Beta-cell Mass Research Articles

1774-P: Verapamil Prevents Decline of IGF-1 in Subjects with T1D

We have previously found that the calcium channel blocker and anti-hypertensive, verapamil, promotes functional beta cell mass and improves glucose homeostasis in diabetic mice and in humans with recent-onset type 1 diabetes (T1D). Surprisingly, we also discovered that verapamil reversed the T1D-associated elevation in T-follicular-helper cell markers in peripheral blood monocytes, suggesting that it also has immunomodulatory effects. Now, a global proteomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of serum samples from T1D subjects at baseline and after 1 year of receiving verapamil or placebo identified insulin-like growth factor 1 (IGF-1) as one of the top proteins with significantly changed abundance over time. Specifically, IGF-1 abundance decreased during year 1 after diagnosis in subjects with T1D receiving placebo, which is consistent with the lower IGF-1 levels reported previously in individuals with T1D as compared to age- and sex-matched healthy subjects. Interestingly, this decline was blunted in subjects receiving verapamil. To further confirm the LC-MS/MS results, we also measured patient serum levels of IGF-1 by ELISA. The results were very much in alignment and again revealed significantly decreased IGF-1 levels in the placebo group a year after diagnosis, but no such effect in the verapamil treatment group, suggesting that verapamil prevents the decline of IGF-1 in subjects with T1D. Of note, IGF-1, which is primarily produced in liver, acts on many tissues, including pancreatic islets promoting pathways involved in cell growth, differentiation and glucose metabolism. In beta cells, IGF-1 has also been shown to control apoptosis. Thus, our results reveal yet another previously unappreciated pathway affected by verapamil that may contribute to the beneficial effects observed with this treatment in the context of T1D. Disclosure G.Xu: None. J.Chen: None. B.Lu: None. W.Qian: None. A.Shalev: Other Relationship; TIXiMED. Funding National Institutes of Health (R01DK078752, U01DK120379)

1731-P: Determining the Mechanistic Relationship between Maternal Diet and Postnatal Beta-Cell Function

Previous studies have shown that intrauterine nutrient levels impact the risk of diabetes in offspring postnatally, but the molecular mechanisms underpinning this phenomenon remain poorly characterized. We hypothesize that maternal malnutrition during gestation may disrupt the fetus’ epigenetic program during development, leading to insufficient functional beta-cell mass postnatally. To this end, we show that: 1) endocrine progenitor cells with different DNA methylation signatures give rise to beta-cell subsets with different functional and proliferative capacity; 2) de novo DNA methyltransferases Dnmt3a and Dnmt3b are downregulated in embryonic endocrine progenitors exposed to a low-protein or high-fat diet in utero, while DNA demethyltransferases Tet1 and Tet2 are upregulated; 3) beta cells in offspring of dams fed a low-protein or high-fat diet during gestation demonstrate reduced expression of genes associated with beta cell maturation and function both during development and postnatally (e.g. Pdx1, MafA); 4) islets from adult mice exposed to maternal high-fat diet in utero have compromised insulin secretion when treated with sustained high glucose or free fatty acids in vitro. These findings are consistent with a model in which abnormal DNA methylation in islet progenitors is a key mechanism by which maternal nutrients mediate postnatal functional beta-cell mass and diabetes risk. Disclosure S.Nevills: None. G.Gu: None. Funding National Institutes of Health (5R01DK125696-03, 5T32HD007502-25)

1754-P: Reduced Incretin Effect Predicts Diabetes Appearance in a Cohort of Nondiabetic Subjects after Acute Beta-Cell Mass Reduction

