2.8%) and least to IHFD (R = 1.1%). Packs/day contributed more than years of smoking to variance in IPFD (R = 4.9 and 0.2%, correspondingly), whereas years of drinking contributed more than average daily alcohol consumption (R = 3.9 and 3.2%, correspondingly). CONCLUSIONS: Tobacco smoking and alcohol consumption contributed more to variance in IPFD than IHFD and SMFD. Smoking contributed more than drinking to variance in IPFD. The daily amount of tobacco smoked appeared to be more important than years of smoking for IPFD.

Associations Between Cannabis Use, Abdominal Fat Phenotypes and Insulin Traits.

BACKGROUND: General obesity has been linked to dysregulation of the endocannabinoid system in humans. However, there is a lack of studies on the relationship between cannabis use and specific abdominal fat phenotypes. The aim was to investigate the associations between cannabis use and magnetic resonance imaging-derived fat phenotypes, as well as indices of insulin sensitivity and insulin secretion. METHODS: In this cross-sectional study, magnetic resonance imaging was used to quantify subcutaneous fat volume (SFV), visceral fat volume (VFV), intra-hepatic fat deposition (IHFD), intra-pancreatic fat deposition (IPFD) and skeletal muscle fat deposition (SMFD) by two independent observers. Insulin sensitivity was determined based on HOMA-IS, Raynaud index and Matsuda index, whereas insulin secretion was determined based on HOMA-ß, insulinogenic index 30' and insulinogenic index 60'. A validated questionnaire was used to ascertain participants' cannabis use. Linear regression models were constructed, adjusting for demographics, glycated hemoglobin, physical activity, tobacco smoking and alcohol consumption. RESULTS: A total of 120 individuals were included. Cannabis use explained 9.2% of variance in IHFD, 4.4% in SMFD, 3.4% in VFV, 0.4% in SFV and 0.2% in IPFD. Regular cannabis users had significantly greater IHFD compared with never users, in both the unadjusted (P = 0.002) and all adjusted (P = 0.002; P = 0.008) analyses. The other fat phenotypes did not differ significantly between either regular or non-regular users compared with never users. Regular cannabis users had significantly greater insulin secretion (as defined by the insulinogenic index 60') compared with never users, in both the unadjusted (P = 0.049) and all adjusted (P = 0.003; P = 0.004) analyses. Cannabis use explained 20.3% of variance in the insulinogenic index 60', but was not significantly associated with the other indices of insulin secretion. There were no significant differences in indices of insulin sensitivity in either regular or non-regular cannabis users compared with never users. CONCLUSION: Regular cannabis use may be a risk factor for non-alcoholic fatty liver disease (but not IPFD) and may alter the neuromodulation of insulin secretion. Further investigations are now warranted to elucidate the mechanisms underlying these associations.

Oxyntomodulin May Distinguish New-Onset Diabetes After Acute Pancreatitis From Type 2 Diabetes.

OBJECTIVE: New-onset diabetes is an important sequela of acute pancreatitis, but there are no biomarkers to differentiate it from the much more common type 2 diabetes. The objective was to investigate whether postprandial circulating levels of gut hormones can serve this purpose. METHODS: This was a case-control study nested into a prospective longitudinal cohort study that included 42 insulin-naive cases with new-onset prediabetes/diabetes after acute pancreatitis (NODAP) and prediabetes/diabetes followed by acute pancreatitis (T2D-AP), sex matched with 21 healthy controls. All individuals underwent a standardized mixed-meal test, and blood samples were assayed for gut hormones (glucose-dependent insulinotropic peptide, glucagon-like peptide-1, oxyntomodulin, and peptide YY). Analysis of variance and linear regression analysis were conducted in unadjusted and adjusted models (accounting for age, homeostatic model assessment of ß-cell function, and magnetic resonance imaging-derived body fat composition). RESULTS: Oxyntomodulin levels were significantly lower in NODAP compared with T2D-AP and healthy controls (P = 0.027 and P = 0.001, respectively, in the most adjusted model). Glucagon-like peptide-1 and peptide YY were significantly lower in NODAP compared with T2D-AP (P = 0.001 and P = 0.014, respectively, in the most adjusted model) but not compared with healthy controls (P = 1.000 and P = 0.265, respectively, in the most adjusted model). Glucose-dependent insulinotropic peptide levels were not significantly different between NODAP and T2D-AP. DISCUSSION: Oxyntomodulin is a promising biomarker to guide the differential diagnosis of new-onset diabetes after acute pancreatitis. However, external validation studies are warranted before it can be recommended for routine use in clinical practice.

