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Glucose Regulates Microtubule Disassembly and the Dose of Insulin Secretion via Tau Phosphorylation.
Ho KH, Yang X, Osipovich AB, Cabrera O, Hayashi ML, Magnuson MA, Gu G, Kaverina I
(2020) Diabetes 69: 1936-1947
MeSH Terms: Animals, Cyclic AMP-Dependent Protein Kinases, Cyclin-Dependent Kinase 5, Glucose, Glycogen Synthase Kinase 3, Insulin Secretion, Insulin-Secreting Cells, Mice, Microtubules, Phosphorylation, Protein Kinase C, tau Proteins
Show Abstract · Added July 2, 2020
The microtubule cytoskeleton of pancreatic islet β-cells regulates glucose-stimulated insulin secretion (GSIS). We have reported that the microtubule-mediated movement of insulin vesicles away from the plasma membrane limits insulin secretion. High glucose-induced remodeling of microtubule network facilitates robust GSIS. This remodeling involves disassembly of old microtubules and nucleation of new microtubules. Here, we examine the mechanisms whereby glucose stimulation decreases microtubule lifetimes in β-cells. Using real-time imaging of photoconverted microtubules, we demonstrate that high levels of glucose induce rapid microtubule disassembly preferentially in the periphery of individual β-cells, and this process is mediated by the phosphorylation of microtubule-associated protein tau. Specifically, high glucose induces tau hyper-phosphorylation via glucose-responsive kinases GSK3, PKA, PKC, and CDK5. This causes dissociation of tau from and subsequent destabilization of microtubules. Consequently, tau knockdown in mouse islet β-cells facilitates microtubule turnover, causing increased basal insulin secretion, depleting insulin vesicles from the cytoplasm, and impairing GSIS. More importantly, tau knockdown uncouples microtubule destabilization from glucose stimulation. These findings suggest that tau suppresses peripheral microtubules turning over to restrict insulin oversecretion in basal conditions and preserve the insulin pool that can be released following stimulation; high glucose promotes tau phosphorylation to enhance microtubule disassembly to acutely enhance GSIS.
© 2020 by the American Diabetes Association.
2 Communities
2 Members
0 Resources
12 MeSH Terms
Myt Transcription Factors Prevent Stress-Response Gene Overactivation to Enable Postnatal Pancreatic β Cell Proliferation, Function, and Survival.
Hu R, Walker E, Huang C, Xu Y, Weng C, Erickson GE, Coldren A, Yang X, Brissova M, Kaverina I, Balamurugan AN, Wright CVE, Li Y, Stein R, Gu G
(2020) Dev Cell 53: 390-405.e10
MeSH Terms: Activating Transcription Factor 4, Animals, Cell Proliferation, DNA-Binding Proteins, Diabetes Mellitus, Female, Heat-Shock Proteins, Humans, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Stress, Physiological, Transcription Factors
Show Abstract · Added May 6, 2020
Although cellular stress response is important for maintaining function and survival, overactivation of late-stage stress effectors cause dysfunction and death. We show that the myelin transcription factors (TFs) Myt1 (Nzf2), Myt2 (Myt1l, Nztf1, and Png-1), and Myt3 (St18 and Nzf3) prevent such overactivation in islet β cells. Thus, we found that co-inactivating the Myt TFs in mouse pancreatic progenitors compromised postnatal β cell function, proliferation, and survival, preceded by upregulation of late-stage stress-response genes activating transcription factors (e.g., Atf4) and heat-shock proteins (Hsps). Myt1 binds putative enhancers of Atf4 and Hsps, whose overexpression largely recapitulated the Myt-mutant phenotypes. Moreover, Myt(MYT)-TF levels were upregulated in mouse and human β cells during metabolic stress-induced compensation but downregulated in dysfunctional type 2 diabetic (T2D) human β cells. Lastly, MYT knockdown caused stress-gene overactivation and death in human EndoC-βH1 cells. These findings suggest that Myt TFs are essential restrictors of stress-response overactivity.
Copyright © 2020 Elsevier Inc. All rights reserved.
3 Communities
1 Members
0 Resources
15 MeSH Terms
Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic β-Cells.