In type 2 diabetes incretin effect (IE) is reduced but still contributes to 20-35% of insulin response to oral glucose. One reason is the impairment of GIP and GLP1 effects. The role of IE in nondiabetic people is still under debate. In this study we evaluated changes in GLP1 levels, differential β-cell responses and IE during oral vs intravenous stimuli in nondiabetic humans before and after pancreatoduodenectomy (PD). We enrolled 37 nondiabetic patients affected by periampullary nonmalignant neoplasms scheduled for PD. Subjects underwent a 2-h hyperglycemic clamp (HC), a 830 kcal mixed meal test (MMT), and an oral glucose tolerance test (OGTT) before and after PD. GLP1 secretion was calculated during MMT stimulation. β-cell glucose sensitivity (βCGS, pmol·min−1m−2·mM−1) was calculated as the ratio of insulin secretion and glucose increments during both HC and MMT. IE was calculated as the ratio of βCGS obtained during MMT and HC. Based on post-PD OGTT, we divided nondiabetic subjects into 3 groups according to glucose tolerance after PD: normal glucose tolerance (postNGT, n=11), impaired glucose tolerance (postIGT, n=15), or diabetes (postDM, n=11). Before surgery, postIGT subjects exhibited increased GLP1 secretion during MMT compared to the other 2 groups (GLP1 AUC: postIGT 12638±688 vs postNGT 6994±1773 vs postDM 6443±1687 pmol/L·min, P<0.05). Further, a similar βCGS was observed in the 3 groups following HC stimulation (postNGT 95.2±15.5 vs postIGT 64.3±8.72 vs postDM 73.8±11.8, P=0.2), while a scaled reduction in βCGS was observed in postIGT and post-DM following MMT (postNGT 206±50.0 vs postIGT 111±19.9 vs postDM 88.2±8.45, P<0.05). Accordingly, we observed a scaled reduction of IE in postIGT and postDM groups (postNGT 2.35±0.52 vs post-IGT 1.37±0.13 vs post-DM 0.86±0.18, P<0.05). Our data show that GLP1 secretion increases in people at risk of IGT, possibly to compensate reduced IE, which seems to predict DM appearance after β-cell mass reduction. Disclosure G.Di giuseppe: None. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. A.Giaccari: Speaker's Bureau; Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi. T.Mezza: None. C.Cefalo: None. S.Moffa: None. G.Ciccarelli: None. L.Soldovieri: None. F.Cinti: None. U.Capece: None. F.Impronta: None. A.Mari: Consultant; Eli Lilly and Company. Funding Università Cattolica del Sacro Cuore; European Foundation for the Study of Diabetes; Ministero della Salute

Glucose-stimulated insulin secretion depends on FFA1 and Gq in neonatal mouse islets

