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Recent evidence has revealed that a change of functional beta cell mass is an essential factor of the pathophysiology of type 2 diabetes (T2DM). Since beta cell dysfunction is not only present in T2DM but also progressively worsens with disease duration, to preserve or recover functional beta cell mass is important in both prevention of the development of T2DM and therapeutic strategies for T2DM. Furthermore, ethnic difference in functional beta cell mass may also need to be taken into account. Recent evidences suggest that Asians have less beta cell functional capacity compared with Caucasians. Preservation or recovery of functional beta cell mass seems to be further emphasized for Asians because of the limited capacity of beta cell. This review summarizes the current knowledge on beta cell dysfunction in T2DM and discusses the similarities and differences in functional beta cell mass between ethnicities in the face of obesity and T2DM. [ABSTRACT FROM AUTHOR]

Bariatric surgery is currently the most effective treatment of obesity, which has spurred an interest in developing pharmaceutical mimetics. It is thought that the marked body weight-lowering effects of bariatric surgery involve stimulated secretion of appetite-regulating gut hormones, including glucagon-like peptide 1. We here report that intestinal expression of secretin is markedly upregulated in a rat model of Roux-en-Y gastric bypass, suggesting an additional role of secretin in the beneficial metabolic effects of Roux-en-Y gastric bypass. We therefore developed novel secretin-based peptide co-agonists and identified a lead compound, GUB06-046, that exhibited potent agonism of both the secretin receptor and glucagon-like peptide 1 receptor. Semi-acute administration of GUB06-046 to lean mice significantly decreased cumulative food intake and improved glucose tolerance. Chronic administration of GUB06-046 to diabetic db/db mice for 8 weeks improved glycemic control, as indicated by a 39% decrease in fasting blood glucose and 1.6% reduction of plasma HbA1c levels. Stereological analysis of db/db mice pancreata revealed a 78% increase in beta-cell mass after GUB06-046 treatment, with no impact on exocrine pancreas mass or pancreatic duct epithelial mass. The data demonstrate beneficial effects of GUB06-046 on appetite regulation, glucose homeostasis, and beta-cell mass in db/db mice, without proliferative effects on the exocrine pancreas and the pancreatic duct epithelium. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aims: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed. Methods: In vitro and ex vivo autoradiography studies of pancreas were performed using [Lu]Lu-DO3A-VS-Cys-Exendin4, in order to investigate the mechanism of uptake as well as the islet uptake contrast in mouse, rat, pig, and non-human primate. The autoradiography results were compared to the in vivo pancreatic uptake as assessed by [Ga]Ga-DO3A-VS-Cys-Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment. Results: [Lu]Lu-DO3A-VS-Cys-Exendin4 displayed the highest islet-to-exocrine pancreas ratio (IPR) in rat (IPR 45) followed by non-human primate and mouse at similar levels (IPR approximately 5) while pigs exhibited negligible IPR (1.1). In vivo pancreas uptake was mainly GLP-1R mediated in all species, but the magnitude of uptake under basal physiology varied significantly in decreasing order: non-human primate, mouse, pig, and rat. The theoretical calculation of islet contribution to the total pancreatic PET signal predicted the in vivo observation of differences in pancreatic uptake of [Ga]Ga-DO3A-VS-Cys-Exendin4. Conclusions: IPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP-1R as an imaging biomarker for pancreatic beta cells. [ABSTRACT FROM AUTHOR]

Background Plasma insulin levels are predominantly the product of the morphological mass of insulin producing beta cells in the pancreatic islets of Langerhans and the functional status of each of these beta cells. Thus, deficiency in either beta cell mass or function, or both, can lead to insufficient levels of insulin, resulting in hyperglycemia and diabetes. Nonetheless, the precise contribution of beta cell mass and function to the pathogenesis of diabetes as well as the underlying mechanisms are still unclear. In the past, this was largely due to the restricted number of technologies suitable for studying the scarcely accessible human beta cells. However, in recent years, a number of new platforms have been established to expand the available techniques and to facilitate deeper insight into the role of human beta cell mass and function as cause for diabetes and as potential treatment targets. Scope of Review This review discusses the current knowledge about contribution of human beta cell mass and function to different stages of type 1 and type 2 diabetes pathogenesis. Furthermore, it highlights standard and newly developed technological platforms for the study of human beta cell biology, which can be used to increase our understanding of beta cell mass and function in human glucose homeostasis. Major Conclusions In contrast to early disease models, recent studies suggest that in type 1 and type 2 diabetes impairment of beta cell function is an early feature of disease pathogenesis while a substantial decrease in beta cell mass occurs more closely to clinical manifestation. This suggests that, in addition to beta cell mass replacement for late stage therapies, the development of novel strategies for protection and recovery of beta cell function could be most promising for successful diabetes treatment and prevention. The use of today's developing and wide range of technologies and platforms for the study of human beta cells will allow for a more detailed investigation of the underlying mechanisms and will facilitate development of treatment approaches to specifically target human beta cell mass and function. [ABSTRACT FROM AUTHOR]

