Increase In Β-cell Mass Research Articles

Expression of FAM159B in Humans, Rats, and Mice: A Cross-species Examination.

Little is known about the adaptor protein FAM159B. To determine whether FAM159B expression findings in rats or mice can be extrapolated to humans, we compared FAM159B expression in healthy tissue samples from all three species using immunohistochemistry. Despite variations in expression intensity, similar FAM159B expression patterns were observed in most organs across species. The most prominent species difference was noted in pancreatic islets; while FAM159B expression was limited to single cells on the outer edges in mice and rats, it was detectable across entire islets in humans. Double-labeling immunohistochemistry revealed partial overlap of FAM159B expression with that of insulin, glucagon, and somatostatin in human islets. By contrast, FAM159B showed complete colocalization with only somatostatin in rats and mice. An additional analysis of FAM159B expression in lean and obese Zucker rats revealed larger islet areas due to increased β-cell mass in obese rats, which was accompanied by a smaller percentage of FAM159B-positive δ-cells per islet area. Beyond the known differences in islet architecture across species, our results point to larger dissimilarities in blood glucose regulation between rodents and humans than generally assumed. Moreover, findings regarding FAM159B expression (and function) cannot be directly transferred between rodents and humans.

Aged garlic extract preserves beta-cell functioning via modulation of nuclear factor kappa-B (NF-κB)/Toll-like receptor (TLR)-4 and sarco endoplasmic reticulum calcium ATPase (SERCA)/Ca2+ in diabetes mellitus

BackgroundPeripheral insulin resistance and compromised insulin secretion from pancreatic β-cells are significant factors and pathogenic hallmarks of diabetes mellitus (DM). NF-κβ/TLR-4 and SERCA/Ca2+ pathways have been identified as potential pathways regulating insulin synthesis by preserving pancreatic β-cell functioning. The current study aimed to evaluate the therapeutic effect of aged garlic extract (AGE) against DM in a streptozotocin (STZ)-induced rat model with particular emphasis on pancreatic β-cell functioning.MethodsAGE was characterized by gas chromatography-mass spectrometry (GC-MS), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) to evaluate its physio-chemical characteristics followed by in-vitro anti-diabetic and antioxidant potential. This was followed by the induction of DM in laboratory animals for investigating the therapeutic action of AGE by evaluating the role of NF-κβ/TLR-4 and the SERCA/Ca2+ pathway. The parameters assessed in the present experimental setup encompassed antioxidant parameters, metabolic indicators, insulin concentration, intracellular calcium levels, apoptotic markers (CCK-8 and Caspase Glo-8), and protein expression (P-62 and APACHE-II).ResultsAGE characterization by SEM, GC-MS, and X-ray diffraction (XRD) revealed the presence of phenylalanine, alliin, S-allylmercaptocysteine (SAMC), tryptophan, 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid as major bioactive constituents of AGE. Metabolic studies, including intraperitoneal glucose tolerance test (IPGTT), revealed significantly lower blood glucose levels in the AGE group compared to the disease control group. In contrast, the intraperitoneal insulin tolerance test (ITT) exhibited no significant difference in insulin sensitivity between the AGE supplementation group and the DM control group. Interestingly, AGE was found to have no significant effect on fasting glucose and serum insulin levels. In contrast, AGE supplementation was found to cause significant hypoglycaemia in postprandial blood glucose and insulin levels. Importantly, AGE causes restoration of intracellular Ca2+ levels by modulation of SERCA/Ca2 functioning and inhibition NF-κB/TLR-4 pathway. AGE was found to interact with and inhibit the DR-5/ caspase-8/3 apoptotic complex. Furthermore, microscopic studies revealed degeneration and apoptotic changes in pancreatic β-cells of the DM control group, while supplementation of AGE resulted in inhibition of apoptotic pathway and regeneration of pancreatic β-cells.ConclusionThe current study suggests that AGE enhance glucose homeostasis by exerting their effects on pancreatic β-cells, without ameliorating peripheral sensitivity. Moreover, AGEs promote an increase in β-cell mass by mitigating the apoptosis of pancreatic β-cells. These findings suggest that AGE could aid in developing a viable alternative therapy for diabetes mellitus (DM).

Whole transcriptome sequencing analyses of islets reveal ncRNA regulatory networks underlying impaired insulin secretion and increased β-cell mass in high fat diet-induced diabetes mellitus.