Aims/hypothesisAfter birth, the neonatal islets gradually acquire glucose-responsive insulin secretion, a process that is subjected to maternal imprinting. Although NEFA are major components of breastmilk and insulin secretagogues, their role for functional maturation of neonatal beta cells is still unclear. NEFA are the endogenous ligands of fatty acid receptor 1 (FFA1, encoded by Ffar1 in mice), a Gq-coupled receptor with stimulatory effect on insulin secretion. This study investigates the role of FFA1 in neonatal beta cell function and in the adaptation of offspring beta cells to parental high-fat feeding.MethodsWild-type (WT) and Ffar1−/− mice were fed high-fat (HFD) or chow diet (CD) for 8 weeks before mating, and during gestation and lactation. Blood variables, pancreas weight and insulin content were assessed in 1-, 6-, 11- and 26-day old (P1–P26) offspring. Beta cell mass and proliferation were determined in P1–P26 pancreatic tissue sections. FFA1/Gq dependence of insulin secretion was evaluated in isolated islets and INS-1E cells using pharmacological inhibitors and siRNA strategy. Transcriptome analysis was conducted in isolated islets.ResultsBlood glucose levels were higher in CD-fed Ffar1−/− P6-offspring compared with CD-fed WT P6-offspring. Accordingly, glucose-stimulated insulin secretion (GSIS) and its potentiation by palmitate were impaired in CD Ffar1−/− P6-islets. In CD WT P6-islets, insulin secretion was stimulated four- to fivefold by glucose and five- and sixfold over GSIS by palmitate and exendin-4, respectively. Although parental HFD increased blood glucose in WT P6-offspring, it did not change insulin secretion from WT P6-islets. In contrast, parental HFD abolished glucose responsiveness (i.e. GSIS) in Ffar1−/− P6-islets. Inhibition of Gq by FR900359 or YM-254890 in WT P6-islets mimicked the effect of Ffar1 deletion, i.e. suppression of GSIS and of palmitate-augmented GSIS. The blockage of Gi/o by pertussis toxin (PTX) enhanced (100-fold) GSIS in WT P6-islets and rendered Ffar1−/− P6-islets glucose responsive, suggesting constitutive activation of Gi/o. In WT P6-islets, FR900359 cancelled 90% of PTX-mediated stimulation, while in Ffar1−/− P6-islets it completely abolished PTX-elevated GSIS. The secretory defect of Ffar1−/− P6-islets did not originate from insufficient beta cells, since beta cell mass increased with the offspring’s age irrespective of genotype and diet. In spite of that, in the breastfed offspring (i.e. P1–P11) beta cell proliferation and pancreatic insulin content had a genotype- and diet-driven dynamic. Under CD, the highest proliferation rate was reached by the Ffar1−/− P6 offspring (3.95% vs 1.88% in WT P6), whose islets also showed increased mRNA levels of genes (e.g. Fos, Egr1, Jun) typically high in immature beta cells. Although parental HFD increased beta cell proliferation in both WT (4.48%) and Ffar1−/− (5.19%) P11 offspring, only the WT offspring significantly increased their pancreatic insulin content upon parental HFD (5.18 µg under CD to 16.93 µg under HFD).Conclusions/interpretationFFA1 promotes glucose-responsive insulin secretion and functional maturation of newborn islets and is required for adaptive offspring insulin secretion in the face of metabolic challenge, such as parental HFD.Graphical

578 Impact of Acellular Fish Skin on Wound Healing in a Standardized Pre-Clinical Model

Abstract Introduction Acellular fish skin has proven to be effective in acute and chronic wound healing. Multiple human studies have to date demonstrated that products from acellular skin grafts accelerate wound healing and are efficacious, safe and cost-effective. Here we wanted to investigate the effects of acellular fish skin on wound healing in a pig model. Methods The primary aim of this study was to investigate the effects of acellular fish skin on wound healing progression in a full thickness skin defect pig model. The superiority of fish skin was tested in a standardized pig model and compared to normal wound healing (without acellular fish skin grafts) (n=6). The experiments were carried out in male landrace pigs with a mean weight of 28.8 +/- 2.8 kg at the start of the study. The experiment lasted for 21 days. Wound documentation, thermography, photo-documentation and wound perfusion were carried out 5, 9, 14 and 21 days post wounding. Results Clinical evaluation of the wounds showed that there were no major differences between the different dressings on day 5 post wounding. On the next evaluation days ( day 9, 14 and 21 post wounding) the acellular fish skin showed rapid epithelialization with minimal wound contraction, when compared to untreated control wounds, which showed significant signs of contraction (i.e. star-like wound appearance). Wound area measurements clearly showed that wound size upon treatment with the acellular fish skin and the untreated control rapidly and significantly decreased through contraction of untreated controls. However, wound perfusion seemed to be affected by the treatment with acellular fish skin. Thermography at day 9 and 14 showed higher surface temperature in treated wounds (d9 and d14; p = 0.0005), followed by a trend towards increased oxygenation and perfusion, analyzed by laser speckle and hyperspectral imaging. Conclusions Acellular fish skin seems to provide fast wound healing and counteract wound contraction. Untreated wounds showed a slight trend of faster healing, but showed significant signs of wound contraction which points towards wound healing by contraction but not by epithelialization. This contraction was not observed in wounds treated with acellular fish skin. Applicability of Research to Practice Standardized preclinical models give valuable insights to the mechanisms of wound healing. Porcine in vivo models are of special interest as the porcine skin is highly similar to human skin with regard to anatomical and physiological structures. Therefore, data generated in such models, as described here, show a high rate of translatability to the human situation.