Beta cell destruction plays a key role in the pathogenesis of type 1 diabetes mellitus. It has also been argued that beta-cell mass is compromised in some cases of type 2 diabetes, although this is still debated. Currently, the failure of oral antidiabetic insulin secretagogue drugs to properly manage type 2 diabetes demands novel approaches for the treatment of this condition. The aim of the present study was to investigate the in vitro and in vivo antidiabetic effect in STZ-induced diabetic rats, and maximum tolerated dose (MTD) safety of novel anthranilic acid derivative, 2, 4-dinitroanilino-benzoic acid ( 1 ). Anthranilic acid derivative 1 was also evaluated for insulinotropic action on STZ-mediated pancreatic beta-cell lesions in diabetic rats. During an eight week study, oral glucose tolerance test, fasting blood glucose, and serum insulin levels, and pancreatic insulin contents were measured in four different groups of Wistar rats; control, STZ-induced diabetic, gliclazide-treated, and anthranilic acid derivative-treated diabetic rats. Beta-cell number and islet area were also quantified, and immunohistochemical study was performed. In vitro studies in cells showed that 2, 4-dinitroanilino-benzoic acid ( 1 ) did not adversely effect the cells viability. We found that the derivative 1 significantly improved the glucose tolerance, fasting blood glucose, and HbA1c levels, serum insulin levels, and pancreatic insulin contents ( P < 0.05), comparable to gliclazide-treated group. The derivative 1 exhibited a significant insulinotropic action on diabetic pancreas, and caused an increased immunoreactivity for insulin, as compared to gliclazide-treated group. Together these results suggest that treatment of diabetic rats with 2, 4-dinitroanilino-benzoic acid ( 1 ) improved the glucose tolerance, fasting blood glucose, and HbA1c levels most probably by restoring the functional activities of the pancreas via its insulinotropic action. This indicates that the derivative 1 can serve as lead for the treatment of diabetes caused by low insulin levels. [ABSTRACT FROM AUTHOR]

To devise successful imaging and therapeutic strategies, the identification of β-cell surface markers is one of the challenges in diabetes research that has to be resolved. We previously showed that IC2, a rat monoclonal IgM antibody, can be used for ex vivo determination of β-cell mass by imaging. Further progress toward the development of an antibody-based imaging agent was hampered by the lack of knowledge regarding the nature and composition of the IC2 antigen. Here, we show a series of systematic experiments involving classical lipid extraction and chromatography techniques combined with immunochemistry, which led to the identification of sphingomyelin as the target antigen assembled in the form of patches on the β-cell surface. Our findings were verified by modulating SM by enzymatic cleavage, downregulation, upregulation, and perturbation of membrane SM and observation of corresponding changes in IC2 binding. Cholesterol participates in stabilization of these patches, as its removal results in loss of IC2 binding. We believe that these findings have implications for identifying future ligands for the proposed antigen for imaging purposes as well as for potential therapy, as sphingomyelin has been shown to play a role in the apoptotic cascade in pancreatic β cells.

Thyroid hormones have important role in metabolism and impairment of glucose metabolism and insulin secretion has been shown in hypothyroid rats but the exact mechanisms for this defect are poorly understood. The aim of this study was to investigate the effect of hypothyroidism on oxidative stress parameters, insulin secretory pathway and histomorphometric changes of pancreas. In the isolated islets of the control and methimazole -treated hypothyroid insulin secretion and content, ATP production, Glucokinase, and hexokinase specific activity and kATP and L-type channels sensitivity were assayed. In order to determine oxidative stress parameters, antioxidant enzymes and lipid peroxidation were measured in pancreatic homogenates. Histomorphometric changes and histochemistry of the islet in both groups were compared. Results showed that plasma glucose and insulin concentration and their area under the curve during IPGTT in hypothyroid group were respectively higher and lower than the controls. In the hypothyroid islets, glucose stimulated insulin secretion, ATP production, hexokinase and glucokinase activities were decreased. Hypothyroid induced a significant increased lipid peroxidation, and decreased the antioxidant enzyme activity. Compared with the control group, insulin antibody positivity, the total volume of the pancreas, islets, and the total number as well as the mean volume of the beta cells were also significantly decreased in the hypothyroid group. These findings indicate that oxidative stress produced under hypothyroidism could have a role in progression of pancreatic β-cell dysfunction, reduced beta cell mass and decreased glucokinase activity, impairing glucose tolerance and insulin secretion. [ABSTRACT FROM AUTHOR]

Purpose: Noninvasive beta cell mass (BCM) quantification is a crucial tool to understand diabetes development and progression. [(111)In]exendin is a promising agent for in vivo beta cell imaging, but tracer testing has been hampered by the lack of well-defined rodent models.Procedures: Biodistribution and pancreatic uptake of [(111)In]exendin were compared in rats and mice. In selected models, the amount of [(111)In]exendin accumulation in the pancreas and other organs was determined using a model of alloxan-induced beta cell loss. GLP-1R expression levels were analyzed by RT-PCR and immunohistochemistry.Results: Namely Brown Norway rats showed beta-cell-specific tracer accumulation and favorable pancreas-to-background ratios for noninvasive BCM determination. Mice displayed receptor-mediated [(111)In]exendin uptake in endocrine and exocrine pancreas, in spite of very low GLP-1R expression in exocrine tissue.Conclusions: Rats display better characteristics for in vivo BCM determination than mice and are suggested as a more adequate model for humans. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Human islets from type 2 diabetic donors are reportedly 80% deficient in the p21 (Cdc42/Rac)-activated kinase, PAK1. PAK1 is implicated in beta cell function and maintenance of beta cell mass. We questioned the mechanism(s) by which PAK1 deficiency potentially contributes to increased susceptibility to type 2 diabetes. Methods: Non-diabetic human islets and INS 832/13 beta cells cultured under diabetogenic conditions (i.e. with specific cytokines or under glucolipotoxic [GLT] conditions) were evaluated for changes to PAK1 signalling. Combined effects of PAK1 deficiency with GLT stress were assessed using classic knockout ( Pak1 ) mice fed a 45% energy from fat/palmitate-based, 'western' diet (WD). INS 832/13 cells overexpressing or depleted of PAK1 were also assessed for apoptosis and signalling changes. Results: Exposure of non-diabetic human islets to diabetic stressors attenuated PAK1 protein levels, concurrent with increased caspase 3 cleavage. WD-fed Pak1 knockout mice exhibited fasting hyperglycaemia and severe glucose intolerance. These mice also failed to mount an insulin secretory response following acute glucose challenge, coinciding with a 43% loss of beta cell mass when compared with WD-fed wild-type mice. Pak1 knockout mice had fewer total beta cells per islet, coincident with decreased beta cell proliferation. In INS 832/13 beta cells, PAK1 deficiency combined with GLT exposure heightened beta cell death relative to either condition alone; PAK1 deficiency resulted in decreased extracellular signal-related kinase (ERK) and B cell lymphoma 2 (Bcl2) phosphorylation levels. Conversely, PAK1 overexpression prevented GLT-induced cell death. Conclusions/interpretation: These findings suggest that PAK1 deficiency may underlie an increased diabetic susceptibility. Discovery of ways to remediate glycaemic dysregulation via altering PAK1 or its downstream effectors offers promising opportunities for disease intervention. [ABSTRACT FROM AUTHOR]

Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16 to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16) and three other gene products, p14 alternate reading frame (p14), p15 and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms. [ABSTRACT FROM AUTHOR]

Aims: To address questions regarding onset and progression of types 1 and 2 diabetes (T1D/T2D), surrogate imaging biomarkers for beta cell function and mass are needed. Here, we assess the potential of GPR44 as a surrogate marker for beta cells, in a direct comparison with clinically used biomarker VMAT2. Methods: GPR44 surface availability was assessed by flow cytometry of human beta cells. RNA transcription levels in different pancreas compartments were evaluated. The density of GPR44 receptor in endocrine and exocrine tissues was assessed by the radiolabeled GPR44 ligand [H]AZD 3825. A direct comparison with the established beta cell marker VMAT2 was performed by radiolabeled [H]DTBZ. Results: GPR44 was available on the cell surface, and pancreatic RNA levels were restricted to the islets of Langerhans. [H]AZD 3825 had nanomolar affinity for GPR44 in human islets and EndoC-βH1 beta cells, and the specific binding to human beta cells was close to 50 times higher than in exocrine preparations. The endocrine-to-exocrine binding ratio was approximately 10 times higher for [H]AZD 3825 than for [H]DTBZ. Conclusion: GPR44 is a highly beta cell-specific target, which potentially offers improved imaging contrast between the human beta cell and the exocrine pancreas. [ABSTRACT FROM AUTHOR]

Purpose: The vesicular monoamine transporter, type 2 (VMAT2) is expressed by insulin producing β cells and was evaluated as a biomarker of β cell mass (BCM) by positron emission tomography (PET) with [(18)F]fluoropropyl-dihydrotetrabenazine ([(18)F]FP-(+)-DTBZ).Procedures: We evaluated the feasibility of longitudinal pancreatic PET VMAT2 quantification in the pancreas in two studies of healthy controls and patients with type 1 or 2 diabetes. VMAT2 binding potential (BPND) was estimated voxelwise using a reference tissue method in a cross-sectional study, followed by assessment of reproducibility using a test-retest paradigm. Metabolic function was evaluated by stimulated c-peptide measurements.Results: Pancreatic BPND was significantly decreased in patients with type 1 diabetes relative to controls and the test-retest variability was 9.4%.Conclusions: Pancreatic VMAT2 content is significantly reduced in long-term diabetes patients relative to controls and repeat scans are sufficiently reproducible to suggest the feasibility clinically VMAT2 measurements in longitudinal studies of new onset diabetes. [ABSTRACT FROM AUTHOR]

Successful advancement in the treatment of diabetes mellitus is not possible without well-established methodology for beta cell mass calculation. Here, we offer the protocol to assess beta cell mass during embryonic development in the mouse. The described protocol has detailed steps on how to process extremely small embryonic pancreatic tissue, cut it on the cryostat, and stain tissue slides for microscopic analysis. The method does not require usage of confocal microscopy and takes advantage of enhanced automated image analysis with proprietary as well as open-source software packages., Competing Interests: Competing interestsThe authors declare no duality of interest associated with this manuscript., (Copyright © 2023 The Authors; This is an open access article under the CC BY-NC license (https://creativecommons.org/licenses/by-nc/4.0/).)

Bariatric surgery is the most effective therapeutic option for obese patients; however, it carries substantial risks, including procedure‑related complications, malabsorption, and hormonal disturbance. Recent years have seen an increase in the bariatric surgeries performed utilizing either an independent or a combination of restrictive and malabsorptive procedures. We review some complications of bariatric procedures more specifically, hypoglycemia and osteoporosis, the recommended preoperative assessment and then regular follow up, and the therapeutic options. Surgeon, internist, and the patient must be aware of the multiple risks of this kind of surgery and the needed assessment and follow up. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Prolactin (PRL)-stimulated beta cell proliferation is critical for maternal pancreatic beta cell mass expansion during pregnancy. However, the molecular effectors of the multiple putative signalling pathways downstream of the PRL receptor (PRL-R) are still elusive. Survivin has been shown to be induced during pregnancy. The aim of the present study was to define the essential role of survivin in gestational beta cell mass expansion. Methods: Expression of survivin was assessed in mouse islets during pregnancy and in insulinoma cells (INS-1) stimulated with PRL. Pregnant mice with targeted deletion of the survivin gene (also known as Birc5) in beta cells were assessed to determine the essential function of survivin in maternal beta cell mass expansion. INS-1 cells stimulated with PRL were used to explore the role of survivin in signalling pathways downstream of the PRL-R. Results: Survivin was significantly upregulated in maternal islets during pregnancy. With PRL stimulation, induction of survivin expression occurred predominantly in the nucleus and was associated with cell cycle progression to S and G2/M phase. Beta cell-specific survivin-knockout pregnant mice displayed glucose intolerance, attenuated beta cell mass expansion and impaired beta cell proliferation, with significant attenuation in the increased expression of Cdk4/ Ccnd1, E2f1, p53 (also known as Trp53) and p21 (also known as Cdkn1a) compared with wild-type controls during pregnancy. Targeted deletion of survivin in INS-1 cells resulted in cell cycle disturbance with an arrest in G1/S phase after PRL stimulation. Inhibitors of Akt, signal transducer and activator of transcription 5 (STAT5), PIM or extracellular signal-regulated kinase (ERK), significantly decreased the expression of survivin in PRL-stimulated INS-1 cells. Conclusions/interpretation: Survivin directly participates in PRL-mediated beta cell proliferation via Akt, STAT5-PIM and ERK signalling pathways during pregnancy. [ABSTRACT FROM AUTHOR]

