Insulin Demand Research Articles

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

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

Bio-Hacking Better Health-Leveraging Metabolic Biochemistry to Maximise Healthspan.

In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and reduced synthesis. Hyperinsulinaemia enforces glucose fuelling, consuming 4 NAD+ to produce 2 acetyl moieties; beta-oxidation, ketolysis and acetoacetate consume 2, 1 and 0, respectively. This decreases sirtuin, PARPs and oxidative management capacity, leaving reactive oxygen species to diffuse to the cytosol, upregulating aerobic glycolysis, NF-kB and cell division signalling. Also, oxidising cardiolipin, reducing oxidative phosphorylation (OXPHOS) and apoptosis ability; driving a tumourigenic phenotype. Over time, increasing senescent/pathological cell populations occurs, increasing morbidity and mortality. Beta-hydroxybutyrate, an antioxidant, metabolite and signalling molecule, increases synthesis of antioxidants via preserving NAD+ availability and enhancing OXPHOS capacity. Fasting and ketogenic diets increase ketogenesis concurrently decreasing insulin secretion and demand; hyperinsulinaemia inhibits ketogenesis. Lifestyles that maintain lower insulin levels decrease antioxidant catabolism, additionally increasing their synthesis, improving oxidative stress management and mitochondrial function and, subsequently, producing healthier cells. This supports tissue and organ health, leading to a better healthspan, the first challenge that must be overcome in the pursuit of youthful longevity.

A Review on alternative treatments of gestational diabetes mellitus: Focus on phytotherapy

Gestational diabetes (GDM) refers to glucose intolerance which manifests as hyperglycemia during pregnancy. Some features related to GDM include insulin resistance, an abnormal increase in weight and increased risks of complications during delivery. Severe cases of GDM can result in hyperinsulinemia, macrosomia, obesity, and type II diabetes in the offspring. Due to changes in placental hormones including estrogen and progesterone observed in normal pregnancy, there is a decrease in the sensitivity of target organs to insulin resulting in a compensatory production of insulin to maintain glucose homeostasis. However, this inability of the β-cells to effectively handle this high demand for insulin can result in GDM. Exercise and dietary therapies are the major treatments for GDM and if these two are not effective, oral hypoglycemic agents and insulin injections are usually considered. There have been concerns about the safety of these oral hypoglycemic agents hence, alternative therapies including the use of medicinal plants are being considered. This review, therefore, aims to explore the modes of action of some medicinal plants, functional foods and bioactive compounds as alternative treatments for gestational diabetes. Google Scholar, ScienceDirect, PubMed, ResearchGate were searched for relevant articles published between 2010-2023 using the keywords “medicinal plants and gestational diabetes”, “bioactive compounds and gestational diabetes”, “functional foods and gestational diabetes”. From the research articles, some of the mechanisms of action include reduced blood glucose level, improved insulin sensitivity, lipid profile and oxidative status, increased body weight of offspring. However, further scientific evidence is required to validate and re-validate their safety and efficacy.Keywords: Gestational diabetes mellitus, hyperglycemia, pregnancy, glucose intolerance, insulin resistance, bioactive compounds.

Model predictive control to account for prolonged changes in insulin requirements following exercise in type 1 diabetes

Automated insulin delivery systems are becoming increasingly available in the treatment of type 1 diabetes. They can improve glycemic outcomes while reducing patient burden, but good glycemic control during and after exercise remains challenging. Exercise causes substantial and prolonged changes in insulin sensitivity that consequently affect insulin requirements, and can lead to late-onset hypoglycemia if not accounted for.Here, we present a model predictive control algorithm that adjusts insulin delivery during the recovery period to improve glycemic outcomes after aerobic exercise. The algorithm continuously estimates insulin sensitivity from glucose measurements via an unscented Kalman filter. It integrates the estimate by continuously updating the target insulin input as well as the process model to account for changing insulin demands. The proposed approach is generic and transferable to other control formulations.We evaluate our new control strategy in-silico using a validated diabetes patient model with aerobic exercise. We consider a virtual patient population in full-day simulations including a wide variety of exercise scenarios covering moderate to high intensities and different timing and duration of the exercise. We demonstrate improved glycemic outcomes over night following a day with exercise for all scenarios and show robustness of our approach to common disturbances.