579 Histopathological Changes in the Endocrine Pancreas of Rats During the Acute Period of Burns

Abstract Introduction Severe burn victims experience a systemic inflammatory response and a hypermetabolic response. Presence of hyperglycemia, even with concurrent hyperinsulinism, is indicative of insufficient insulin secretion from beta cells to overcome the glycemia. However, the underlying molecular mechanisms of beta-cell failure in patients with acquired insulin resistance after burn trauma are not clearly understood. Our aim in this study was to describe the histopathological changes in the pancreatic islets secondary to severe burns in an experimental animal model. Methods Fourteen Wistar albino rats were randomly divided into 2 groups: the sham group and the burn group. A full-thickness burn model was designed to induce a burn of 25% total body surface area. Seven days after burn induction and sham procedure, pancreatectomy was performed. Pancreatic tissues were examined under light microscopy, and islet size and cellularity were calculated. Results The histopathologic examination was unremarkable, but the mean number of islets per pancreatic tissue was lower in the burn group than in the sham group. We observed a significant difference in the mean number of cells per one islet between the 2 groups, with the cell count higher in the burn group (P < .05). Conclusions During the acute phase of burn injury in rats, we observed a decrease in the number of pancreatic islets with remarkable hypercellularity. Further studies are needed to determine the histological and cellular basis of these changes. Applicability of Research to Practice Major burn injury causes severe alterations in beta-cell mass, which increases and decreases both function and mass to maintain the glycemic level within a very narrow physiological range. Patients with acute and prolonged hyperglycemia can have complications leading to impaired wound healing, increased skin graft loss, increased muscle protein catabolism, increased incidence of infections, and mortality. Therefore, a detailed understanding of the pancreatic changes under different preexisting conditions and therapeutic interventions in the context of a major burn trauma might guide treatment options.

MTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation.

The mammalian target of rapamycin inhibitors (mTOR-Is, Sirolimus, and Everolimus) are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions (including proteins and lipids synthesis, autophagy, cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis). Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival (by accelerating the development of the chronic allograft damage) and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several in vitro and in animal models, the real impact of mTOR-Is on PTDM is still debated and the entire biological machinery is poorly recognized. Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics (particularly for the clinical translational research), we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.

Glucolipotoxic Stress-Induced Mig6 Desensitizes EGFR Signaling and Promotes Pancreatic Beta Cell Death.

A loss of functional beta cell mass is a final etiological event in the development of frank type 2 diabetes (T2D). To preserve or expand beta cells and therefore treat/prevent T2D, growth factors have been considered therapeutically but have largely failed to achieve robust clinical success. The molecular mechanisms preventing the activation of mitogenic signaling pathways from maintaining functional beta cell mass during the development of T2D remain unknown. We speculated that endogenous negative effectors of mitogenic signaling cascades impede beta cell survival/expansion. Thus, we tested the hypothesis that a stress-inducible epidermal growth factor receptor (EGFR) inhibitor, mitogen-inducible gene 6 (Mig6), regulates beta cell fate in a T2D milieu. To this end, we determined that: (1) glucolipotoxicity (GLT) induces Mig6, thereby blunting EGFR signaling cascades, and (2) Mig6 mediates molecular events regulating beta cell survival/death. We discovered that GLT impairs EGFR activation, and Mig6 is elevated in human islets from T2D donors as well as GLT-treated rodent islets and 832/13 INS-1 beta cells. Mig6 is essential for GLT-induced EGFR desensitization, as Mig6 suppression rescued the GLT-impaired EGFR and ERK1/2 activation. Further, Mig6 mediated EGFR but not insulin-like growth factor-1 receptor nor hepatocyte growth factor receptor activity in beta cells. Finally, we identified that elevated Mig6 augmented beta cell apoptosis, as Mig6 suppression reduced apoptosis during GLT. In conclusion, we established that T2D and GLT induce Mig6 in beta cells; the elevated Mig6 desensitizes EGFR signaling and induces beta cell death, suggesting Mig6 could be a novel therapeutic target for T2D.

