Extracellular electrophysiology on clonal human ß-cell spheroids.

Background: Pancreatic islets are important in nutrient homeostasis and improved cellular models of clonal origin may very useful especially in view of relatively scarce primary material. Close 3D contact and coupling between ß-cells are a hallmark of physiological function improving signal/noise ratios. Extracellular electrophysiology using micro-electrode arrays (MEA) is technically far more accessible than single cell patch clamp, enables dynamic monitoring of electrical activity in 3D organoids and recorded multicellular slow potentials (SP) provide unbiased insight in cell-cell coupling. Objective: We have therefore asked whether 3D spheroids enhance clonal ß-cell function such as electrical activity and hormone secretion using human EndoC-ßH1, EndoC-ßH5 and rodent INS-1 832/13 cells. Methods: Spheroids were formed either by hanging drop or proprietary devices. Extracellular electrophysiology was conducted using multi-electrode arrays with appropriate signal extraction and hormone secretion measured by ELISA. Results: EndoC-ßH1 spheroids exhibited increased signals in terms of SP frequency and especially amplitude as compared to monolayers and even single cell action potentials (AP) were quantifiable. Enhanced electrical signature in spheroids was accompanied by an increase in the glucose stimulated insulin secretion index. EndoC-ßH5 monolayers and spheroids gave electrophysiological profiles similar to EndoC-ßH1, except for a higher electrical activity at 3 mM glucose, and exhibited moreover a biphasic profile. Again, physiological concentrations of GLP-1 increased AP frequency. Spheroids also exhibited a higher secretion index. INS-1 cells did not form stable spheroids, but overexpression of connexin 36, required for cell-cell coupling, increased glucose responsiveness, dampened basal activity and consequently augmented the stimulation index. Conclusion: In conclusion, spheroid formation enhances physiological function of the human clonal ß-cell lines and these models may provide surrogates for primary islets in extracellular electrophysiology.

Beta cell dedifferentiation in type 1 diabetes: sacrificing function for survival?

The pathogeneses of type 1 and type 2 diabetes involve the progressive loss of functional beta cell mass, primarily attributed to cellular demise and/or dedifferentiation. While the scientific community has devoted significant attention to unraveling beta cell dedifferentiation in type 2 diabetes, its significance in type 1 diabetes remains relatively unexplored. This perspective article critically analyzes the existing evidence for beta cell dedifferentiation in type 1 diabetes, emphasizing its potential to reduce beta cell autoimmunity. Drawing from recent advancements in both human studies and animal models, we present beta cell identity as a promising target for managing type 1 diabetes. We posit that a better understanding of the mechanisms of beta cell dedifferentiation in type 1 diabetes is key to pioneering interventions that balance beta cell function and immunogenicity.

High Prevalence of A-ß+ Ketosis-Prone Diabetes in Children with Type 2 Diabetes and Diabetic Ketoacidosis at Diagnosis: Evidence from the Rare and Atypical Diabetes Network (RADIANT).

Background: A-ß+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved ß-cell function in persons with a phenotype of obesity-associated type 2 diabetes (T2D). The prevalence of KPD has not been evaluated in children. We investigated children with DKA at "T2D" onset and determined the prevalence and characteristics of pediatric A-ß+ KPD within this cohort. Methods: We reviewed the records of 716 children with T2D at a large academic hospital and compared clinical characteristics of those with and without DKA at onset. In the latter group, we identified patients with A-ß+ KPD using criteria of the Rare and Atypical Diabetes Network (RADIANT) and defined its prevalence and characteristics. Results: Mean age at diagnosis was 13.7 ± 2.4 years: 63% female; 59% Hispanic, 29% African American, 9% non-Hispanic White, and 3% other. Fifty-six (7.8%) presented with DKA at diagnosis and lacked islet autoantibodies. Children presenting with DKA were older and had lower C-peptide and higher glucose concentrations than those without DKA. Twenty-five children with DKA (45%) met RADIANT A-ß+ KPD criteria. They were predominantly male (64%), African American or Hispanic (96%), with substantial C-peptide (1.3 ± 0.7 ng/mL) at presentation with DKA and excellent long-term glycemic control (HbA1c 6.6% ± 1.9% at follow-up (median 1.3 years postdiagnosis)). Conclusions: In children with a clinical phenotype of T2D and DKA at diagnosis, approximately half meet criteria for A-ß+ KPD. They manifest the key characteristics of obesity, preserved ß-cell function, male predominance, and potential to discontinue insulin therapy, similar to adults with A-ß+ KPD.