Purpose: In order to evaluate future β cell tracers in vivo, we aimed to develop a standardized in vivo method allowing semiquantitative measurement of a prospective β cell tracer within the pancreas. Procedures: 2-[I]Iodo- l-phenylalanine ([I]IPA) and [Lys([In]DTPA)]exendin-3 ([In]Ex3) pancreatic uptake and biodistribution were evaluated using SPECT, autoradiography, and an ex vivo biodistribution study in a controlled unilaterally nephrectomized mouse β cell depletion model. Semiquantitative measurement of the imaging results was performed using [I]IPA to delineate the pancreas and [In]Ex3 as a β cell tracer. Results: The uptake of [I]IPA was highest in the pancreas. Aside from the kidneys, the uptake of [In]Ex3 was highest in the pancreas and lungs. Autoradiography showed only uptake of [In]Ex3 in insulin-expressing cells. Semiquantitative measurement of [In]Ex3 in the SPECT images based on the delineation of the pancreas with [I]IPA showed a high correlation with the [In]Ex3 uptake data of the pancreas obtained by dissection. A strong positive correlation was observed between the relative insulin positive area and the pancreas-to-blood ratios of [In]Ex3 uptake as determined by counting with a gamma counter and the semiquantitative analysis of the SPECT images. Conclusions: [I]IPA is a promising tracer to delineate pancreatic tissue on SPECT images. It shows a high uptake in the pancreas as compared to other abdominal tissues. This study also demonstrates the feasibility and accuracy to measure the β cell mass in vivo in an animal model of diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Non-invasive imaging of beta cells is a much-needed development but is one that faces significant biological and technological hurdles. A relevant imaging method should at least allow for an evaluation over time of the mass of beta cells under physiological and pathological conditions, and for an assessment of novel therapies. We, therefore, investigated the ability of a new MRI probe to repeatedly measure the loss of beta cells in a rodent model. Methods: We developed an innovative nanoparticle probe that targets the glucagon-like peptide 1 receptor, and can be used for both fluorescence imaging and MRI. Using fluorescence, we characterised the specificity and biodistribution of the probe. Using 1.5T MRI, we longitudinally imaged the changes in insulin content in male and female mice of the RIP-DTr strain, which mimic the changes expected in type 1 and type 2 diabetes, respectively. Results: We showed that this probe selectively labelled beta cells in situ, imaged in vivo native pancreatic islets and evaluated their loss after diphtheria toxin administration, in a model of graded beta cell deletion. Thus, using clinical MRI, the probe quantitatively differentiates, in the same mouse strain, between female animals featuring a 50% loss of beta cells and the males featuring an almost complete loss of beta cells. Conclusions/interpretation: The approach addresses several of the hurdles that have so far limited the non-invasive imaging of beta cells, including the potential to repeatedly monitor the very same animals using clinically available equipment, and to differentiate graded losses of beta cells. [ABSTRACT FROM AUTHOR]

Background: Assuming that ileal stimulation by food may increase incretin secretion, we aimed to investigate whether ileal interposition obtains adequate pancreatic islet viability and function after intramuscular islet transplantation in diabetic rats. Methods: We investigated four groups of eight Wistar rats: ileal interposition + islet transplantation, islet transplantation, ileal interposition, and diabetic control. All rats were subjected to streptozotocin-induced diabetes. We used the C-peptide/glucose ratio and islet image to investigate beta cell mass, and plasma glucagon like peptide-1 (GLP-1) measure. Results: Ileal interposition was effective in preserving function and increasing islet mass in animals with islets transplanted into alginate microcapsules. The plasma GLP-1 level in the diabetic control rats was a basal concentration (4.1 ± 1.2 pM). GLP-1 level after ileal interposition + islet transplantation (12.3 ± 3.3 pM) was significantly higher ( p < .05) than in the islet transplantation group (8.2 ± 2.4 pM) and ileal interposition group rats (7.6 ± 1.8 pM). Conclusions: Ileal interposition positively influenced beta cell viability after intramuscular transplantation of pancreatic islets in diabetic rats. [ABSTRACT FROM AUTHOR]

Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and age-dependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes. [ABSTRACT FROM AUTHOR]