Variant rs17619600 in the gene encoding serotonin receptor 2B (HTR2B) increases the risk of gestational diabetes mellitus: a case–control study

BackgroundDuring pregnancy, the increase in maternal insulin resistance is compensated by hyperplasia and increased function of maternal pancreatic beta cells; the failure of this compensatory mechanism is associated with gestational diabetes mellitus (GDM). Serotonin participates in beta cell adaptation, acting downstream of the prolactin pathway; the blocking of serotonin receptor B (HTR2B) signaling in pregnant mice impaired beta cell expansion and caused glucose intolerance. Thus, given the importance of the serotoninergic system for the adaptation of beta cells to the increased insulin demand during pregnancy, we hypothesized that genetic variants (single nucleotide polymorphisms [SNPs]) in the gene encoding HTR2B could influence the risk of developing GDM.MethodsThis was a case–control study. Five SNPs (rs4973377, rs765458, rs10187149, rs10194776, and s17619600) in HTR2B were genotyped by real-time polymerase chain reaction in 453 women with GDM and in 443 pregnant women without GDM.ResultsOnly the minor allele C of SNP rs17619600 conferred an increased risk for GDM in the codominant model (odds ratio [OR] 2.15; 95% confidence interval [CI] 1.53–3.09; P < 0.0001) and in the rare dominant model (OR 2.32; CI 1.61–3.37; P < 0.0001). No associations were found between the SNPs and insulin use, maternal weight gain, newborn weight, or the result of postpartum oral glucose tolerance test (OGTT). In the overall population, carriers of the XC genotype (rare dominant model) presented a higher area under the curve (AUC) of plasma glucose during the OGTT, performed for diagnostic purposes, compared with carriers of the TT genotype of rs17619600.ConclusionsSNP rs17619600 in the HTR2B gene influences glucose homeostasis, probably affecting insulin release, and the presence of the minor allele C was associated with a higher risk of GDM.

Benefits of Huangqi Herbal Treatment for Patients with Diabetes Mellitus

Introduction: Diabetes mellitus (DM) is a metabolic disorder caused by abnormalities in insulin secretion and an imbalance between insulin supply and demand. In Traditional Chinese Medicine (TCM), diabetes mellitus is better known as Xiao Ke. In TCM, Xiao Ke disease is caused by internal heat exhaustion deficiency, and one of the traditional treatments for diabetes is the herbal Huang Qi (Radix astragali). Method: This research is a case study, where the researcher makes an in-depth observation of the use of Huang Qi herbs in diabetes mellitus patients. Result and Discussion: The results of diabetes treatment in the initial observation of the patient's blood sugar were 152 mg/dL, and in week 4, it decreased to 86 mg/dL. Isoflavonoids, saponins, and polysaccharides are the three main types of beneficial compounds that have pharmacological activity and therapeutic efficacy in many diseases, one of which is diabetes. In TCM, Huang Qi is beneficial for tonifying Qi and strengthening Yang in spleen Qi deficiency so that the spleen can increase its effectiveness in transformation and transportation. Conclusion: The results of the treatment of diabetes mellitus, or Xiao Ke, using Huang Qi herbs are proven to be able to reduce blood sugar levels in diabetics.

1498-P: Preemptive Insulin Supplementation for Islet Graft Protection, Optimal Blood Glucose Control, and Fetal Development during the Pregnancy in Insulin-Independent Patient after Islet Transplantation