Network representation of multicellular activity in pancreatic islets: Technical considerations for functional connectivity analysis.

Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect of metabolic homeostasis. Despite the inherent heterogeneity and multimodal activity of individual cells, intercellular coupling acts as a homogenizing force, enabling coordinated responses through the propagation of intercellular waves. Disruptions in this coordination are implicated in irregular insulin secretion, a hallmark of diabetes. Recently, innovative approaches, such as integrating multicellular calcium imaging with network analysis, have emerged for a quantitative assessment of the cellular activity in islets. However, different groups use distinct experimental preparations, microscopic techniques, apply different methods to process the measured signals and use various methods to derive functional connectivity patterns. This makes comparisons between findings and their integration into a bigger picture difficult and has led to disputes in functional connectivity interpretations. To address these issues, we present here a systematic analysis of how different approaches influence the network representation of islet activity. Our findings show that the choice of methods used to construct networks is not crucial, although care is needed when combining data from different islets. Conversely, the conclusions drawn from network analysis can be heavily affected by the pre-processing of the time series, the type of the oscillatory component in the signals, and by the experimental preparation. Our tutorial-like investigation aims to resolve interpretational issues, reconcile conflicting views, advance functional implications, and encourage researchers to adopt connectivity analysis. As we conclude, we outline challenges for future research, emphasizing the broader applicability of our conclusions to other tissues exhibiting complex multicellular dynamics.

The association of insulin responses and insulin sensitivity with cognition in adults with pre-diabetes: The Diabetes Prevention Program Outcomes Study.

OBJECTIVE: Dysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant(s) of dysglycemia, impaired insulin sensitivity (ISens) or the islet ß-cell's response (IResp), contribute to poorer cognitive function, independent of dysglycemia is not established. Among 1052 adults with pre-diabetes from the Diabetes Prevention Program Outcomes Study (DPPOS), we investigated the relationship between IResp, ISens and cognitive function. RESEARCH DESIGN AND METHODS: IResp was estimated by the insulinogenic index (IGI; pmol/mmol) and ISens as 1/fasting insulin from repeated annual oral glucose tolerance tests. The mean IResp and mean ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and executive function (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Linear regression models were run for each cognitive outcome and were adjusted for dysglycemia and other factors. RESULTS: Higher IResp was associated with poorer performance on the DSST (-0.69 points per 100 unit increase in IGI, 95 % CI: -1.37, -0.01). ISens was not associated with DSST, nor were IResp or ISens associated with performance on the SEVLT. CONCLUSIONS: These results suggest that a greater ß-cell response in people at high risk for type 2 diabetes is associated with poorer executive function, independent of dysglycemia and ISens.

From islet transplantation to beta-cell regeneration: an update on beta-cell-based therapeutic approaches in type 1 diabetes.