Our study aims to identify novel non-coding RNA-mRNA regulatory networks associated with β-cell dysfunction and compensatory responses in obesity-related diabetes. Glucose metabolism, islet architecture and secretion, and insulin sensitivity were characterized in C57BL/6J mice fed on a 60% high-fat diet (HFD) or control for 24 weeks. Islets were isolated for whole transcriptome sequencing to identify differentially expressed (DE) mRNAs, miRNAs, IncRNAs, and circRNAs. Regulatory networks involving miRNA-mRNA, lncRNA-mRNA, and lncRNA-miRNA-mRNA were constructed and functions were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Despite compensatory hyperinsulinemia and a significant increase in β-cell mass with a slow rate of proliferation, HFD mice exhibited impaired glucose tolerance. In isolated islets, insulin secretion in response to glucose and palmitic acid deteriorated after 24 weeks of HFD. Whole transcriptomic sequencing identified a total of 1324 DE mRNAs, 14 DE miRNAs, 179 DE lncRNAs, and 680 DE circRNAs. Our transcriptomic dataset unveiled several core regulatory axes involved in the impaired insulin secretion in HFD mice, such as miR-6948-5p/Cacna1c, miR-6964-3p/Cacna1b, miR-3572-5p/Hk2, miR-3572-5p/Cckar and miR-677-5p/Camk2d. Additionally, proliferative and apoptotic targets, including miR-216a-3p/FKBP5, miR-670-3p/Foxo3, miR-677-5p/RIPK1, miR-802-3p/Smad2 and ENSMUST00000176781/Caspase9 possibly contribute to the increased β-cell mass in HFD islets. Furthermore, competing endogenous RNAs (ceRNA) regulatory network involving 7 DE miRNAs, 15 DE lncRNAs and 38 DE mRNAs might also participate in the development of HFD-induced diabetes. The comprehensive whole transcriptomic sequencing revealed novel non-coding RNA-mRNA regulatory networks associated with impaired insulin secretion and increased β-cell mass in obesity-related diabetes.

Synergistic effects of GABA and hypoglycemic drugs

Diabetes mellitus (DM) is the leading cause of premature death and disability. Despite a significant number of drugs, the effectiveness of therapy aimed at normalizing the level of glycemia and preventing complications does not fully satisfy doctors and patients. Therefore, the search for new approaches for the prevention and treatment of DM and its complications continues. Significant resources are used to develop new drugs, but recently the possibility of using «old» widely available drugs with newly discovered pleiotropic properties has been substantiated. These may include preparations of gammaaminobutyric acid (GABA) and agents that directly or indirectly activate GABAergic transmission, which have a pronounced pancreatic protective effect, which has been widely discussed in foreign literature over the past 10-15 years. However, there are few such publications in the domestic literature.It has been established that the content of GABA in β-cells in patients with type 1 and type 2 diabetes is reduced and this correlates with the severity of the disease. Genetic suppression of GABA receptors causes a significant decrease in the mass of β-cells and glucose-stimulated insulin secretion, which confirms the importance of GABA in ensuring glucose homeostasis and the advisability of replenishing the GABA deficiency in DM with its additional administration. It has been established that in animals with DM, GABA suppresses apoptosis and stimulates the regeneration of β-cells, increases β-cell mass and insulin production.Experimental data have been obtained indicating a synergistic effect of GABA when combined with glucagon-like peptide-1 (GLP-1) receptor agonists, DPP-4 inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, when a more pronounced pancreoprotective effect is observed, due to decrease in oxidative and nitrosative stress, inflammation, increase in the level of Klotho protein, Nrf-2 activity and antioxidant defense enzymes, suppression of NF-kB activity and expression of pro-inflammatory cytokines. As a result, all this leads to a decrease in apoptosis and death of β-cells, an increase in β-cell mass, insulin production and, at the same time, a decrease in glucagon levels and insulin resistance.The review substantiates the feasibility of using GABA and drugs with a positive GABAeric effect in combination with new generation antidiabetic agents: GLP-1 receptor agonists, DPP-4 inhibitors and SGLT-2 inhibitors in order to increase their antidiabetic potential.The search was carried out in the databases Pubmed, eLibrary, Medline. Keywords: diabetes mellitus, gamma-aminobutyric acid, glucagon-like peptide-1, GLP-1 receptor agonists, glucose-dependent insulinotropic peptide, dipeptidyl peptidase inhibitors, sodium-glucose cotransporter 2 inhibitors. The search was carried out from 2000 to 2022, but the review presents the results studies published mainly in the last 3 years, due to the requirements of the journal for the maximum amount of work and the number of sources.