Metabolomics analysis of islet regeneration in partial pancreatectomy mice reveals increased levels of long-chain fatty acids and activated cAMP signaling pathway

Islet regeneration is a complex process involving multiple metabolic adaptions, but the specific characterization of the islet metabolome in relation to cell proliferation has not been established. This study aimed to investigate the metabolomic changes of regenerative islets from partial pancreatectomy (Ppx) mice and speculate underlying mechanisms. Islet samples were collected from C57/BL6 mice undergoing 70–80% Ppx or sham surgery, followed by analyses of glucose homeostasis, islet morphology, and untargeted metabolomics profiles using liquid chromatography-tandem mass spectrometry (LC-MS/MS). There is no difference in blood glucose and body weight between sham and Ppx mice. After surgery, the Ppx mice showed impaired glucose tolerance, increased Ki67 positive beta cells, and elevated beta-cell mass. LC-MS/MS analysis identified fourteen differentially changed metabolites in islets of Ppx mice, including long-chain fatty acids (e.g., docosahexaenoic acid) and amino acid derivatives (e.g., creatine). Pathway analysis based on the KEGG database revealed five significantly enriched signaling pathways including cAMP signaling pathway. Further immunostaining assay on pancreatic tissue sections showed the levels of p-CREB, a transcription factor downstream of cAMP, elevated in islets from Ppx mice. In conclusion, our results demonstrate that islet regeneration involves metabolic alterations in long-chain fatty acids and amino acid derivatives, as well as the activation of the cAMP signaling pathway.

The Proliferative and Functional Roles of CEBP/A in Ins-1 832/13 Cells and Primary Rat Islets

The beta cell transcription factor Nkx6.1, when overexpressed in primary rodent and human islets, is sufficient to enhance beta cell proliferation, increase insulin secretion and enhance cell survival. We have sought to define the transcriptional targets of Nkx6.1 that allow for its ability to increase functional beta cell mass. We have shown that Nkx6.1 induces expression of the transcription factor CEBP/A. CEBP/A overexpression is sufficient to induce proliferation of Ins-1 832/13 cells and primary rat islets. CEBP/A overexpression enhances glucose stimulated insulin secretion from primary rat islets, while decreasing total insulin content. Finally, CEBPa overexpression protects Ins-1 832/13 cells from thapsigargin and glucolipotoxicity induced cell death but fails to protect against etoposide and camptothecin induced cell death. These data suggest that CEBP/A may play a critical role in Nkx6.1 mediated expansion of functional beta cell mass through a endoplasmic reticulum stress-mediated pathway. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Irisin administration restores beta-cell functional mass in a mouse model of type 2 diabetes

Aim: Irisin is a hormone secreted by skeletal muscle able to improve metabolic homeostasis. Serum irisin levels are reduced in type 2 diabetes (T2D), while exogenous irisin administration improves glycemic control in diabetic mice. We have previously demonstrated that irisin promotes beta-cell survival and function both in vitro and in vivo in healthy wild type mice. We have also demonstrated that irisin restores the defective glucose-stimulated insulin secretion (GSIS) and reduces apoptosis in human pancreatic islets from patients with T2D. Nevertheless, the beta-cellular effects of in vivo irisin administration to T2D mice are still unknown. Methods: C57Bl/6 mice (n = 8) were fed a high-fat diet (HFD, 60% of energy deriving from fat) for 10 weeks and then intraperitoneally injected with streptozotocin (STZ, 100 mg/kg) to induce diabetes. Four standard diet (SD)-fed mice were used as control. HFD/STZ mice were treated with 0.5 μg/g irisin (n = 4) or vehicle (n = 4), for 14 days. Fasting glycemia, insulinemia, body weight, glucose tolerance, and pancreatic islet function were assessed. Pancreatic islet architecture was also evaluated through immunofluorescence analyses. Results: Compared to SD mice, HFD/STZ mice showed higher fasting glycemia and body weight, glucose intolerance, and reduced GSIS; in addition, HFD/STZ mice showed reduced islet volume (-78%), beta-cell area (-35%), and insulin content (-60%), and increased alpha-cell area (+54%). Irisin administration significantly restored glycemia (-31%), body weight (-13%), glucose tolerance (-27%), GSIS (+23%), islet volume (+61%), beta-cell area (+34%) and alpha-cell area (-49%), and insulin content (+36%). Of note, irisin induced a 9-fold increase in beta-cell proliferation rate. Conclusions: These results show that irisin improves glycemic homeostasis and restores the functional beta-cell mass when administered in vivo to diabetic mice, probably by promoting beta-cell proliferation.