INTRODUCTION: Type 1 diabetes (T1D) mellitus is an autoimmune disease in which immune cells, predominantly effector T cells, destroy insulin-secreting beta-cells. Beta-cell destruction led to various consequences ranging from retinopathy and nephropathy to neuropathy. Different strategies have been developed to achieve normoglycemia, including exogenous glucose compensation, whole pancreas transplantation, islet transplantation, and beta-cell replacement. AREAS COVERED: The last two decades of experience have shown that indigenous glucose compensation through beta-cell regeneration and protection is a peerless method for T1D therapy. Tremendous studies have tried to find an unlimited source for beta-cell regeneration, on the one hand, and beta-cell protection against immune attack, on the other hand. Recent advances in stem cell technology, gene editing methods, and immune modulation approaches provide a unique opportunity for both beta-cell regeneration and protection. EXPERT OPINION: Pluripotent stem cell differentiation into the beta-cell is considered an unlimited source for beta-cell regeneration. Devising engineered pancreas-specific regulatory T cells using Chimeric Antigen Receptor (CAR) technology potentiates an effective immune tolerance induction for beta-cell protection. Beta-cell regeneration using pluripotent stem cells and beta-cell protection using pancreas-specific engineered regulatory T cells promises to develop a curative protocol in T1D.

Baseline phenotypes with preserved ß-cell function and high insulin concentrations have the best improvements in glucose tolerance after weight loss: results from the prospective DEXLIFE and EGIR-RISC studies.

BACKGROUND: Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss. METHODS: In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538). RESULTS: Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and ß-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model. CONCLUSIONS: Individuals with preserved ß-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss.

Pancreatic beta-cell mass and function and therapeutic implications of using antidiabetic medications in type 2 diabetes.

Nowadays, the focus of diabetes treatment has switched from lowering the glucose level to preserving glycemic homeostasis and slowing the disease progression. The main pathophysiology of both type 1 diabetes and long-standing type 2 diabetes is pancreatic ß-cell mass loss and dysfunction. According to recent research, human pancreatic ß-cells possess the ability to proliferate in response to elevated insulin demands. It has been demonstrated that in insulin-resistant conditions in humans, such as obesity or pregnancy, the ß-cell mass increases. This ability could be helpful in developing novel treatment approaches to restore a functional ß-cell mass. Treatment strategies aimed at boosting ß-cell function and mass may be a useful tool for managing diabetes mellitus and stopping its progression. This review outlines the processes of ß-cell failure and detail the many ß-cell abnormalities that manifest in people with diabetes mellitus. We also go over standard techniques for determining the mass and function of ß-cells. Lastly, we provide the therapeutic implications of utilizing antidiabetic drugs in controlling the mass and function of pancreatic ß-cells.

Prolactin effects on the pathogenesis of diabetes mellitus.

BACKGROUND: Prolactin (PRL) is a pituitary hormone promoting lactation in response to the suckling reflex. Beyond its well-known effects, novel tissue-specific and metabolic functions of PRL are emerging. AIMS: To dissect PRL as a critical mediator of whole-body gluco-insulinemic sensitivity. METHODS: PubMed-based search with the following terms 'prolactin', 'glucose metabolism', 'type 2 diabetes mellitus', 'type 1 diabetes mellitus', 'gestational diabetes mellitus' was performed. DISCUSSION: The identification of the PRL-glucose metabolism network poses the basis for unprecedented avenues of research in the pathogenesis of diabetes mellitus type 1 or 2, as well as of gestational diabetes. In this regard, it is of timely relevance to define properly the homeostatic PRL serum levels since glucose metabolism could be influenced by the circulating amount of the hormone. RESULTS: This review underscores the basic mechanisms of regulation of pancreatic ß-cell functions by PRL and provides a revision of articles which have investigated the connection between PRL unbalancing and diabetes mellitus. Future studies are needed to elucidate the burden and the role of PRL in the regulation of glucose metabolism and determine the specific PRL threshold that may impact the management of diabetes. CONCLUSION: A careful evaluation and context-driven interpretation of PRL levels (e.g., pregnancy, PRL-secreting pituitary adenomas, drug-related hyper- and hypoprolactinemia) could be critical for the correct screening and management of glucometabolic disorders, such as type 1 or 2 as well as gestational diabetes mellitus.

High-Intensity Interval Versus Moderate-Intensity Continuous Exercise Training on Glycemic Control, Beta Cell Function, and Aerobic Fitness in Women with Type 2 Diabetes.