Pregnancy increases metabolic demand for insulin, which may lead to the exhaustion of intraportally transplanted islets and postgestational hyperglycemia. Here we report a successful long-term preservation of islet graft function after two subsequent pregnancies while applying preemptive insulin supplementation. 29-year-old female with T1DM achieved long-term insulin independence with HbA1c &amp;lt;5.8% after a single intraportal islet transplant. Before conception, mycophenolate was replaced with azathioprine and tacrolimus target trough level was decreased to 4-6ng/ml. The patient became pregnant twice, 5 years and 7.5 years after her islet transplantation. During the first and second pregnancy patient preemptively supplemented with insulin up to 35-70u/day and up to 35 units daily, respectively to target fasting blood glucose below 90mg/ml. Postpartum the patient was successfully weaned off insulin maintaining optimal blood glucose control with HbA1c below 5.7%. Islet graft function before and after the pregnancy remained optimal as reflected by BETA-2 above 17 and comparable c-peptide secretion and peak blood glucose levels below 130mg/ml during the 8.5-year follow-up in Mixed Meal Tolerance Test. Both newborns were premature and delivered at 34 weeks with emergent c-sections due to preeclampsia. Unfortunately, the first newborn died due to necrotizing enterocolitis. The second child has been developing appropriately up-to-date three months after her birth. Our report confirms that insulin supplementation during pregnancy in insulin-independent patients after islet transplantation was safe and effective in maintaining optimal blood glucose control and islet graft function in the long term. It also underscores the high-risk nature of pregnancy in islet transplant recipients and the need for close clinical monitoring. Disclosure S.Gondek: None. L.Wang: None. M.Tibudan: None. R.Barth: None. J.Fung: None. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.Ogledzinski: None. W.Lin: None. K.Milejczyk: None. B.Juengel: None. L.Potter: None. P.J.Bachul: None. L.Basto: None. L.Perea: None.

213-LB: Impact of Alpha- and Beta-Cell Dysfunction on the Longitudinal Progression to Type 2 Diabetes

T2D results from glucotoxicity-driven impairment of insulin secretion which limits compensation for increased insulin demand. Increased demand results from insulin resistance and elevated hepatic glucose production (HGP). Increased HGP can result either from insulin resistance or alpha-cell dysregulation leading to hyperglucagonemia. Objectives: To investigate with a mathematical model whether increased HGP and progression to T2D could result from impaired glucagon secretion in addition to insulin resistance. Toward this end, we developed a realistic model of beta-cell growth, death and function and interfaced it with a previously validated model of glucose-insulin-glucagon dynamics. Methods: A previously published model of longitudinal progression to T2D over years was extended to include glucagon dynamics. The beta cell mass/function equation was parametrized by interfacing with results from a previously published paper on modeling isoglycemic, intravenous glucose infusion tests to obtain snapshots of the metabolic state. The range of parameters observed in the cohort studied cover the gamut from normal, insulin sensitive to normal, insulin resistant to T2D patients, and was used to calibrate the model. The influence of insulin resistance and impaired glucagon secretion as they develop over time was included in the combined model to see how they impact the balance between enhanced and impaired beta-cell function and mass. Results and Conclusion: When only insulin sensitivity was allowed to decrease, the normal subjects did not transition to T2D. This was because the glucose levels were not elevated sufficiently to upset the balance between enhancement and impairment and lead to a catastrophic decline in insulin secretion. Including time-dependent impairment of glucagon suppression, in addition to declining insulin sensitivity, was sufficient to lead to the significant imbalance required to progress to T2D diabetes. Thus, both appear to be required. Disclosure V. Subramanian: None. A. Sherman: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK131328)

1257-P: Changes in Circulating Pancreatic Islet-Specific MicroRNA-375 Levels and Improvements in Insulin Sensitivity and Glucose Metabolism in Response to Weight-Loss Diets with Different Compositions of Macronutrients—The POUNDS Lost Trial

Pancreatic islet-specific microRNA-375 (miR-375) regulates insulin secretion and has an essential role in β-cell compensation when escalating insulin demand. We recently reported that changes in circulating miR-375 were associated with improved diabetogenic fat depots. Here, we investigated whether changes in circulating miR-375 induced by weight-loss diet interventions with different macronutrient intakes (fat, carbohydrate (carb), and protein) were related to improved insulin sensitivity and glucose metabolism. This study included participants from the POUNDS Lost trial with available data on circulating miR-375-3p at baseline (n=520) and its changes from baseline to 6 months after weight-loss diet interventions (n=508). At baseline, higher levels of miR-375 were related to lower degrees of BMI, total adipose tissue mass, and whole-body fat content (P &amp;lt;0.05 for all). There was a significant increase in miR-375 levels from baseline to 6 months (P by paired t-test &amp;lt;0.001). We found that associations of changes in miR-375 with changes in fasting insulin, glucose, and insulin resistance (HOMA-IR) were significantly modified by carb and fat intakes (P interaction &amp;lt;0.05 for all). In response to a low-fat and high-carb diet, a greater increase in miR-375 was significantly associated with larger reductions of fasting insulin and HOMA-IR at 6 months, regardless of baseline miR-375 levels. On the other hand, in response to a high-fat and low-carb diet intervention, there were significant positive associations between miR-375 changes and changes in glucose, insulin, and HOMA-IR. These results suggest that changes in the pancreatic islet-specific miRNA expression are associated with weight-loss diet intervention outcomes on insulin sensitivity and glucose metabolism. Different macronutrient intakes may modify these associations. Disclosure Y.Heianza: None. Q.Xue: None. H.Ma: None. G.Bray: Advisory Panel; Medifast, Inc., Herbalife International of America, Inc. F.Sacks: None. L.Qi: None. Funding National Institutes of Health (DK091718, DK100383, DK115679)

