Incretin-responsive human pancreatic adipose tissue organoids: A functional model for fatty pancreas research

Objective: Infiltration of adipocytes into the pancreatic parenchyma has been linked to impaired insulin secretion in individuals with increased genetic risk of T2D and prediabetic conditions. However, the study of this ectopic fat depot has been limited by the lack of suitable in vitro models. Methods: Here, we developed a novel 3D model of functionally mature human pancreatic adipose tissue organoids by aggregating human pancreatic adipose tissue-derived stromal vascular fraction (SVF) cells into organoids and differentiating them over 19 days. Results: These organoids carry biological properties of the in situ pancreatic fat, presenting levels of adipogenic markers comparable to native pancreatic adipocytes and improved lipolytic and anti-lipolytic response compared to conventional 2D cultures. The organoids harbour a small population of immune cells, mimicking in vivo adipose environment. Furthermore, they express GIPR, allowing investigation of incretin effects in pancreatic fat. In accordance, GIP and the dual GLP1R/GIPR agonist tirzepatide stimulate lipolysis but had distinct effects on the expression of proinflammatory cytokines. Conclusions: This novel adipose organoid model is a valuable tool to study the metabolic impact of incretin signalling in pancreatic adipose tissue, revealing potential therapeutic targets of incretins beyond islets. The donor-specific metabolic memory of these organoids enables examination of the pancreatic fat-islet crosstalk in a donor-related metabolic context

Short-term variability of proton density fat fraction in pancreas and liver assessed by multiecho chemical-shift encoding-based MRI at 3 T.

Background: Quantification of pancreatic fat (PF) and intrahepatic lipids (IHL) is of increasing interest in subjects at risk for metabolic diseases. There is limited data available on short- and medium-term variability of PF/IHL and on their dependence on nutritional status. Purpose: To assess short-term intraday variations of PF/IHL after a high-fat meal as well as medium-term changes after 5 days of high-caloric diet. Study Type: Prospective cohort study. Subjects: A total of 12 subjects (six males) for intraday variations study, 15 male subjects for medium-term high-caloric diet study and 11 age- and body mass index (BMI)-matched controls. Field Strength/Sequence: A 3 T; chemical-shift encoded multiecho gradient echo sequence. Assessment: For the intraday study, subjects were scanned after overnight fasting and after a high fat meal on the same day. For the medium-term study, 26 subjects were scanned after overnight fasting with 15/11 rescanned after 5 days of high-calorie diet/isocaloric diet. Proton density fat fraction (PDFF) maps were generated inline on the scanner. Regions of interest were manually drawn in head, body, and tail of pancreas and in the liver by a medical physicist and a doctoral student (26/4 years of experience). PF was calculated as the average of the head, body, and tail measurements. Statistical Tests: Repeated measurements ANOVA for assessing changes in PF/IHL, linear correlation analyses for assessing relationships of PF/IHL with BMI. Significance level P < 0.05 for all. Results: Nonsignificant changes in PF (2.6 ± 1.0 vs. 2.7 ± 0.9% after high-fat meal, 1.4 ± 0.8 vs. 1.5 ± 0.6% [high-caloric diet] and 1.5 ± 0.8 vs. 1.8 ± 1.0% [isocaloric control group]), nonsignificant changes in IHL after high-fat meal (2.6 ± 1.3 vs. 2.5 ± 0.9%) and in the control group (1.1 ± 0.6 vs. 1.2 ± 1.1%), significantly increased IHL after high-caloric diet (1.7 ± 2.2% vs. 2.7 ± 3.6%). Nonsignificant changes in PF (2.6 ± 1.0 vs. 2.7 ± 0.9% after high-fat meal, 1.4 ± 0.8 vs. 1.5 ± 0.6% [high-caloric diet] and 1.5 ± 0.8 vs. 1.8 ± 1.0% [isocaloric control group]), nonsignificant changes in IHL after high-fat meal (2.6 ± 1.3 vs. 2.5 ± 0.9%) and in the control group (1.1 ± 0.6 vs. 1.2 ± 1.1%), significantly increased IHL after 5-days of high-caloric diet (1.7 ± 2.2% vs. 2.7 ± 3.6%). Data Conclusion: Time of day and nutritional status have no significant influence on PF/IHL and are therefore not likely to be major confounders in epidemiologic or clinical studies. Evidence Level: 2. Technical Efficacy: Stage 1

58-OR: Remission of Prediabetes upon Weight Loss Depends on Insulin Sensitivity

The Prediabetes Lifestyle Intervention Study (PLIS) - a multicenter study conducted by the German Center for Diabetes Research - showed that intensified compared to conventional lifestyle intervention led to higher probability to normalize glucose regulation. Here, we examined clinical traits determining remission of prediabetes in PLIS participants with a clinically relevant weight loss of ≥5% of their initial body weight after 12 months of lifestyle intervention. Of 11participants, 298 achieved a weight loss of ≥5 %. We classified individuals as responders, who returned to normal glucose regulation by fasting glucose, 2h OGTT plasma glucose and HbA1c (n=128) and compared them to non-responders (n =170) . There were no differences in BMI change (-3.43 ±2.02 kg/m2 in responders, -2.83 ±1.37 in non-responders, p = 0.68) , whole body fat mass loss (6.7 ± 4.9 l vs. 5.9 ±4.5, p = 0.25) or reduction in liver fat (6.1 ±6.3 percentage points vs. 6.6 ±6.4, p = 0.59) . Similarly, there was no difference in change of insulin secretion between responders and non-responders. In contrast, responders improved insulin sensitivity significantly more than non-responders (Insulin Sensitivity Index +4.5 ±4.7, vs. +2.3 ±3.1, p &amp;lt; 0.01) . We conclude that, in prediabetes, weight loss induced return to normal glucose regulation primarily depends on improvements in insulin sensitivity, contrasting recently reported mechanisms of diabetes remission. Disclosure A.Sandforth: None. K.D.Lange: None. R.Wagner: Advisory Panel; Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. German center for diabetes research: n/a. A.F.Pfeiffer: None. M.Roden: Advisory Panel; Eli Lilly and Company, Research Support; Boehringer Ingelheim International GmbH, Nutricia, Speaker's Bureau; Novo Nordisk. A.Fritsche: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Jumpertz von schwartzenberg: None. A.L.Birkenfeld: None. </jats:sec

Lower hepatic fat is associated with improved insulin secretion in a high-risk prediabetes subphenotype during lifestyle intervention.

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. One thousand forty-five participants from the Prediabetes Lifestyle Intervention Study (PLIS) were assigned to 6 recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time-points during a 1-yr intervention. We also analyzed the change of glycemia, insulin sensitivity and liver fat. All pre-diabetes high-risk clusters (cluster 3, 5 and 6) had improved glycemic traits during lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (p&lt;0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (pinteraction&lt;0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes. Prediabetes is a heterogenous condition comprising subphenotypes with different risks of diabetes and its complications (1). From its two key features, insulin resistance and impaired insulin secretion, insulin resistance can be clearly improved by lifestyle intervention (LI); however, it is not known, if LI can improve insulin secretion in specific subphenotypes of reduced insulin secretion (2). Recently, we described 6 clusters of prediabetic metabolism (1). Two of these clusters (cluster 3 and 5) have high risk of progression to diabetes. Another group (cluster 6) has an intermediate risk of diabetes as these persons are capable of compensating insulin resistance via hyperinsulinemia over years. In this study, we retrospectively stratified participants of a large multi-center study into these novel clusters of prediabetic metabolism (1) and investigated whether LI improved their insulin secretion and other glycemic traits