Objective: This study aimed to compare the effects of High-Intensity Interval Training (HIIT) and Moderate-Intensity Continuous Training (MICT) on glycemic control, beta-cell function, and aerobic fitness in women with Type 2 Diabetes Mellitus (T2DM). Methods: Thirty-six women with T2DM were assigned equally to HIIT, MICT, and control (CON) groups. Participants in the exercise cohorts underwent a 12-week training regimen (three sessions per week), while the CON group maintained an inactive lifestyle. Glycaemia variables, beta-cell function, maximal oxygen uptake (VO2max), lipid profiles, and body composition were assessed at baseline and post-intervention. Results: Both HIIT and MICT interventions led to significant improvements in glucose, insulin, HbA1c, and insulin resistance index. Moreover, visceral adiposity index (VAI), lipid accumulation product (LAP), total cholesterol (TC), and low-density lipoprotein (LDL) levels significantly decreased in the HIIT and MICT groups after 12 weeks. Triglyceride (TG) levels decreased only after MICT, while high-density lipoprotein (HDL) levels increased after both interventions. Maximal oxygen uptake (VO2max), body mass, body mass index (BMI), and waist circumference (WC) significantly improved in all exercise groups. Notably, the HIIT group showed greater reductions in body mass compared to MICT. Nevertheless, beta-cell function remained unaltered after these two exercise regimens. Conclusion: Both HIIT and MICT interventions effectively managed T2DM in women, regardless of exercise intensity. The HIIT regimen can be considered for time-efficient lifestyle interventions in people with T2DM.

Comparison of ß-Cell Function and Insulin Sensitivity Between Normal-Weight and Obese Chinese With Young-Onset Type 2 Diabetes.

Normal-weight individuals with usual-onset type 2 diabetes have reduced ß-cell function and greater insulin sensitivity compared with their obese counterparts. The relative contribution of ß-cell dysfunction and insulin resistance to young-onset type 2 diabetes (YOD) among normal-weight individuals is not well established. In 44 individuals with YOD (24 with normal weight and 20 with obesity) and 24 healthy control individuals with normoglycemia (12 with normal weight and 12 with obesity), we conducted 2-h 12 mmol/L hyperglycemic clamps to measure acute (0-10 min) and steady-state (100-120 min) insulin and C-peptide responses, as well as insulin sensitivity index. Normal-weight individuals with YOD had lower acute insulin response, steady-state insulin and C-peptide responses, and a higher insulin sensitivity index compared with their obese counterparts with YOD. Compared with BMI-matched healthy control individuals, normal-weight individuals with YOD had lower acute and steady-state insulin and C-peptide responses but a similar insulin sensitivity index. The impairment of steady-state ß-cell response relative to healthy control individuals was more pronounced in normal-weight versus obese individuals with YOD. In conclusion, normal-weight Chinese with YOD exhibited worse ß-cell function but preserved insulin sensitivity relative to obese individuals with YOD and BMI-matched healthy individuals with normoglycemia. The selection of glucose-lowering therapy should account for pathophysiological differences underlying YOD between normal-weight and obese individuals.

Role of ß-cell autophagy in ß-cell physiology and the development of diabetes.

Elucidating the molecular mechanism of autophagy was a landmark in understanding not only the physiology of cells and tissues, but also the pathogenesis of diverse diseases, including diabetes and metabolic disorders. Autophagy of pancreatic ß-cells plays a pivotal role in the maintenance of the mass, structure and function of ß-cells, whose dysregulation can lead to abnormal metabolic profiles or diabetes. Modulators of autophagy are being developed to improve metabolic profile and ß-cell function through the removal of harmful materials and rejuvenation of organelles, such as mitochondria and endoplasmic reticulum. Among the known antidiabetic drugs, glucagon-like peptide-1 receptor agonists enhance the autophagic activity of ß-cells, which might contribute to the profound effects of glucagon-like peptide-1 receptor agonists on systemic metabolism. In this review, the results from studies on the role of autophagy in ß-cells and their implication in the development of diabetes are discussed. In addition to non-selective (macro)autophagy, the role and mechanisms of selective autophagy and other minor forms of autophagy that might occur in ß-cells are discussed. As ß-cell failure is the ultimate cause of diabetes and unresponsiveness to conventional therapy, modulation of ß-cell autophagy might represent a future antidiabetic treatment approach, particularly in patients who are not well managed with current antidiabetic therapy.