Context-dependent effects of CCN2 on β-cell mass expansion and indicators of cell stress in the setting of acute and chronic stress.

Stimulation of functional β-cell mass expansion can be beneficial for the treatment of type 2 diabetes. Our group has previously demonstrated that the matricellular protein CCN2 can induce β-cell mass expansion during embryogenesis, and postnatally during pregnancy and after 50% β-cell injury. The mechanism by which CCN2 stimulates β-cell mass expansion is unknown. However, CCN2 does not induce β-cell proliferation in the setting of euglycemic and optimal functional β-cell mass. We thus hypothesized that β-cell stress is required for responsiveness to CCN2 treatment. In this study, a doxycycline-inducible β-cell-specific CCN2 transgenic mouse model was utilized to evaluate the effects of CCN2 on β-cell stress in the setting of acute (thapsigargin treatment ex vivo) or chronic [high-fat diet or leptin receptor haploinsufficiency (db/+) in vivo] cellular stress. CCN2 induction during 1 wk or 10 wk of high-fat diet or in db/+ mice had no effect on markers of β-cell stress. However, CCN2 induction did result in a significant increase in β-cell mass over high-fat diet alone when animals were fed high-fat diet for 10 wk, a duration known to induce insulin resistance. CCN2 induction in isolated islets treated with thapsigargin ex vivo resulted in upregulation of the gene encoding the Nrf2 transcription factor, a master regulator of antioxidant genes, suggesting that CCN2 further activates this pathway in the presence of cell stress. These studies indicate that the potential of CCN2 to induce β-cell mass expansion is context-dependent and that the presence of β-cell stress does not ensure β-cell proliferation in response to CCN2.NEW & NOTEWORTHY CCN2 promotes β-cell mass expansion in settings of suboptimal β-cell mass. Here, we demonstrate that the ability of CCN2 to induce β-cell mass expansion in the setting of β-cell stress is context-dependent. Our results suggest that β-cell stress is necessary but insufficient for CCN2 to increase β-cell proliferation and mass. Furthermore, we found that CCN2 promotes upregulation of a key antioxidant transcription factor, suggesting that modulation of β-cell oxidative stress contributes to the actions of CCN2.

Development of Therapeutic Agents with a Novel Mechanism of Action Targeting Pancreatic β-Cells for Diabetes.

Although diabetes is associated with an increased risk of various diseases, including cancer and infectious diseases, no definitive cure has yet been found. Long-term treatment for blood glucose control significantly reduces the QOL. Pancreatic β-cells are the only cells that can lower blood glucose levels by secreting insulin. Therefore, maintaining insulin-secreting β-cells is crucial in preventing the progression of diabetes and improving the QOL. We have investigated the mechanisms for the regulation of insulin secretion, the prevention of β-cell apoptosis, and the increase in β-cell mass. In particular, we have elucidated the involvement of type I diacylglycerol kinase (DGK) in the regulation of insulin secretion and the effects of nitric oxide (NO) signaling and natural products in suppressing β-cell death. In addition, we have elucidated the function of DGKδ as a suppressor of β-cell proliferation. This review introduces the findings of our study leading to development of novel anti-diabetic therapeutics that targets pancreatic β-cells.

Signaling pathways that regulate adaptive β‐cell proliferation for the treatment of diabetes

The decline in β-cell mass due to the failure of β-cell compensation is one cause of the development of type 2 diabetes. Therefore, elucidation of the mechanism by which an adaptive increase in β-cell mass occurs in vivo will lead to the development of a cure for diabetes. Insulin and insulin receptor (IR)-mediated signaling pathways play an important role in the mechanism that increases β-cell mass by compensatory β-cell proliferation in response to chronic insulin resistance. However, whether IR is required for compensatory β-cell proliferation remains controversial in some situations. It might be possible that IR acts as a scaffold for the signaling complex independent of its ligand. It has also been reported that the forkhead box protein M1/polo-like kinase 1/centromere protein A pathway plays a central role in adaptive β-cell proliferation during diet-induced obesity, hyperglycemia, pregnancy, aging and acute insulin resistance. We recently reported that the cross-talk of islets with fat tissue, in addition to the liver, through humoral factors is involved in adaptive β-cell proliferation. This accommodative response of β-cell proliferation through adipocytes was observed particularly under an acute insulin resistance state in an IR/insulin signal-independent and forkhead box protein M1/polo-like kinase 1/centromere protein A pathway-dependent manner. A remaining barrier for the treatment of human diabetes using β-cells is the differences between human and rodent islets. In this review, the focus is on signaling pathways that regulate adaptive β-cell proliferation for the treatment of diabetes considering the abovementioned issues.