Persistence of long-term insulin independence after islet transplantation and two subsequent pregnancies.

Pregnancy increases metabolic demand for insulin and may lead to the exhaustion of intraportally transplanted islets and post-gestational hyperglycemia. To prevent these complications, we implemented preemptive insulin supplementation during two subsequent pregnancies in an insulin-independent islet transplant recipient. This strategy resulted in optimal blood glucose control during the pregnancies, the preservation of the optimal islet graft function and the postpartum maintenance of long-term insulin independence.

Alpine Diet in Valmalenco (Lombardy, Italy): Nutritional Features of Spontaneous Plants and Traditional Dishes.

Along the Alps, the Alpine diet is considered to be one of the most common nutritional models. Next to traditional animal-based products, spontaneous plants of the territory are collected and eaten. The aim of this study is to evaluate the nutritional features of selected autochthonous plants of the territory and the typical recipe of green gnocchi. The analyses of proximate composition, carotenoid, total phenol, and mineral contents in raw and cooked plant samples and the chemical composition and in vitro starch digestibility in green and control gnocchi were performed. Except for Aruncus dioicus, all the wild plants contained high levels of carotenoids (15-20 mg/100 g FW), mainly as xanthophylls. Rumex acetosa showed the highest levels of total phenols (554 mg GAE/100 g FW), and Urtica dioica can be considered to be a good dietary source of iron, calcium, and magnesium (4.9, 410, and 72 mg/100 g FW). Cooking significantly decreased the potassium and magnesium contents in all wild species, and total phenols and carotenoids in Aruncus dioicus, Blitum bonus-henricus, and Silene vulgaris (p < 0.05). The slowly digestible fraction of starch (%SDS/available starch), which is inversely correlated to insulin demand, was significantly increased in green gnocchi compared to matched control gnocchi (p < 0.05). Traditional consumption of spontaneous plants in the Alpine regions might increase the dietary intakes of several bioactive substances and contribute to cover the nutritional needs of micronutrients.

Development of human insulin precursor expressed from P.pastoris-X33 in a 10L-fermenter

Human insulin is a hormone that regulate blood glucose in human. Due to the vital role of insulin and the trend of diabetic case globally, insulin demand has been rise in the world. Indonesia as a country that had diabetic patient more than 10 million people in 2017 is still imported raw material of human insulin. The development of production process of human insulin is needed in order to support government objective to be independence in medicine aspect. Human insulin precursor (HIP) expressed from a Pichia pastoris X33/pD902-IP had been developed and optimised in a small scale. However, the scaling up in fermenter 10L has not been studied. Using a 10L-fermenter the fermentation system of P.pastoris X33/pD902-IP was developed. Fermentation done in 120 hours using a basal salt medium (half concentration) for the vegetative and induction media. To induce HIP expression, methanol is fed by pulse strategy with a gradient concentration 1-3% for 48 hours. The dry cell weight (DCW) and HIP titer were 72 g/L and 192 mg/L, respectively. This development is the first fermentation process of HIP in fermenter 10L in Indonesia.

Nutrient regulation of the islet epigenome controls adaptive insulin secretion.

Adaptation of the islet β cell insulin-secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. β Cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.

Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo

Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand.