Comparison of an oral mixed meal plus arginine and intravenous glucose, GLP-1 plus arginine to unmask residual islet function in longstanding type 1 diabetes.

Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alpha cell response are also part of the islet dysfunction. A three-phase [euglycemia, hyperglycemia, and hyperglycemia + glucagon-like peptide 1 (GLP-1)] clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase. On another day, a mixed meal stimulation test with a subsequent intravenous arginine bolus was performed. C-peptide was detectable in a subgroup of subjects at baseline (2/15) or only after stimulation (3/15). When detectable, C-peptide increased 2.9-fold [95% CI: 1.2-7.1] during the hyperglycemia phase and 14.1-fold [95% CI: 3.1-65.2] during the hyperglycemia + GLP-1 phase, and 22.3-fold [95% CI: 5.6-89.1] during hyperglycemia + GLP-1 + arginine phase when compared with baseline. The same subset of patients with a C-peptide response were identified during the mixed meal stimulation test as during the clamp. There was an inhibition of glucagon secretion (0.72-fold, [95% CI: 0.63-0.84]) during the glucose clamp irrespective of the presence of detectable beta cell function. Proinsulin was only present in a subset of subjects with detectable C-peptide (3/15) and proinsulin mimicked the C-peptide response to the different stimuli when detectable. Residual beta cells in longstanding type 1 diabetes respond adequately to different stimuli and could be of clinical benefit.NEW & NOTEWORTHY If beta cell function is detectable, the beta cells react relatively normal to the different stimuli except for the first phase response to intravenous glucose. An oral mixed meal followed by an intravenous arginine bolus can identify residual beta cell function/mass as well as the more commonly used glucose potentiated arginine-induced insulin secretion during a hyperglycemic clamp.

Autologous intraarterial pancreatic bone-marrow mononuclear cells infusion in T2D patients: Changes on beta-cells function, insulin resistance, and inflammatory marker.

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease. Many drugs currently being used for the management of T2D have minimal effect on pancreatic beta cells regeneration. Cell-based therapies might provide potential benefits in this aspect. METHODS: A pilot study in five T2D patients with 12 months follow-up was performed to evaluate the effect of autologous bone marrow mononuclear stem cells (BM-MNCs) infusion into pancreatic arteries on the insulin requirement, beta-cell function, insulin resistance, and systemic inflammatory marker (CRP). RESULTS: The primary endpoint, a 50 % reduction of total insulin doses from baseline, was not achieved in this study. However, a trend of increasing fasting C-peptide (p = 0.07) and C-peptide 60' (p = 0.07) and 90' (p = 0.07) after a mixed-meal tolerance test was observed 12 months post-infusion compared to baseline levels. A similar result was observed for the homeostatic model assessment of beta cell function (HOMA1-B), an index for beta cell function. No improvement was observed for insulin resistance measured by homeostasis model assessment of insulin resistance (HOMA1-IR) and systemic inflammatory parameter. CONCLUSION: Intraarterial pancreatic autologous BM-MNCs infusion might potentially improve beta cell function in T2D patients, although further study is needed to confirm this finding.

Mouse islet-derived stellate cells are similar to, but distinct from, mesenchymal stromal cells and influence the beta cell function.