The role of preproglucagon peptides in regulating β-cell morphology and responses to streptozotocin-induced diabetes.

Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the β-cell is altered after metabolic stress, such as high-fat diet or the β-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in β-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (GcgNull) mice and mice with Gcg expression either specifically within the pancreas (GcgΔPanc) or the intestine (GcgΔIntest). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in GcgNull mice compared with wild-type mice. When Gcg was functional only in the intestine, plasma glucagon-like peptide-1 (GLP-1) levels were fully restored but these mice did not have any additional protection from STZ-induced diabetes. Pancreatic Gcg reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, GcgNull mice had increased pancreas mass via both α- and β-cell hyperplasia and reactivation of Gcg in the intestine normalized β- but not α-cell mass, whereas pancreatic reactivation normalized both β- and α-cell mass. GcgNull and GcgΔIntest mice maintained higher β-cell mass after treatment with STZ compared with control and GcgΔPanc mice. Although in vivo insulin response to glucose was normal, global lack of Gcg impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of Gcg either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal Gcg reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of β-cell mass in the GcgNull mice compensated for decreased individual β-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes.NEW & NOTEWORTHY We examined the role of Gcg on β-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased β-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized β-cell mass and glucose-stimulated insulin secretion. Increased β-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes.

Harnessing Human Pluripotent Stem Cell-Derived Pancreatic In Vitro Models for High-Throughput Toxicity Testing and Diabetes Drug Discovery.

The long-standing goals in diabetes research are to improve β-cell survival, functionality and increase β-cell mass. Current strategies to manage diabetes progression are still not ideal for sustained maintenance of normoglycemia, thereby increasing demand for the development of novel drugs. Available pancreatic cell lines, cadaveric islets, and their culture methods and formats, either 2D or 3D, allow for multiple avenues of experimental design to address diverse aims in the research setting. More specifically, these pancreatic cells have been employed in toxicity testing, diabetes drug screens, and with careful curation, can be optimized for use in efficient high-throughput screenings (HTS). This has since spearheaded the understanding of disease progression and related mechanisms, as well as the discovery of potential drug candidates which could be the cornerstone for diabetes treatment. This book chapter will touch on the pros and cons of the most widely used pancreatic cells, including the more recent human pluripotent stem cell-derived pancreatic cells, and HTS strategies (cell models, design, readouts) that can be used for the purpose of toxicity testing and diabetes drug discovery.

A Novel Small-molecule Activator of Lyn Kinase for the Treatment of Type 1 Diabetes

It is recently known that individuals with long-standing type 1 diabetes (T1D) still have surviving functional β cells. Thus, strategies to promote β-cell protection/replication should be used in the adjuvant therapy of T1D. Our lab has extensively characterized Lyn kinase as a critical regulator of β-cell mass. We herein hypothesized that pharmacological activation of Lyn could stimulate β-cell regeneration and improve glucose control in animal models of T1D. A short treatment of 7 days with MLR1023, a specific activator of Lyn, was sufficient to improve glucose tolerance, and to induce a 2-fold increase in β-cell mass in diabetic NOD mice.

γ-aminobutyric acid modulates α-cell hyperplasia but not β-cell regeneration induced by glucagon receptor antagonism in type 1 diabetic mice.