Osipovich AB, Stancill JS, Cartailler JP, Dudek KD, Magnuson MA
(2020) Diabetes 69: 1476-1491
MeSH Terms: Animals, Calcium, Cells, Cultured, Diet, High-Fat, Female, Gene Expression Regulation, Glucose, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mitochondria, Overnutrition, Sex Characteristics, Transcriptome
Show Abstract · Added April 28, 2020
A sustained increase in intracellular Ca concentration (referred to hereafter as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic β-cell failure. To determine the additive effects of excitotoxicity and overnutrition on β-cell function and gene expression, we analyzed the impact of a high-fat diet (HFD) on knockout mice. Excitotoxicity caused β-cells to be more susceptible to HFD-induced impairment of glucose homeostasis, and these effects were mitigated by verapamil, a Ca channel blocker. Excitotoxicity, overnutrition, and the combination of both stresses caused similar but distinct alterations in the β-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid β-oxidation, and mitochondrial biogenesis and their key regulator Overnutrition worsened excitotoxicity-induced mitochondrial dysfunction, increasing metabolic inflexibility and mitochondrial damage. In addition, excitotoxicity and overnutrition, individually and together, impaired both β-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of β-cell epigenetic and transcriptional program. Sex had an impact on all β-cell responses, with male animals exhibiting greater metabolic stress-induced impairments than females. Together, these findings indicate that a sustained increase in intracellular Ca, by altering mitochondrial function and impairing β-cell identity, augments overnutrition-induced β-cell failure.
© 2020 by the American Diabetes Association.
2 Communities
3 Members
0 Resources
15 MeSH Terms
The Peripheral Peril: Injected Insulin Induces Insulin Insensitivity in Type 1 Diabetes.
Gregory JM, Cherrington AD, Moore DJ
(2020) Diabetes 69: 837-847
MeSH Terms: Animals, Diabetes Mellitus, Type 1, Gene Expression Regulation, Humans, Insulin, Insulin Resistance
Show Abstract · Added April 22, 2020
Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable consistency and considerable magnitude. Although therapeutic innovations are continuing to normalize dysglycemia, a sizable body of data suggests a second metabolic abnormality-iatrogenic hyperinsulinemia-principally drives insulin resistance and its consequences in this population and has not been addressed. We review this evidence to show that injecting insulin into the peripheral circulation bypasses first-pass hepatic insulin clearance, which leads to the unintended metabolic consequence of whole-body insulin resistance. We propose restructuring insulin therapy to restore the physiological insulin balance between the hepatic portal and peripheral circulations and thereby avoid the complications of life-long insulin resistance. As technology rapidly advances and our ability to ensure euglycemia improves, iatrogenic insulin resistance will become the final barrier to overcome to restore normal physiology, health, and life in type 1 diabetes.
© 2020 by the American Diabetes Association.
0 Communities
2 Members
0 Resources
6 MeSH Terms
Ins1-Cre and Ins1-CreER Gene Replacement Alleles Are Susceptible To Silencing By DNA Hypermethylation.
Mosleh E, Ou K, Haemmerle MW, Tembo T, Yuhas A, Carboneau BA, Townsend SE, Bosma KJ, Gannon M, O'Brien RM, Stoffers DA, Golson ML
(2020) Endocrinology 161:
MeSH Terms: Alleles, Animals, Cells, Cultured, DNA Methylation, Female, Gene Silencing, HEK293 Cells, Humans, Insulin, Insulin-Secreting Cells, Integrases, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Organ Specificity, Recombination, Genetic
Show Abstract · Added May 12, 2020
Targeted gene ablation studies of the endocrine pancreas have long suffered from suboptimal Cre deleter strains. In many cases, Cre lines purportedly specific for beta cells also displayed expression in other islet endocrine cells or in a subset of neurons in the brain. Several pancreas and endocrine Cre lines have experienced silencing or mosaicism over time. In addition, many Cre transgenic constructs were designed to include the hGH mini-gene, which by itself increases beta-cell replication and decreases beta-cell function. More recently, driver lines with Cre or CreER inserted into the Ins1 locus were generated, with the intent of producing β cell-specific Cre lines with faithful recapitulation of insulin expression. These lines were bred in multiple labs to several different mouse lines harboring various lox alleles. In our hands, the ability of the Ins1-Cre and Ins1-CreER lines to delete target genes varied from that originally reported, with both alleles displaying low levels of expression, increased levels of methylation compared to the wild-type allele, and ultimately inefficient or absent target deletion. Thus, caution is warranted in the interpretation of results obtained with these genetic tools, and Cre expression and activity should be monitored regularly when using these lines.
© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
1 Communities
0 Members
0 Resources
18 MeSH Terms
Coregulator Sin3a Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response.