The accurate quantification of beta cell mass in humans is one of the key challenges in understanding the role of beta cell loss and dysfunction in the pathogenesis of diabetes mellitus. Autopsy studies indicate that beta cell loss is not only a hallmark of autoimmune diabetes but also plays a pivotal role in type 2 diabetes, owing to the toxic effects of lipids, glucose and cytokines. Thus, there is an urgent need for non-invasive clinical techniques for beta cell mass quantification, which should be optimally integrated into standard diagnostic equipment in hospitals. In this issue of Diabetologia (Brom et al DOI ) it is reported that single photon emission computed tomography (SPECT) data with indium-labelled glucagon-like peptide-1 (GLP-1) receptor agonist exendin-3 correlate with the morphometric analysis of beta cell mass in a rat model of alloxan-induced diabetes. With this validation, the authors were able to demonstrate a significant loss of beta cell mass in C-peptide-negative type 1 diabetic patients. Thus, indium-labelled exendin-3 could serve as a model tracer for future studies of larger cohorts of diabetic patients to monitor the dynamics of beta cell loss and regeneration. Despite the recent progress from SPECT imaging data there remain open questions that await clarification in the near future such as variations in GLP-1 receptor density and physiological variation of beta cell mass in relation to beta cell function. The use of GLP-1-based tracer analysis may open new clinical avenues for non-invasive quantification of beta cell mass in patients with newly diagnosed type 1 diabetes and prediabetic individuals with high titres of autoantibodies. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: A reliable method for in vivo quantification of pancreatic beta cell mass (BCM) could lead to further insight into the pathophysiology of diabetes. The glucagon-like peptide 1 receptor, abundantly expressed on beta cells, may be a suitable target for imaging. We investigated the potential of radiotracer imaging with the GLP-1 analogue exendin labelled with indium-111 for determination of BCM in vivo in a rodent model of beta cell loss and in patients with type 1 diabetes and healthy individuals. Methods: The targeting of In-labelled exendin was examined in a rat model of alloxan-induced beta cell loss. Rats were injected with 15 MBq In-labelled exendin and single photon emission computed tomography (SPECT) acquisition was performed 1 h post injection, followed by dissection, biodistribution and ex vivo autoradiography studies of pancreatic sections. BCM was determined by morphometric analysis after staining with an anti-insulin antibody. For clinical evaluation SPECT was acquired 4, 24 and 48 h after injection of 150 MBq In-labelled exendin in five patients with type 1 diabetes and five healthy individuals. The tracer uptake was determined by quantitative analysis of the SPECT images. Results: In rats, In-labelled exendin specifically targets the beta cells and pancreatic uptake is highly correlated with BCM. In humans, the pancreas was visible in SPECT images and the pancreatic uptake showed high interindividual variation with a substantially lower uptake in patients with type 1 diabetes. Conclusions/interpretation: These studies indicate that In-labelled exendin may be suitable for non-invasive quantification of BCM. Trial registration ClinicalTrials.gov NCT01825148, EudraCT: 2012-000619-10 [ABSTRACT FROM AUTHOR]

The development of pancreatic cancer (PC) is associated with worsening of glucose tolerance. However, there is limited information about the effects of PC on islet morphology. The aim of this study was to elucidate changes in alpha and beta cell mass in patients with PC. We enrolled 30 autopsy cases with death due to PC (9 with diabetes; DM) and 31 age- and BMI-matched autopsy cases without PC (controls, 12 with DM). Tumor-free pancreatic sections were stained for insulin and glucagon, and fractional beta cell (BCA) and alpha cell area (ACA) were quantified. In addition, expression of de-differentiation markers, i.e., ALDH1A3 and UCN3, was qualitatively evaluated. The pancreas of subjects with PC showed atrophic and fibrotic changes. There was no significant difference in BCA in subjects with PC compared to controls (1.53 ± 1.26% vs. 0.95 ± 0.42%, p = 0.07). However, ACA and ACA to BCA ratio were significantly higher in subjects with PC compared to controls (2.48 ± 2.39% vs. 0.53 ± 0.26% and 1.94 ± 1.93 vs. 0.59 ± 0.26, respectively, both p < 0.001). Increased ACA to BCA ratio was observed in subjects with PC irrespective of the presence of DM. Qualitative evaluation of ALDH1A3 and UCN3 expression showed no significant difference between the groups. In conclusion, in subjects with PC, alpha to beta cell mass ratio is increased, which may contribute to the increased risk of worsening glucose metabolism. Further studies are warranted to elucidate the mechanisms of increased alpha to beta cell mass in patients with PC.