AIMS: Evidence is accumulating of the therapeutic benefits of mesenchymal stromal cells (MSCs) in diabetes-related conditions. We have identified a novel population of stromal cells within islets of Langerhans - islet stellate cells (ISCs) - which have a similar morphology to MSCs. In this study we characterize mouse ISCs and compare their morphology and function to MSCs to determine whether ISCs may also have therapeutic potential in diabetes. METHODS: ISCs isolated from mouse islets were compared to mouse bone marrow MSCs by analysis of cell morphology; expression of cell-surface markers and extracellular matrix (ECM) components; proliferation; apoptosis; paracrine activity; and differentiation into adipocytes, chondrocytes and osteocytes. We also assessed the effects of co-culture with ISCs or MSCs on the insulin secretory capacity of islet beta cells. RESULTS: Although morphological similar, ISCs were functionally distinct from MSCs. Thus, ISCs were less proliferative and more apoptotic; they had different expression levels of important paracrine factors; and they were less efficient at differentiation down multiple lineages. Co-culture of mouse islets with ISCs enhanced glucose induced insulin secretion more effectively than co-culture with MSCs. CONCLUSIONS: ISCs are a specific sub-type of islet-derived stromal cells that possess biological behaviors distinct from MSCs. The enhanced beneficial effects of ISCs on islet beta cell function suggests that they may offer a therapeutic target for enhancing beta cell functional survival in diabetes.

Early-Pregnancy Serum Maternal and Placenta-Derived Exosomes miRNAs Vary Based on Pancreatic ß-Cell Function in GDM.

CONTEXT: Pancreatic ß-cell function impairment is a key mechanism for developing gestational diabetes mellitus (GDM). Maternal and placental exosomes regulate maternal and placental responses during hyperglycemia. Studies have associated exosomal micro-RNAs (miRNAs) with GDM development. To date, no studies have been reported that evaluate the profile of miRNAs present in maternal and placental exosomes in the early stages of gestation from pregnancies that develop GDM. OBJECTIVE: We assessed whether early-pregnancy serum maternal and placenta-derived exosomes miRNA profiles vary according to pancreatic ß-cell function in women who will develop GDM. METHODS: A prospective nested case-control study was used to identify exosomal miRNAs that vary in early-pregnancy stages (<18 weeks of gestation) from women with normoglycemia and those who developed GDM based on their pancreatic ß-cell function using the homeostasis model assessment of pancreatic ß-cell function (HOMA-%ß) index. Early-pregnancy serum maternal and placenta-derived exosomes were isolated to obtain miRNA profiles. Potential target and pathway analyses were performed to identify molecular and metabolic pathways associated with the exosomal miRNAs identified. RESULTS: In early-pregnancy stages, serum maternal exosome size and concentration are modified in GDM group and fluctuate according to HOMA-%ß index. Serum maternal exosomal hsa-miR-149-3p and hsa-miR-455-3p in GDM are related to insulin secretion and signaling, lipolysis, and adipocytokine signaling. Early-pregnancy serum placenta-derived exosomes hsa-miR-3665 and hsa-miR-6727-5p in GDM are related to regulating genes involved in response to immunological tolerance of pregnancy and pathways associated with placental dysfunction. CONCLUSION: Early serum exosomal miRNAs differ depending on their origin (maternal or placental) and pancreatic ß-cell function. This research provides insights into the interactions between maternal and placental exosomal miRNAs and may have implications for identifying potential biomarkers or therapeutic targets for GDM.

Comparison of beta-cell function between Hong Kong Chinese with young-onset type 2 diabetes and late-onset type 2 diabetes.