Yang X, Graff SM, Heiser CN, Ho KH, Chen B, Simmons AJ, Southard-Smith AN, David G, Jacobson DA, Kaverina I, Wright CVE, Lau KS, Gu G
(2020) Diabetes 69: 1219-1231
MeSH Terms: Aging, Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium, Cell Survival, Diabetes Mellitus, Female, Gene Expression Regulation, Developmental, Homeostasis, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Nerve Tissue Proteins, Repressor Proteins, Sin3 Histone Deacetylase and Corepressor Complex
Show Abstract · Added April 7, 2020
Swi-independent 3a and 3b (Sin3a and Sin3b) are paralogous transcriptional coregulators that direct cellular differentiation, survival, and function. Here, we report that mouse Sin3a and Sin3b are coproduced in most pancreatic cells during embryogenesis but become much more enriched in endocrine cells in adults, implying continued essential roles in mature endocrine cell function. Mice with loss of in endocrine progenitors were normal during early postnatal stages but gradually developed diabetes before weaning. These physiological defects were preceded by the compromised survival, insulin-vesicle packaging, insulin secretion, and nutrient-induced Ca influx of -deficient β-cells. RNA sequencing coupled with candidate chromatin immunoprecipitation assays revealed several genes that could be directly regulated by Sin3a in β-cells, which modulate Ca/ion transport, cell survival, vesicle/membrane trafficking, glucose metabolism, and stress responses. Finally, mice with loss of both and in multipotent embryonic pancreatic progenitors had significantly reduced islet cell mass at birth, caused by decreased endocrine progenitor production and increased β-cell death. These findings highlight the stage-specific requirements for the presumed "general" coregulators Sin3a and Sin3b in islet β-cells, with Sin3a being dispensable for differentiation but required for postnatal function and survival.
© 2020 by the American Diabetes Association.
2 Communities
2 Members
0 Resources
16 MeSH Terms
Transendothelial Insulin Transport is Impaired in Skeletal Muscle Capillaries of Obese Male Mice.
Williams IM, McClatchey PM, Bracy DP, Bonner JS, Valenzuela FA, Wasserman DH
(2020) Obesity (Silver Spring) 28: 303-314
MeSH Terms: Animals, Capillaries, Endothelium, Vascular, Insulin, Male, Mice, Mice, Obese, Muscle, Skeletal, Obesity
Show Abstract · Added March 30, 2020
OBJECTIVE - The continuous endothelium of skeletal muscle (SkM) capillaries regulates insulin's access to skeletal myocytes. Whether impaired transendothelial insulin transport (EIT) contributes to SkM insulin resistance (IR), however, is unknown.
METHODS - Male and female C57/Bl6 mice were fed either chow or a high-fat diet for 16 weeks. Intravital microscopy was used to measure EIT in SkM capillaries, electron microscopy to assess endothelial ultrastructure, and glucose tracers to measure indices of glucose metabolism.
RESULTS - Diet-induced obesity (DIO) male mice were found to have a ~15% reduction in EIT compared with lean mice. Impaired EIT was associated with a 45% reduction in endothelial vesicles. Despite impaired EIT, hyperinsulinemia sustained delivery of insulin to the interstitial space in DIO male mice. Even with sustained interstitial insulin delivery, DIO male mice still showed SkM IR indicating severe myocellular IR in this model. Interestingly, there was no difference in EIT, endothelial ultrastructure, or SkM insulin sensitivity between lean female mice and female mice fed a high-fat diet.
CONCLUSIONS - These results suggest that, in male mice, obesity results in ultrastructural alterations to the capillary endothelium that delay EIT. Nonetheless, the myocyte appears to exceed the endothelium as a contributor to SkM IR in DIO male mice.
© 2020 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).
0 Communities
1 Members
0 Resources
9 MeSH Terms
Associations of Thigh and Abdominal Adipose Tissue Radiodensity with Glucose and Insulin in Nondiabetic African-Ancestry Men.
Tilves C, Zmuda JM, Kuipers AL, Carr JJ, Terry JG, Wheeler V, Peddada SD, Nair S, Miljkovic I
(2020) Obesity (Silver Spring) 28: 404-411
MeSH Terms: Adipose Tissue, Adiposity, Adult, African Continental Ancestry Group, Aged, Blood Glucose, Body Composition, Cross-Sectional Studies, Glucose, Humans, Insulin, Intra-Abdominal Fat, Male, Middle Aged, Obesity, Overweight, Subcutaneous Fat, Thigh, West Indies
Show Abstract · Added January 10, 2020
OBJECTIVE - Decreased radiodensity of adipose tissue (AT) located in the visceral AT (VAT), subcutaneous AT (SAT), and intermuscular AT (IMAT) abdominal depots is associated with hyperglycemia, hyperinsulinemia, and insulin resistance independent of AT volumes. These associations were sought in African-ancestry men, who have higher risk for type 2 diabetes and have been underrepresented in previous studies.