The islets of Langerhans constitute the endocrine part of the pancreas and are responsible for maintenance of blood glucose homeostasis. They are deeply embedded in the exocrine pancreas, limiting their accessibility for functional studies. Understanding regulation of function and survival and assessing the clinical outcomes of individual treatment strategies for diabetes requires a monitoring system that continuously reports on the endocrine pancreas. We describe the application of a natural body window that successfully reports on the properties of in situ pancreatic islets. As proof of principle, we transplanted "reporter islets" into the anterior chamber of the eye of leptin-deficient mice. These islets displayed obesity-induced growth and vascularization patterns that were reversed by leptin treatment. Hence, reporter islets serve as optically accessible indicators of islet function in the pancreas, and also reflect the efficacy of specific treatment regimens aimed at regulating islet plasticity in vivo. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The stress-activated nuclear protein transcription regulator 1 (NUPR1) is induced in response to glucose and TNF-α, both of which are elevated in type 2 diabetes, and Nupr1 has been implicated in cell proliferation and apoptosis cascades. We used Nupr1 mice to study the role of Nupr1 in glucose homeostasis under normal conditions and following maintenance on a high-fat diet (HFD). Methods: Glucose homeostasis in vivo was determined by measuring glucose tolerance, insulin sensitivity and insulin secretion. Islet number, morphology and beta cell area were assessed by immunofluorescence and morphometric analysis, and islet cell proliferation was quantified by analysis of BrdU incorporation. Islet gene expression was measured by gene arrays and quantitative RT-PCR, and gene promoter activities were monitored by measuring luciferase activity. Results: Nupr1 mice had increased beta cell mass as a consequence of enhanced islet cell proliferation. Nupr1-dependent suppression of beta cell Ccna2 and Tcf19 promoter activities was identified as a mechanism through which Nupr1 may regulate beta cell cycle progression. Nupr1 mice maintained on a normal diet were mildly insulin resistant, but were normoglycaemic with normal glucose tolerance because of compensatory increases in basal and glucose-induced insulin secretion. Nupr1 deletion was protective against HFD-induced obesity, insulin resistance and glucose intolerance. Conclusions/interpretation: Inhibition of NUPR1 expression or activity has the potential to protect against the metabolic defects associated with obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in non-diabetic individuals with obesity and cardiovascular disease. However, their effect on beta cell mass in normoglycaemic conditions is not clear. Here, we investigate the effects of the GLP-1RA liraglutide on beta cell mass and function in normoglycaemic mice. Methods: C57BL/6J mice were treated with the GLP-1RA liraglutide or PBS and fed a control or high-fat diet (HFD) for 1 or 6 weeks. Glucose and insulin tolerance tests were performed after 6 weeks. BrdU was given to label proliferating cells 1 week before the animals were killed. The pancreas was taken for either histology or islet isolation followed by a glucose-induced insulin-secretion test. Results: Treatment with liraglutide for 6 weeks led to increased insulin sensitivity and attenuation of HFD-induced insulin resistance. A reduction in beta cell mass was observed in liraglutide-treated control and HFD-fed mice at 6 weeks, and was associated with a lower beta cell proliferation rate after 1 week of treatment. A similar reduction in alpha cell mass occurred, resulting in an unchanged alpha to beta cell ratio. In contrast, acinar cell proliferation was increased. Finally, islets isolated from liraglutide-treated control mice had enhanced glucose-induced insulin secretion. Conclusions/interpretation: Our data show that GLP-1RA treatment in normoglycaemic mice leads to increases in insulin sensitivity and beta cell function that are associated with reduced beta cell mass to maintain normoglycaemia. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Imaging of beta cell mass (BCM) is a major challenge in diabetes research. The vesicular monoamine transporter 2 (VMAT2) is abundantly expressed in human beta cells. Radiolabelled analogues of tetrabenazine (TBZ; a low-molecular-weight, cell-permeant VMAT2-selective ligand) have been employed for pancreatic islet imaging in humans. Since reports on TBZ-based VMAT2 imaging in rodent pancreas have been fraught with confusion, we compared VMAT2 gene expression patterns in the mouse, rat, pig and human pancreas, to identify appropriate animal models with which to further validate and optimise TBZ imaging in humans. Methods: We used a panel of highly sensitive VMAT2 antibodies developed against equivalently antigenic regions of the transporter from each species in combination with immunostaining for insulin and species-specific in situ hybridisation probes. Individual pancreatic islets were obtained by laser-capture microdissection and subjected to analysis of mRNA expression of VMAT2. Results: The VMAT2 protein was not expressed in beta cells in the adult pancreas of common mouse or rat laboratory strains, in contrast to its expression in beta cells (but not other pancreatic endocrine cell types) in the pancreas of pigs and humans. VMAT2- and tyrosine hydroxylase co-positive (catecholaminergic) innervation was less abundant in humans than in rodents. VMAT2-positive mast cells were identified in the pancreas of all species. Conclusions/interpretation: Primates and pigs are suitable models for TBZ imaging of beta cells. Rodents, because of a complete lack of VMAT2 expression in the endocrine pancreas, are a 'null' model for assessing interference with BCM measurements by VMAT2-positive mast cells and sympathetic innervation in the pancreas. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We used the GK/Par rat, a spontaneous model of type 2 diabetes with early defective beta cell neogenesis, to determine whether the development of GK/Par offspring in a non-diabetic intrauterine/postnatal environment would prevent the alteration of fetal beta cell mass (BCM) and ultimately decrease the risk of diabetes later in adult life. Methods: We used an embryo-transfer approach, with fertilised GK/Par ovocytes (oGK) being transferred into pregnant Wistar (W) or GK/Par females (pW and pGK). Offspring were phenotyped at fetal age E18.5 and at 10 weeks of age, for BCM, expression of genes of pancreatic progenitor cell regulators ( Igf2, Igf1r, Sox9, Pdx1 and Ngn3), glucose tolerance and insulin secretion. Results: (1) Alterations in neogenesis markers/regulators and BCM were as severe in the oGK/pW E18.5 fetuses as in the oGK/pGK group. (2) Adult offspring from oGK transfers into GK (oGK/pGK/sGK) had the expected diabetic phenotype compared with unmanipulated GK rats. (3) Adult offspring from oGK reared in pW mothers and milked by GK foster mothers had reduced BCM, basal hyperglycaemia, glucose intolerance and low insulin, to an extent similar to that of oGK/pGK/sGK offspring. (4) In adult offspring from oGK transferred into pW mothers and milked by their W mothers (oGK/pW/sW), the phenotype was similar to that in oGK/pGK/sGK or oGK/pW/sGK offspring. Conclusions/interpretation: These data support the conclusion that early BCM alteration and subsequent diabetes risk in the GK/Par model are not removed despite normalisation of the prenatal and postnatal environments, either isolated or combined. [ABSTRACT FROM AUTHOR]

Progressive loss of β-cell mass (BCM) has a pernicious influence on type 2 diabetes mellitus (T2DM); evaluation of BCM has conventionally required an invasive method that provides only cross-sectional data. However, a noninvasive approach to longitudinal assessment of BCM in living subjects using an indium 111-labeled exendin-4 derivative ([Lys12( 111 In-BnDTPA-Ahx)]exendin-4) ( 111 In-exendin-4) has been developed recently. Imeglimin is a novel antidiabetic agent that is reported to improve glycemic control and glucose-stimulated insulin secretion (GSIS) via augmentation of mitochondrial function. However, the influence of imeglimin on BCM is not fully understood. We have investigated the effects of imeglimin on BCM in vivo in prediabetic db/db mice using a noninvasive 111 In-exendin-4 single-photon emission computed tomography/computed tomography (SPECT/CT) technique. During the 5-week study period, imeglimin treatment attenuated the progression of glucose intolerance, and imeglimin-treated mice retained greater BCM than control, which was consistent with the results of 111 In-exendin-4 SPECT/CT scans. Furthermore, immunohistochemical analysis revealed reduced β-cell apoptosis in the imeglimin-treated db/db mice, and also lowered release of cytosolic cytochrome c protein in the β cells. Furthermore, electron microscopy observation and membrane potential measurement revealed improved structural integrity and membrane potential of the mitochondria of imeglimin-treated islets, respectively. These results demonstrate attenuation of progression of BCM loss in prediabetic db/db mice partly via inhibition of mitochondria-mediated apoptosis., Competing Interests: NI received joint research grants from Daiichi Sankyo Co., Ltd., Terumo Co., Ltd., and Drawbridge Health, Inc.; received speaker honoraria from Kowa Pharmaceutical Co., Ltd., MSD, Astellas Pharma Inc., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Mitsubishi Tanabe Pharma Co., Ltd.; received scholarship grants from Kissei Pharmaceutical Co., Ltd., Sanofi, Daiichi-Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Japan Tobacco Inc., Kyowa Kirin Co., Sumitomo Pharma Co., Ltd., Astellas Pharma Inc., MSD, Eli Lilly Japan, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co. Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Novartis Pharma K.K., Teijin Pharma Ltd., and Life Scan Japan Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fauzi, Murakami, Fujimoto, Botagarova, Sakaki, Kiyobayashi, Ogura and Inagaki.)