AIMS: We compared beta-cell function in Chinese with type 2 diabetes diagnosed at age < 40 years (young-onset diabetes, YOD) and ≥ 40 years (late-onset diabetes, LOD). METHODS: In this cross-sectional study, we selected participants from two cohorts of people with type 2 diabetes recruited in 1996-2012 (n = 4,376) and 2020-2021 (n = 794). Multivariable linear regression models were applied to compare homeostasis model assessment of beta-cell function (HOMA2-%B) and fasting plasma C-peptide across diabetes duration at enrolment between YOD and LOD. RESULTS: The YOD group (n = 1,876, mean [SD] age: 39.9 [7.5] years, median [IQR] diabetes duration: 6 [2-12] years) was more likely to have family history of diabetes (61.6 % vs 43.6 %), obesity (41.9 % vs 26.8 %), dyslipidaemia (61.7 % vs 54.4 %), and worse glycaemic control (mean HbA1c 7.7 % vs 7.4 %) than those with LOD (n = 3,294, age: 60.8 [10.6] years, diabetes duration: 5 [1-10] years). When compared to people with LOD, HOMA2-%B and fasting plasma C-peptide were lower in the YOD group, consistently among those with BMI < 27.5 kg/m2 and HOMA2-IR ≤ 1.6 (median value), adjusted for year at enrolment, sex, diabetes duration, family history of diabetes, HbA1c, weight and lipid indices (p < 0.01). Cross-sectionally, the slopes of decline in HOMA2-%B by diabetes duration were greater in YOD than LOD among individuals with BMI < 27.5 kg/m2 (p-interaction = 0.015). CONCLUSIONS: Chinese with YOD had accelerated loss of beta-cell function than those with LOD especially in non-obese individuals.

Phagocytosis by macrophages promotes pancreatic ß cell mass reduction after parturition in mice.

Elucidating the mechanism(s) modulating appropriate tissue size is a critical biological issue. Pancreatic ß cells increase during pregnancy via cellular proliferation, but how ß cells promptly decrease to the original amount after parturition remains unclear. Herein, we demonstrate the role and mechanism of macrophage accumulation in this process. In the final stage of pregnancy, HTR1D signaling upregulates murine ß cell CXCL10, thereby promoting macrophage accumulation in pancreatic islets via the CXCL10-CXCR3 axis. Blocking this mechanism by administering an HTR1D antagonist or the CXCR3 antibody and depleting islet macrophages inhibited postpartum ß cell mass reduction. ß cells engulfed by macrophages increased in postpartum islets, but Annexin V administration suppressed this engulfment and the postpartum ß cell mass reduction, indicating the accumulated macrophages to phagocytose ß cells. This mechanism contributes to both maintenance of appropriate ß cell mass and glucose homeostasis promptly adapting to reduced systemic insulin demand after parturition.

Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy.

AIMS/HYPOTHESIS: Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first 5 years postpartum in women reflecting the full spectrum of gestational glucose tolerance (spanning normoglycaemia to gestational diabetes) and hence a range of future diabetic risk. METHODS: In this study, 302 women with normal glucose tolerance (NGT) on OGTT at 3 months postpartum underwent repeat OGTT at 1 year, 3 years and 5 years, enabling serial assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, HOMA-IR) and beta cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index [IGI]/HOMA-IR). Determinants of prediabetes/diabetes were ranked by change in concordance index (CCI) of Cox proportional hazard regression models. RESULTS: Over 5 years of follow-up, 89 women progressed from NGT to prediabetes/diabetes (progressors). At 3 months postpartum, though all women were normoglycaemic, future progressors had higher fasting glucose (p=0.03) and 2 h glucose (p<0.0001) than non-progressors, coupled with higher BMI (p=0.001), greater insulin resistance (both Matsuda index and HOMA-IR, p≤0.02) and poorer beta cell function (both ISSI-2 and IGI/HOMA-IR, p≤0.006). Unlike their peers, progressors exhibited deteriorating beta cell function from 1 year to 5 years (both p<0.0001). On regression analyses, the dominant determinants of progression to prediabetes/diabetes were time-varying ISSI-2 (change in CCI 25.2%) and IGI/HOMA-IR (13.0%), in contrast to time-varying Matsuda index (2.9%) and HOMA-IR (0.5%). Neither time-varying BMI nor waist were significant predictors after adjustment for beta cell function and insulin sensitivity/resistance. CONCLUSION/INTERPRETATION: Declining beta cell function is the dominant determinant of incident prediabetes/diabetes in young women following pregnancy.