To investigate whether treatment with γ-aminobutyric acid (GABA) alone or in combination with glucagon receptor (GCGR) monoclonal antibody (mAb) exerted beneficial effects on β-cell mass and α-cell mass, and to explore the origins of the regenerated β-cells in mice with type 1 diabetes (T1D). Streptozotocin (STZ)-induced T1D mice were treated with intraperitoneal injection of GABA (250μg/kg per day) and/or REMD 2.59 (a GCGR mAb, 5mg/kg per week), or IgG dissolved in PBS for 8weeks. Plasma hormone levels and islet cell morphology were evaluated by ELISA and immunofluorescence, respectively. The origins of the regenerated β-cells were analyzed by double-immunostaining, α-cell lineage-tracing and BrdU-tracing studies. After the 8-week treatment, GABA or GCGR mAb alone or in combination ameliorated hyperglycemia in STZ-induced T1D mice. GCGR mAb upregulated plasma insulin level and increased β-cell mass, and GABA appeared to have similar effects in T1D mice. However, combination treatment did not reveal any additive or synergistic effect. Interestingly, the GCGR mAb-induced increment of plasma glucagon level and α-cell mass was attenuated by the combined treatment of GABA. In addition, duct-derived β-cell neogenesis and α-to-β cell conversion but not β-cell proliferation contributed to the increased β-cell mass in T1D mice. These results suggested that GABA attenuated α-cell hyperplasia but did not potentiates β-cell regeneration induced by GCGR mAb in T1D mice. Our findings provide novel insights into a combination treatment strategy for β-cell regeneration in T1D.

Pleiotrophin Expression and Actions in Pancreatic β-Cells.

Pleiotrophin (PTN) is a heparin-binding cytokine that is widely expressed during early development and increases in maternal circulation during pregnancy.Aged PTN-deficient mice exhibit insulin resistance, suggesting a role in metabolic control. The objectives of this study were to determine if PTN is expressed in mouse pancreatic β-cells in young vs. adult animals, and its effects on DNA synthesis, β-cell gene expression and glucose-stimulated insulin secretion (GSIS). The Ptn gene was expressed in isolated fractions of young mouse β-cells, especially within immature β-cells with low glucose transporter 2 expression. Expression was retained in the adult pancreas but did not significantly change during pregnancy. PTN and its receptor, phosphotyrosine phosphatase-β/ζ, were also expressed in the proliferative INS1E β-cell line. Fluorescence immunohistochemistry showed that PTN peptide was present in islets of Langerhans in adult mice, associated predominantly with β-cells. The percentage of β-cells staining for PTN did not alter during mouse pregnancy, but intense staining was seen during β-cell regeneration in young mice following depletion of β-cells with streptozotocin. Incubation of INS1E cells with PTN resulted in an increased DNA synthesis as measured by Ki67 localization and increased expression of Pdx1 and insulin. However, both DNA synthesis and GSIS were not altered by PTN in isolated adult mouse islets. The findings show that Ptn is expressed in mouse β-cells in young and adult life and could potentially contribute to adaptive increases in β-cell mass during early life or pregnancy.

A high-fat diet catalyzes progression to hyperglycemia in mice with selective impairment of insulin action in Glut4-expressing tissues

Insulin resistance impairs postprandial glucose uptake through glucose transporter type 4 (GLUT4) and is the primary defect preceding type 2 diabetes. We previously generated an insulin-resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in the muscle, adipose, and neuronal subpopulations. However, the rate of diabetes in GIRKO mice remained low prior to 6 months of age on normal chow diet (NCD), suggesting that additional factors/mechanisms are responsible for adverse metabolic effects driving the ultimate progression of overt diabetes. In this study, we characterized the metabolic phenotypes of the adult GIRKO mice acutely switched to high-fat diet (HFD) feeding in order to identify additional metabolic challenges required for disease progression. Distinct from other diet-induced obesity (DIO) and genetic models (e.g., db/db mice), GIRKO mice remained leaner on HFD feeding, but developed other cardinal features of insulin resistance syndrome. GIRKO mice rapidly developed hyperglycemia despite compensatory increases in β-cell mass and hyperinsulinemia. Furthermore, GIRKO mice also had impaired oral glucose tolerance and a limited glucose-lowering benefit from exendin-4, suggesting that the blunted incretin effect contributed to hyperglycemia. Secondly, GIRKO mice manifested severe dyslipidemia while on HFD due to elevated hepatic lipid secretion, serum triglyceride concentration, and lipid droplet accumulation in hepatocytes. Thirdly, GIRKO mice on HFD had increased inflammatory cues in the gut, which were associated with the HFD-induced microbiome alterations and increased serum lipopolysaccharide (LPS). In conclusion, our studies identified important gene/diet interactions contributing to diabetes progression, which might be leveraged to develop more efficacious therapies.