Pancreatic β-cell mass (BCM) has an importance in the pathophysiology of diabetes mellitus. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged as a promising tool for BCM evaluation. While glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is known to be involved in high-fat diet (HFD)-induced obesity, the effect of GIP on BCM is still controversial. In this study, we investigated indium 111 ( 111 In)-labeled exendin-4 derivative ([Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4) single-photon emission computed tomography/computed tomography (SPECT/CT) as a tool for evaluation of longitudinal BCM changes in HFD-induced obese mice, at the same time we also investigated the effects of GIP on BCM in response to HFD using GIP-knockout (GIP -/- ) mice. 111 In-exendin-4 SPECT/CT was able to distinguish control-fat diet (CFD)-fed mice from HFD-fed mice and the pancreatic uptake values replicated the BCM measured by conventional histological methods. Furthermore, BCM expansions in HFD-fed mice were demonstrated by time-course changes of the pancreatic uptake values. Additionally, 111 In-exendin-4 SPECT/CT demonstrated the distinct changes in BCM between HFD-fed GIP -/- (GIP -/- +HFD) and wild-type (WT+HFD) mice; the pancreatic uptake values of GIP -/- +HFD mice became significantly lower than those of WT+HFD mice. The different changes in the pancreatic uptake values between the two groups preceded those in fat accumulation and insulin resistance. Taken together with the finding of increased β-cell apoptosis in GIP -/- +HFD mice compared with WT+HFD mice, these data indicated that GIP has preferable effects on BCM under HFD. Therefore, 111 In-exendin-4 SPECT/CT can be useful for evaluating increasing BCM and the role of GIP in BCM changes under HFD conditions., Competing Interests: NI received joint research grants from Daiichi Sankyo Co., Ltd., Terumo Co., Ltd., and Drawbridge, Inc.; received speaker honoraria from Kowa Pharmaceutical Co., Ltd., MSD, Astellas Pharma Inc., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Mitsubishi Tanabe Pharma Co., Ltd.; received scholarship grants from Kissei Pharmaceutical Co., Ltd., Sanofi, Daiichi-Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Japan Tobacco Inc., Kyowa Kirin Co., Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., MSD, Eli Lilly Japan, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co. Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Novartis Pharma K.K., Teijin Pharma Ltd., and Life Scan Japan Inc. NH received scholarship grant from Mitsubishi Tanabe Pharma Co., and Ono Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kiyobayashi, Murakami, Harada, Fujimoto, Murata, Fujita, Hamamatsu, Ikeguchi-Ogura, Hatoko, Lu, Yamane and Inagaki.)

Aims/hypothesis: Individuals carrying type 2 diabetes risk alleles in TCF7L2 display decreased beta cell levels of T cell factor 7 like-2 (TCF7L2) immunoreactivity, and impaired insulin secretion and beta cell sensitivity to glucagon-like peptide 1 (GLP-1). Here, we sought to determine whether selective deletion of Tcf7l2 in mouse pancreas impairs insulin release and glucose homeostasis. Methods: Pancreas-specific Tcf7l2-null ( pTcf7l2) mice were generated by crossing mice carrying conditional knockout alleles of Tcf7l2 ( Tcf7l2-flox) with mice expressing Cre recombinase under the control of the Pdx1 promoter ( Pdx1. Cre). Gene expression was assessed by real-time quantitative PCR and beta cell mass by optical projection tomography. Glucose tolerance, insulin secretion from isolated islets, and plasma insulin, glucagon and GLP-1 content were assessed by standard protocols. Results: From 12 weeks of age, pTcf7l2 mice displayed decreased oral glucose tolerance vs control littermates; from 20 weeks they had glucose intolerance upon administration of glucose by the intraperitoneal route. pTcf7l2 islets displayed impaired insulin secretion in response to 17 (vs 3.0) mmol/l glucose (54.6 ± 4.6%, p < 0.01) or to 17 mmol/l glucose plus 100 nmol/l GLP-1 (44.3 ± 4.9%, p < 0.01) compared with control islets. Glp1r (42 ± 0.08%, p < 0.01) and Ins2 (15.4 ± 4.6%, p < 0.01) expression was significantly lower in pTcf7l2 islets than in controls. Maintained on a high-fat (but not on a normal) diet, pTcf7l2 mice displayed decreased expansion of pancreatic beta cell volume vs control littermates. No differences were observed in plasma insulin, proinsulin, glucagon or GLP-1 concentrations. Conclusions/interpretation: Selective deletion of Tcf7l2 in the pancreas replicates key aspects of the altered glucose homeostasis in human carriers of TCF7L2 risk alleles, indicating the direct role of this factor in controlling beta cell function. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Diabetes frequently develops in patients with pancreatic disorders. We aimed to determine the lower threshold of beta cell area for diabetes manifestation as well as the impact of insulin sensitivity on glucose homoeostasis in patients with pancreatic diabetes. Methods: Eighty-two patients undergoing pancreatic surgery underwent pre-operative oral glucose challenge. Fractional pancreatic beta cell area was determined, and indices of insulin sensitivity and beta cell function were calculated. Results: HbA and glucose levels were similar in patients with high and intermediate beta cell area, but were significantly higher in those with the lowest beta cell area ( p < 0.0001). Insulin secretion was reduced only in patients with the lowest beta cell area ( p < 0.001). The relative beta cell deficits at the onset of diabetes and impaired glucose tolerance were 64% and 21%, respectively, based on 2 h glucose levels. Deteriorating insulin sensitivity was associated with a small increase in the incidence of diabetes. Conclusions/interpretation: In conclusion, pancreatic diabetes probably develops after a reduction in beta cell area of ~65%. Post-challenge glucose excursions are much more closely related to pancreatic beta cell area than to fasting glycaemia, thereby underlining the usefulness of the OGTT in patients with pancreatic disorders. [ABSTRACT FROM AUTHOR]