Deciphering the gene regulatory network associated with anti-apoptosis in the pancreatic islets of type 2 diabetes mice using computational approaches

&lt;abstract&gt; &lt;p&gt;Type 2 diabetes (T2D) is a major global health problem often caused by the inability of pancreatic islets to compensate for the high insulin demand due to apoptosis. However, the complex mechanisms underlying the activation of apoptosis and its counter process, anti-apoptosis, during T2D remain unclear. In this study, we employed bioinformatics and systems biology approaches to understand the anti-apoptosis-associated gene expression and the biological network in the pancreatic islets of T2D mice. First, gene expression data from four peripheral tissues (islets, liver, muscle and adipose) were used to identify differentially expressed genes (DEGs) in T2D compared to non-T2D mouse strains. Our comparative analysis revealed that &lt;italic&gt;Gm2036&lt;/italic&gt; is upregulated across all four tissues in T2D and is functionally associated with increased cytosolic Ca&lt;sup&gt;2+&lt;/sup&gt; levels, which may alter the signal transduction pathways controlling metabolic processes. Next, our study focused on islets and performed functional enrichment analysis, which revealed that upregulated genes are significantly associated with sucrose and fructose metabolic processes, as well as negative regulation of neuron apoptosis. Using the Ingenuity Pathway Analysis (IPA) tool of QIAGEN, gene regulatory networks and their biological effects were analyzed, which revealed that glucose is associated with the underlying change in gene expression in the islets of T2D; and an activated gene regulatory network—containing upregulated &lt;italic&gt;CCK, ATF3, JUNB, NR4A1, GAST&lt;/italic&gt; and downregulated &lt;italic&gt;DPP4&lt;/italic&gt;—is possibly inhibiting apoptosis of islets and β-cells in T2D. Our computational-based study has identified a putative regulatory network that may facilitate the survival of pancreatic islets in T2D; however, further validation in a larger sample size is needed. Our results provide valuable insights into the underlying mechanisms of T2D and may offer potential targets for developing more efficacious treatments.&lt;/p&gt; &lt;/abstract&gt;

Soluble T-cadherin promotes pancreatic β-cell proliferation by upregulating Notch signaling

Endogenous humoral factors that link systemic and/or local insulin demand topancreatic β-cells have not been identified. Here, we demonstrated that T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin primarily expressed in vascular endothelial cells and cardiac and skeletal muscle cells, but not in pancreatic β-cells, was secreted as soluble forms and was important for β-cell proliferation. Cdh13 (T-cadherin) knockout mice exhibited impaired glucose handling due to attenuated β-cell proliferation under high-fat diet conditions. The gene expression analyses indicated the impairment in cell cycle and Notch signaling in the islets of T-cadherin knockout mice under high-fat diet conditions. In streptozotocin-induced diabetes, the replacement of soluble T-cadherin improved β-cell mass and blood glucose levels in T-cadherin knockout mice. Recombinant soluble T-cadherin upregulated Notch signaling in cultured murine islets. We concluded that soluble T-cadherin could work as an endogenous humoral factor whose signaling pathways including Notch signaling regulate β-cell proliferation under diabetic conditions in mice.

Vitamin D Repletion and AA/EPA Intake in Children with Type 1 Diabetes: Influences on Metabolic Status.

A cohort of 40 children with T1D was recruited, mean age 9.7 years (7.1; 13), with onset of T1D in the last 5 years: some at onset (n: 20, group A) and others after 18.0 ± 5 months (n: 20; group B). Twenty healthy children were compared as control subjects (CS). Dietary intakes were assessed through a diary food frequency questionnaire. Moreover, dried blood spots were used to test AA/EPA ratio by gas chromatography. T1D children had a lower percentage of sugar intake (p &lt; 0.02) than CS. Furthermore, group B introduced a greater amount of AA with the diet (g/day; p &lt; 0.05) than CS (p &lt; 0.01) and group A (p &lt; 0.01). Children with an AA/EPA ratio ≤ 22.5 (1st quartile) required a lower insulin demand and had higher 25OHD levels than those who were in the higher quartiles (p &lt; 0.05). Subjects with DKA (9/40) had levels of 25OHD (p &lt; 0.05) and C-peptide (p &lt; 0.05) lower than those without DKA. Moreover, analyzing the food questionnaire in group A, subjects with DKA showed a lower intake of proteins, sugars, fiber (g/day; p&lt; 0.05), vitamin D, EPA, and DHA (g/day; p &lt; 0.01) compared to subjects without DKA. Non-linear associations between vitamin D intake (p &lt; 0.0001; r2:0.580) and linear between EPA intake and C-peptide (p &lt; 0.05; r: 0.375) were found in all subjects. The study shows a relationship between vitamin D status, AA/EPA ratio, and metabolic state, probably due to their inflammatory and immune mechanisms. A different bromatological composition of the diet could impact the severity of the onset.