FORMULATION, OPTIMISATION AND CHARACTERISATION OF ARTOCARPUS ALTILIS LOADED LIPOSOMES FOR ANTIDIABETIC ACTIVITY

Background: Artocarpus altilis primarily comprises phenolic phytoconstituents such as flavonoids, arylbenzofurans, and stilbenoids. This plant has traditionally been known to have glycemic control properties. This study used a design expert approach to create and test Artocarpus altilis liposomes for antidiabetic activity. Methods: Design Expert 13 software developed and optimised the liposomal formulation. The optimised formulation was tested for antidiabetic properties in a Streptozotocin-nicotinamide-induced model for 28 days, followed by an oral glucose tolerance test. Biochemical parameters such as lipid profile and glycogen content were also measured at the end of the study. Results: The formation of Artocarpus altilis loaded liposomes was confirmed by SEM analysis and entrapment efficiency. Further pharmacology research revealed that Artocarpus altilis lowers blood glucose levels by sensitising insulin secretion, maintaining pancreatic beta cell mass, increasing glucose uptake in skeletal muscles, and regulating lipid profiles. Conclusion: The current study reflected the formulation of Artocarpus altilis loaded liposomes, its entrapment efficiency, stability study, and its antidiabetic evaluation based on in vivo results.

Non-invasive imaging of functional pancreatic islet beta-cell mass in people with type 1 diabetes mellitus.

To investigate whether manganese-enhanced magnetic resonance imaging can assess functional pancreatic beta-cell mass in people with type 1 diabetes mellitus. In a prospective case-control study, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma C-peptide concentrations respectively. Pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = -0.054, p = 0.880). There were no statistically significant correlations between manganese uptake and age, body-mass index, or glycated haemoglobin. There was strong intra-observer (mean difference: 0.31 (limits of agreement -1.42 to 2.05) mL/100 g of tissue/min; intra-class correlation, ICC = 0.99), inter-observer (-1.23 (-5.74 to 3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan (-0.72 (-2.9 to 1.6) mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake. Manganese-enhanced magnetic resonance imaging provides a potential reproducible non-invasive measure of functional beta-cell mass in people with type 1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoring disease progression and assessing novel immunomodulatory interventions.

Vitamin D in Diabetes: Uncovering the Sunshine Hormone's Role in Glucose Metabolism and Beyond.

Over the last decades, epidemiology and functional studies have started to reveal a pivotal role of vitamin D in both type 1 and type 2 diabetes pathogenesis. Acting through the vitamin D receptor (VDR), vitamin D regulates insulin secretion in pancreatic islets and insulin sensitivity in multiple peripheral metabolic organs. In vitro studies and both T1D and T2D animal models showed that vitamin D can improve glucose homeostasis by enhancing insulin secretion, reducing inflammation, reducing autoimmunity, preserving beta cell mass, and sensitizing insulin action. Conversely, vitamin D deficiency has been shown relevant in increasing T1D and T2D incidence. While clinical trials testing the hypothesis that vitamin D improves glycemia in T2D have shown conflicting results, subgroup and meta-analyses support the idea that raising serum vitamin D levels may reduce the progression from prediabetes to T2D. In this review, we summarize current knowledge on the molecular mechanisms of vitamin D in insulin secretion, insulin sensitivity, and immunity, as well as the observational and interventional human studies investigating the use of vitamin D as a treatment for diabetes.