For more than a decade, researchers have been trying to develop non-invasive imaging techniques for the in vivo measurement of viable pancreatic beta cells. However, in spite of intense research efforts, only one tracer for positron emission tomography (PET) imaging is currently under clinical evaluation. To many diabetologists it may remain unclear why the imaging world struggles to develop an effective method for non-invasive beta cell imaging (BCI), which could be useful for both research and clinical purposes. Here, we provide a concise overview of the obstacles and challenges encountered on the way to such BCI, in both native and transplanted islets. We discuss the major difficulties posed by the anatomical and cell biological features of pancreatic islets, as well as the chemical and physical limits of the main imaging modalities, with special focus on PET, SPECT and MRI. We conclude by indicating new avenues for future research in the field, based on several remarkable recent results. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Ciliary neurotrophic factor (CNTF) improves metabolic variables of obese animals with characteristics of type 2 diabetes, mainly by reducing insulin resistance. We evaluated whether CNTF was able to improve other metabolic variables in mouse models of type 2 diabetes, such as beta cell mass and insulin clearance, and whether CNTF has any effect on non-obese mice with characteristics of type 2 diabetes. Methods: Neonatal mice were treated with 0.1 mg/kg CNTF or citrate buffer via intraperitoneal injections, before injection of 250 mg/kg alloxan. HEPG2 cells were cultured for 3 days in the presence of citrate buffer, 1 nmol/l CNTF or 50 mmol/l alloxan or a combination of CNTF and alloxan. Twenty-one days after treatment, we determined body weight, epididymal fat weight, blood glucose, plasma insulin, NEFA, glucose tolerance, insulin resistance, insulin clearance and beta cell mass. Finally, we assessed insulin receptor and protein kinase B phosphorylation in peripheral organs, as well as insulin-degrading enzyme (IDE) protein production and alternative splicing in the liver and HEPG2 cells. Results: CNTF improved insulin sensitivity and beta cell mass, while reducing glucose-stimulated insulin secretion and insulin clearance in Swiss mice, improving glucose handling in a non-obese type 2 diabetes model. This effect was associated with lower IDE production and activity in liver cells. All these effects were observed even at 21 days after CNTF treatment. Conclusions/interpretation: CNTF protection against type 2 diabetes is partially independent of the anti-obesity actions of CNTF, requiring a reduction in insulin clearance and increased beta cell mass, besides increased insulin sensitivity. Furthermore, knowledge of the long-term effects of CNTF expands its pharmacological relevance. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. Methods: Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg day. Results: Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats. Conclusions/interpretation: These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure. [ABSTRACT FROM AUTHOR]

Clinical islet transplantation is being investigated as a permanent cure for type 1 diabetes mellitus (T1DM). Currently, intraportal infusion of islets is the favoured procedure, but several novel implantation sites have been suggested. Noninvasive longitudinal methodologies are an increasingly important tool for assessing the fate of transplanted islets, their mass, function and early signs of rejection. This article reviews the approaches available for islet graft imaging by positron emission tomography and progress in the field, as well as future challenges and opportunities. [ABSTRACT FROM AUTHOR]

Purpose: We have generated transgenic mouse lines expressing the positron emission tomography (PET) reporter gene, sr39tk, under the control of the mouse insulin I promoter (MIP-sr39tk) to image endogenous islets using PET.Procedures: The MIP-sr39tk transgene was constructed using the 8.3 kb fragment of the mouse insulin I promoter and the sr39tk coding sequence from the mrfp-hrl-ttk trifusion construct. Expression of sr39TK in beta cells was confirmed by fluorescence immunohistochemistry of pancreatic sections. Histological sections were used to determine beta cell mass, islet area and islet number. Beta cell function was determined using intraperitoneal glucose tolerance tests. For ex vivo biodistrubution, mice were injected i.v. with 9.25 MBq [(18)F]fluorohydroxymethyl-butyl-guanine (FHBG), euthanized 1 h later and pancreata and other organs were collected and counted. For PET scans, mice were injected i.v. with 9.25 MBq [(18)F]FHBG, and dynamic scans were conducted for 1 h, followed by a 30 min static acquisition. To induce type 1 diabetes-like symptoms, MIP-sr39tk mice were injected i.p. with 40 mg/kg streptozotocin (STZ) once per day for five consecutive days, and biodistribution and PET scans were conducted thereafter.Results: Ex vivo quantification of [(18)F]FHBG uptake in the pancreas showed a 4.5-fold difference in transgenic vs. non-transgenics, confirming that expression of sr39TK results in the retention of the PET tracer. In STZ-treated MIP-sr39tk mice, impairments in glucose tolerance and decreases in beta cell mass correlated significantly with a diminishment in [(18)F]FHBG uptake before fasting hyperglycemia became apparent.Conclusions: The MIP-sr39tk mouse demonstrates that PET imaging can detect changes in beta cell mass that precede the onset of diabetes. [ABSTRACT FROM AUTHOR]