Single-nucleus RNA-Seq reveals singular gene signatures of human ductal cells during adaptation to insulin resistance.

Adaptation to increased insulin demand is mediated by β cell proliferation and neogenesis, among other mechanisms. Although it is known that pancreatic β cells can arise from ductal progenitors, these observations have been limited mostly to the neonatal period. We have recently reported that the duct is a source of insulin-secreting cells in adult insulin-resistant states. To further explore the signaling pathways underlying the dynamic β cell reserve during insulin resistance, we undertook human islet and duct transplantations under the kidney capsule of immunodeficient NOD/SCID-γ (NSG) mouse models that were pregnant, were insulin-resistant, or had insulin resistance superimposed upon pregnancy (insulin resistance + pregnancy), followed by single-nucleus RNA-Seq (snRNA-Seq) on snap-frozen graft samples. We observed an upregulation of proliferation markers (e.g., NEAT1) and expression of islet endocrine cell markers (e.g., GCG and PPY), as well as mature β cell markers (e.g., INS), in transplanted human duct grafts in response to high insulin demand. We also noted downregulation of ductal cell identity genes (e.g., KRT19 and ONECUT2) coupled with upregulation of β cell development and insulin signaling pathways. These results indicate that subsets of ductal cells are able to gain β cell identity and reflect a form of compensation during the adaptation to insulin resistance in both physiological and pathological states.

Thiosulfate sulfurtransferase prevents hyperglycemic damage to the zebrafish pronephros in an experimental model for diabetes

Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), also known as Rhodanese, was initially discovered as a cyanide detoxification enzyme. However, it was recently also found to be a genetic predictor of resistance to obesity-related type 2 diabetes. Diabetes type 2 is characterized by progressive loss of adequate β-cell insulin secretion and onset of insulin resistance with increased insulin demand, which contributes to the development of hyperglycemia. Diabetic complications have been replicated in adult hyperglycemic zebrafish, including retinopathy, nephropathy, impaired wound healing, metabolic memory, and sensory axonal degeneration. Pancreatic and duodenal homeobox 1 (Pdx1) is a key component in pancreas development and mature beta cell function and survival. Pdx1 knockdown or knockout in zebrafish induces hyperglycemia and is accompanied by organ alterations similar to clinical diabetic retinopathy and diabetic nephropathy. Here we show that pdx1-knockdown zebrafish embryos and larvae survived after incubation with thiosulfate and no obvious morphological alterations were observed. Importantly, incubation with hTST and thiosulfate rescued the hyperglycemic phenotype in pdx1-knockdown zebrafish pronephros. Activation of the mitochondrial TST pathway might be a promising option for therapeutic intervention in diabetes and its organ complications.

Roles of FoxM1-driven basal β-cell proliferation in maintenance of β-cell mass and glucose tolerance during adulthood.

ABSTRACTAims/IntroductionWhether basal β‐cell proliferation during adulthood is involved in maintaining sufficient β‐cell mass, and if so, the molecular mechanism(s) underlying basal β‐cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in ‘adaptive’ β‐cell proliferation, which facilitates rapid increases in β‐cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of β‐cell FoxM1 in ‘basal’ β‐cell proliferation under normal conditions and in the maintenance of sufficient β‐cell mass as well as glucose homeostasis during adulthood.Materials and MethodsFoxM1 deficiency was induced specifically in β‐cells of 8‐week‐old mice, followed by analyzing its short‐ (2 weeks) and long‐ (10 months) term effects on β‐cell proliferation, β‐cell mass, and glucose tolerance.ResultsFoxM1 deficiency suppressed β‐cell proliferation at both ages, indicating critical roles of FoxM1 in basal β‐cell proliferation throughout adulthood. While short‐term FoxM1 deficiency affected neither β‐cell mass nor glucose tolerance, long‐term FoxM1 deficiency suppressed β‐cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long‐term β‐cell FoxM1 deficiency. Therefore, β‐cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long‐term β‐cell FoxM1 deficiency.ConclusionsBasal low‐level proliferation of β‐cells during adulthood is important for maintaining sufficient β‐cell mass and good glucose tolerance and β‐cell FoxM1 underlies this mechanism. Preserving β‐cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age.