Dual effect of RYGB on the entero-insular axis: How GLP-1 is enhanced by surgical duodenal exclusion

BackgroundThe role of the ileum and Glucagon Like Peptide-1 (GLP-1) secretion in the pathophysiological processes underlying the effects of Roux-en-Y gastric bypass (RYGB) on type 2 Diabetes mellitus (T2DM) improvement has been previously determined. However, the roles of duodenal exclusion and Glucose Insulinotropic Peptide (GIP) secretion change is not clear. To clarify this aspect, we compared the pathophysiological mechanisms triggered by RYGB, which implies the early arrival of food to the ileum with duodenal exclusion, and through pre-duodenal ileal transposition (PdIT), with early arrival of food to the ileum but without duodenal exclusion, in a nondiabetic rodent model. Methods: We compared plasma and insulin, glucose (OGTT), GIP and GLP-1 plasma levels, ileal and duodenal GIP and GLP-1 tissue expression and beta-cell mass for n = 12 Sham-operated, n = 6 RYGB-operated, and n = 6 PdIT-operated Wistar rats. Results: No surgery induced changes in blood glucose levels after the OGTT. However, RYGB induced a significant and strong insulin response that increased less in PdIT animals. Increased beta-cell mass was found in RYGB and PdIT animals as well as similar GLP-1 secretion and GLP-1 intestinal expression. However, differential GIP secretion and GIP duodenal expression were found between RYGB and PdIT. Conclusion: The RYGB effect on glucose metabolism is mostly due to early ileal stimulation; however, duodenal exclusion potentiates the ileal response within RYGB effects through enhanced GIP secretion.

Paternal sleep deprivation induces metabolic perturbations in male offspring via altered LRP5 DNA methylation of pancreatic islets.

Diabetes and metabolic perturbation are global health challenges. Sleep insufficiency may trigger metabolic dysregulation leading to diabetes. However, the intergenerational transmission of this environmental information is not clearly understood. The research objective was to determine the possible effect of paternal sleep deprivation on the metabolic phenotype of the offspring and to investigate the underlying mechanism of epigenetic inheritance. Male offspring of sleep-deprived fathers exhibit glucose intolerance, insulin resistance, and impaired insulin secretion. In these SD-F1 offspring, a reduction in beta cell mass and proliferation of beta cells were observed. Mechanistically, in pancreatic islets of SD-F1 offspring, we identified alterations in DNA methylation at the promoter region of the LRP5(LDL receptor related protein 5)gene, a coreceptor of Wnt signaling, resulting in downregulation of downstream effectors cyclin D1, cyclin D2, and Ctnnb1. Restoration of Lrp5 in the pancreas of SD-F1 male mice could improve impaired glucose tolerance and expression of cyclin D1, cyclin D2, and Ctnnb1. This study might significantly contribute to our understanding of the effects of sleeplessness on health and metabolic disease risk from the perspective of the heritable epigenome.

IDF2022-0608 Long-term exercise preserves pancreatic islet structure and beta-cell mass through attenuation of islet fibrosis

IDF2022-0608 Long-term exercise preserves pancreatic islet structure and beta-cell mass through attenuation of islet fibrosis

C-peptide Targets and Patient-centered Outcomes of Relevance to Cellular Transplantation for Diabetes.