Reduced insulin sensitivity and increased β/α cell mass is associated with reduced hepatic insulin-degrading enzyme activity in pregnant rats

AimsPregnancy is associated with the development of a transitory insulin resistance that parallels with the upregulation of pancreatic β-cell function and mass. These metabolic adaptations guarantee the higher insulin demand, but there is no evidence of whether insulin clearance contributes to this process. Thus, we investigated some of the hepatic parameters related to insulin clearance during rat pregnancy. We also investigated some molecular parameters in the hypothalamus. Main methodsWe evaluated the body mass and food intake, insulin sensitivity, β- and α-cell masses, insulin clearance based on an exogenous insulin load, hepatic insulin-degrading enzyme (IDE) activity, and hepatic and hypothalamic protein content of IDE and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) in three periods of gestation in Wistar rats. Key findingsIn the first week of pregnancy, both insulin sensitivity and clearance increased, a pattern that inverted in the third week of gestation (reduced insulin sensitivity and clearance). Diminished insulin clearance was associated with lower hepatic IDE activity and higher pancreatic β- and α-cell masses. No alteration in the hepatic IDE and CEACAM protein content was observed throughout pregnancy, but hypothalamic IDE protein content was significantly reduced in the late gestation period. SignificanceIn conclusion, elevated insulin demand in the late period of gestation occurs not only as a result of increased β-cell mass and function but also by a potential reduction in hepatic insulin clearance. Knowing this physiological process may be valuable when considering gestational diabetes mellitus results from a failure in insulin supply during pregnancy.

Glucokinase is required for high-starch diet-induced β-cell mass expansion in mice.

Aims/IntroductionWe aimed to determine whether glucokinase is required for β‐cell mass expansion induced by high‐starch diet (HSTD)‐feeding, as has been shown in its high‐fat diet‐induced expansion.Materials and MethodsEight‐week‐old male wild‐type (Gck+/+ ) or glucokinase haploinsufficient (Gck+/− ) mice were fed either a normal chow (NC) or an HSTD for 15 weeks. The bodyweight, glucose tolerance, insulin sensitivity, insulin secretion and β‐cell mass were assessed.ResultsBoth HSTD‐fed Gck+/+ and Gck+/− mice had significantly higher bodyweight than NC‐fed mice. Insulin and oral glucose tolerance tests revealed that HSTD feeding did not affect insulin sensitivity nor glucose tolerance in either the Gck+/+ or Gck+/− mice. However, during the oral glucose tolerance test, the 15‐min plasma insulin concentration after glucose loading was significantly higher in the HSTD group than that in the NC group for Gck+/+ , but not for Gck+/− mice. β‐Cell mass was significantly larger in HSTD‐fed Gck+/+ mice than that in NC‐fed Gck+/+ mice. In contrast, the β‐cell mass of the HSTD‐fed Gck+/− mice was not different from that of the NC‐fed Gck+/− mice.ConclusionsThe results showed that HSTD feeding would increase pancreatic β‐cell mass and insulin secretion in Gck+/+ , but not Gck+/− mice. This observation implies that glucokinase in β‐cells would be required for the increase in β‐cell mass induced by HSTD feeding.

Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.

Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing β-Cell Mass in db/db Mice.

Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related to excess glucose signaling by glucokinase activation toward β-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as β-cell function and mass using a mouse model of type 2 diabetes. Our results showed that in db/db mice with glucokinase haploinsufficiency, glucose tolerance was ameliorated by augmented insulin secretion associated with the increase in β-cell mass when compared with db/db mice. Gene expression profiling and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db mice was associated with lower expression of stress-related genes, greater expression of transcription factors involved in the maintenance and maturation of β-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve β-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signaling in β-cells by inhibiting glucokinase could prevent β-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving β-cell mass. Therefore, glucokinase inactivation in β-cells, paradoxically, could be a potential strategy for the treatment of type 2 diabetes.

TGF-β Signaling in Pancreatic Islet β Cell Development and Function.

Pancreatic islet beta cells (β-cells) synthesize and secrete insulin in response to rising glucose levels and thus are a prime target in both major forms of diabetes. Type 1 diabetes ensues due to autoimmune destruction of β-cells. On the other hand, the prevailing insulin resistance and hyperglycemia in type 2 diabetes (T2D) elicits a compensatory response from β-cells that involves increases in β-cell mass and function. However, the sustained metabolic stress results in β-cell failure, characterized by severe β-cell dysfunction and loss of β-cell mass. Dynamic changes to β-cell mass also occur during pancreatic development that involves extensive growth and morphogenesis. These orchestrated events are triggered by multiple signaling pathways, including those representing the transforming growth factor β (TGF-β) superfamily. TGF-β pathway ligands play important roles during endocrine pancreas development, β-cell proliferation, differentiation, and apoptosis. Furthermore, new findings are suggestive of TGF-β's role in regulation of adult β-cell mass and function. Collectively, these findings support the therapeutic utility of targeting TGF-β in diabetes. Summarizing the role of the various TGF-β pathway ligands in β-cell development, growth and function in normal physiology, and during diabetes pathogenesis is the topic of this mini-review.