Relationship of pancreas volume to tobacco smoking and alcohol consumption following pancreatitis.

BACKGROUND: Tobacco smoking and alcohol consumption are established risk factors for diseases of the pancreas. With the recent advances in imaging modalities (such as magnetic resonance (MR) imaging), opportunities have arisen to study pancreas size, in both health and disease. Studies investigating the relationship between tobacco smoking, alcohol consumption, and total pancreas volume (TPV) - a holistic measure of pancreatic exocrine reserve - are lacking. The aim of the present study was to investigate the associations between MR-derived TPV and tobacco smoking/alcohol consumption. METHODS: This cross-sectional study recruited individuals with a history of pancreatitis and healthy controls. A validated questionnaire was used to ascertain current and lifetime tobacco smoking and alcohol consumption. TPV was quantified using MR images by two independent raters. Generalized additive models and linear regression analyses were conducted and adjusted for demographic, metabolic, and pancreatitis-related factors. RESULTS: A total of 107 individuals following pancreatitis and 38 healthy controls were included. There was no statistically significant difference in TPV between any of the tobacco smoking/alcohol consumption categories of individuals following pancreatitis and healthy controls, in both unadjusted and adjusted analyses. In individuals following pancreatitis, multivariate linear regression found no association between TPV and 7 smoking- and alcohol-related variables. Sensitivity analyses constrained to individuals who did not abstain from either smoking or drinking following their first attack of pancreatitis did not yield statistical significance with TPV. In post-hoc analysis, age was significantly inversely associated with TPV in the most adjusted model (p = 0.016). CONCLUSIONS: This is the first study to investigate the association between tobacco smoking, alcohol consumption, and MR-derived TPV following pancreatitis. It appears that age, but not tobacco smoking or alcohol consumption, is associated with a significantly reduced TPV.

Associations between intra-pancreatic fat deposition and circulating levels of cytokines.

While a plethora of studies have been conducted to investigate the associations between pro-inflammatory cytokines and obesity, the inter-relationship between pro-inflammatory cytokines and intra-pancreatic fat deposition (IPFD) has been poorly investigated. In the present study, circulating levels of C-C motif chemokine ligand 2 (CCL2), interleukin-6 (IL-6), leptin, and tumor necrosis factor-alpha (TNFα) were measured in 90 individuals after acute pancreatitis (AP) as well as 21 healthy non-obese individuals. Magnetic resonance imaging was used to quantify IPFD and visceral-to-subcutaneous fat volume ratio by two independent raters. Linear regression analyses were performed to investigate the associations between IPFD and each cytokine, adjusting for demographic, metabolic, and pancreatitis-related factors, as well as abdominal fat distribution. In healthy non-obese individuals, IPFD was not significantly associated with any of the studied cytokines in both the unadjusted and adjusted models. In individuals after AP, IPFD was significantly associated with leptin in the models adjusted for age and sex (ß = 0.063 [95% confidence interval: 0.007, 0.119], P = 0.026); age, sex, visceral-to-subcutaneous fat volume ratio, glycated hemoglobin, and pancreatitis-related factors (ß = 0.056 [95% confidence interval: 0.000, 0.111], P = 0.049). Also, IPFD was significantly associated with TNFα in the unadjusted model (ß = 0.102 [95% confidence interval: 0.002, 0.202], P = 0.045) and the model adjusted for age, sex, visceral-to-subcutaneous fat volume ratio, glycated hemoglobin, and pancreatitis-related factors (ß = 0.128 [95% confidence interval: 0.034, 0.223], P = 0.008). The associations between IPFD and IL-6, CCL2 were not statistically significant, in both the unadjusted and adjusted models. These findings indicate that leptin and TNFα are associated with IPFD independent of abdominal fat distribution and other covariates in individuals after AP. The role of IPFD in low-grade inflammation warrants further investigations.