C-peptide levels are a key measure of beta-cell mass following islet transplantation, but threshold values required to achieve clinically relevant patient-centered outcomes are not yet established. We conducted a cross-sectional retrospective cohort study evaluating patients undergoing islet transplantation at a single center from 1999 to 2018. Cohorts included patients achieving insulin independence without hypoglycemia, those with insulin dependence without hypoglycemia, and those with recurrent symptomatic hypoglycemia. Primary outcome was fasting C-peptide levels at 6 to 12 mo postfirst transplant; secondary outcomes included stimulated C-peptide levels and BETA-2 scores. Fasting and stimulated C-peptide and BETA-2 cutoff values for determination of hypoglycemic freedom and insulin independence were evaluated using receiver operating characteristic curves. We analyzed 192 patients, with 122 (63.5%) being insulin independent without hypoglycemia, 61 (31.8%) being insulin dependent without hypoglycemia, and 9 (4.7%) experiencing recurrent symptomatic hypoglycemia. Patients with insulin independence had a median (interquartile range) fasting C-peptide level of 0.66 nmol/L (0.34 nmol/L), compared with 0.49 nmol/L (0.25 nmol/L) for those being insulin dependent without hypoglycemia and 0.07 nmol/L (0.05 nmol/L) for patients experiencing hypoglycemia ( P < 0.001). Optimal fasting C-peptide cutoffs for insulin independence and hypoglycemia were ≥0.50 nmol/L and ≥0.12 nmol/L, respectively. Cutoffs for insulin independence and freedom of hypoglycemia using stimulated C-peptide were ≥1.2 nmol/L and ≥0.68 nmol/L, respectively, whereas optimal cutoff BETA-2 scores were ≥16.4 and ≥5.2. We define C-peptide levels and BETA-2 scores associated with patient-centered outcomes. Characterizing these values will enable evaluation of ongoing clinical trials with islet or stem cell therapies.

TXNIP overexpression in mice enhances streptozotocin-induced diabetes severity

Thioredoxin-interacting protein (TXNIP) is a key player in the endocrine pancreas; it induces beta cell apoptosis, such that TXNIP deficiency promotes beta cell survival. To study its function in more detail, we generated transgenic mice with ubiquitous overexpression of TXNIP. CBATXNIP/+ mice were investigated under basal conditions and after being challenged in diet-induced obesity (DIO) and streptozotocin-induced type 1 diabetes mellitus (T1DM) models. TXNIP overexpression caused no effect in the DIO model, contrasting to the already reported TXNIP-deficient mice. However, in the T1DM background, CBATXNIP/+ animals showed significantly enhanced blood glucose and increased glucose levels in a glucose tolerance test. Finally, the beta cell mass of CBATXNIP/+ transgenic animals in the T1DM model was significantly reduced compared to control littermates. Our study demonstrates that overexpression of TXNIP doesn't affect blood glucose parameters under basal conditions. However, overexpression of TXNIP in a T1DM model enhances the severity of the disease.

The Adaptor Protein NumbL Is Involved in the Control of Glucolipotoxicity-Induced Pancreatic Beta Cell Apoptosis.

Avoiding the loss of functional beta cell mass is critical for preventing or treating diabetes. Currently, the molecular mechanisms underlying beta cell death are partially understood, and there is a need to identify new targets for developing novel therapeutics to treat diabetes. Previously, our group established that Mig6, an inhibitor of EGF signaling, mediates beta cell death under diabetogenic conditions. The objective here was to clarify the mechanisms linking diabetogenic stimuli to beta cell death by investigating Mig6-interacting proteins. Using co-immunoprecipitation and mass spectrometry, we evaluated the binding partners of Mig6 under both normal glucose (NG) and glucolipotoxic (GLT) conditions in beta cells. We identified that Mig6 interacted dynamically with NumbL, whereas Mig6 associated with NumbL under NG, and this interaction was disrupted under GLT conditions. Further, we demonstrated that the siRNA-mediated suppression of NumbL expression in beta cells prevented apoptosis under GLT conditions by blocking the activation of NF-κB signaling. Using co-immunoprecipitation experiments, we observed that NumbL's interactions with TRAF6, a key component of NFκB signaling, were increased under GLT conditions. The interactions among Mig6, NumbL, and TRAF6 were dynamic and context-dependent. We proposed a model wherein these interactions activated pro-apoptotic NF-κB signaling while blocking pro-survival EGF signaling under diabetogenic conditions, leading to beta cell apoptosis. These findings indicated that NumbL should be further investigated as a candidate anti-diabetic therapeutic target.