Imeglimin preserves islet β-cell mass in Type 2 diabetic ZDF rats.

ObjectivesType 2 diabetes (T2D) is driven by progressive dysfunction and loss of pancreatic β‐cell mass. Imeglimin is a first‐in‐class novel drug candidate that improves glycaemia and glucose‐stimulated insulin secretion in preclinical models and patients. Given evidence that imeglimin can attenuate β‐cell dysfunction and protect β cells in vitro, we postulated that imeglimin could also exert longer term effects to prevent pancreatic β‐cell death and preserve functional β‐cell mass in vivo.MethodsZucker diabetic fatty (ZDF) male rats were treated by oral gavage with imeglimin at a standard dose of 150 mg/kg or vehicle, twice daily for five weeks. At treatment completion, oral glucose tolerance tests were performed in fasted animals before a thorough histomorphometry and immunohistochemical analysis was conducted on pancreas tissue slices to assess cellular composition and disease status.ResultsImeglimin treatment significantly improved glucose‐stimulated insulin secretion (augmentation of the insulinogenic index) and improved glycaemia. Both basal insulinaemia and pancreatic insulin content were also increased by imeglimin. In ZDF control rats, islet structure was disordered with few β‐cells; after imeglimin treatment, islets appeared healthier with more normal morphology in association with a significant increase in insulin‐positive β‐cells. The increase in β‐cell mass was associated with a greater degree of β‐cell proliferation in the presence of reduced apoptosis. Unexpectedly, a decrease in as a α‐cell mass was also documented due to an apparent antiproliferative effect of imeglimin on this cell type.ConclusionIn male ZDF rats, chronic imeglimin treatment corrects a paramount component of type 2 diabetes progression: progressive loss of functional β‐cell mass. In addition, imeglimin may also moderate a‐cell turnover to further ameliorate hyperglycaemia. Cumulatively, these cellular effects suggest that imeglimin may provide for disease modifying effects to preserve functional β‐cell mass.

GABA requires GLP-1R to exert its pancreatic function during STZ challenge.

Gamma-aminobutyric acid (GABA) administration attenuates streptozotocin (STZ)-induced diabetes in rodent models with unclear underlying mechanisms. We found that GABA and Sitagliptin possess additive effect on pancreatic β-cells, which prompted us to ask the existence of common or unique targets of GLP-1 and GABA in pancreatic β-cells. Effect of GABA on expression of thioredoxin-interacting protein (TxNIP) was assessed in the INS-1 832/13 (INS-1) cell line, WT and GLP-1R-/- mouse islets. GABA was also orally administrated in STZ-challenged WT or GLP-1R-/- mice, followed by immunohistochemistry assessment of pancreatic islets. Effect of GABA on Wnt pathway effector β-catenin (β-cat) was examined in INS-1 cells, WT and GLP-1R-/- islets. We found that GABA shares a common feature with GLP-1 on inhibiting TxNIP, while this function was attenuated in GLP-1R-/- islets. In WT mice with STZ challenge, GABA alleviated several 'diabetic syndromes', associated with increased β-cell mass. These features were virtually absent in GLP-1R-/- mice. Knockdown TxNIP in INS-1 cells increased GLP-1R, Pdx1, Nkx6.1 and Mafa levels, associated with increased responses to GABA or GLP-1 on stimulating insulin secretion. Cleaved caspase-3 level can be induced by high-glucose, dexamethasone, or STZ in INS-1 cell, while GABA treatment blocked the induction. Finally, GABA treatment increased cellular cAMP level and β-cat S675 phosphorylation in WT but not GLP-1R-/- islets. We, hence, identified TxNIP as a common target of GABA and GLP-1 and suggest that, upon STZ or other stress challenge, the GLP-1R-cAMP-β-cat signaling cascade also mediates beneficial effects of GABA in pancreatic β-cell, involving TxNIP reduction.