METHODS - This cross-sectional analysis included 505 nondiabetic men of African-Caribbean ancestry (median age: 61 years; median BMI: 26.8 kg/m ) from the Tobago Health Study. AT volumes and radiodensities were assessed using computed tomography, including abdominal (VAT and SAT) and thigh (IMAT) depots. Associations between AT radiodensities were assessed with fasting serum glucose and insulin and with insulin resistance (updated homeostatic model assessment of insulin resistance, HOMA2-IR).
RESULTS - Higher radiodensity in any AT depot was associated with lower log-insulin and log-HOMA2-IR (β range: -0.16 to -0.18 for each; all P < 0.0001). No AT radiodensity was associated with glucose. Thigh IMAT radiodensity associations were independent of, and similar in magnitude to, VAT radiodensities. Model fit statistics suggested that AT radiodensities were a better predictor for insulin and insulin resistance compared with AT volumes in individuals with overweight and obesity.
CONCLUSIONS - AT radiodensities at multiple depots are significantly associated with insulin and insulin resistance in African-ancestry men.
© 2019 The Obesity Society.
0 Communities
2 Members
0 Resources
19 MeSH Terms
Lipid Droplet Accumulation in Human Pancreatic Islets Is Dependent On Both Donor Age and Health.
Tong X, Dai C, Walker JT, Nair GG, Kennedy A, Carr RM, Hebrok M, Powers AC, Stein R
(2020) Diabetes 69: 342-354
MeSH Terms: Acinar Cells, Adolescent, Adult, Age Factors, Aged, Animals, Child, Child, Preschool, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Embryonic Stem Cells, Female, Glucagon-Secreting Cells, Humans, Infant, Insulin-Secreting Cells, Islets of Langerhans, Islets of Langerhans Transplantation, Lipid Droplets, Male, Mice, Microscopy, Electron, Microscopy, Fluorescence, Middle Aged, Rats, Tissue Donors, Young Adult
Show Abstract · Added March 29, 2020
Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell-derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.
© 2019 by the American Diabetes Association.
0 Communities
1 Members
0 Resources
27 MeSH Terms
Roux-en-Y gastric bypass surgery improves hepatic glucose metabolism and reduces plasma kisspeptin levels in morbidly obese patients with type 2 diabetes.
Flynn CR, Albaugh VL, Tamboli RA, Gregory JM, Bosompem A, Sidani RM, Winnick JJ
(2020) Am J Physiol Gastrointest Liver Physiol 318: G370-G374
MeSH Terms: Adolescent, Adult, Anastomosis, Roux-en-Y, Blood Glucose, Diabetes Mellitus, Type 2, Female, Glucagon, Glucose, Humans, Insulin, Kisspeptins, Liver, Male, Middle Aged, Obesity, Morbid, Treatment Outcome, Young Adult
Show Abstract · Added November 12, 2019
Roux-en-Y gastric bypass surgery (RYGB) is known to improve whole-body glucose metabolism in patients with type 2 diabetes (T2D), although the mechanisms are not entirely clear and are likely multifactorial. The aim of this study was to assess fasting hepatic glucose metabolism and other markers of metabolic activity before and after RYGB in patients with and without T2D. Methods: Metabolic characteristics of patients who are obese with T2D were compared with those without the disease (non-T2D) before and 1 and 6 mo after RYGB. Fasting plasma insulin and the insulin:glucagon ratio were markedly reduced as early as 1 mo after RYGB in both patients with T2D and without T2D. Despite this reduction, endogenous glucose production and fasting plasma glucose levels were lower in both groups after RYGB, with the reductions being much larger in T2D. Plasma kisspeptin, an inhibitor of insulin secretion, was reduced only in T2D after surgery. Improved hepatic glucose metabolism and lower plasma kisspeptin in T2D after RYGB may link improved hepatic function with enhanced insulin responsiveness after surgery. Our manuscript is the first, to the best of our knowledge, to present data showing that Roux-en-Y gastric bypass surgery (RYGB) lowers fasting kisspeptin levels in patients who are obese with type 2 diabetes. This lowering of kisspeptin is important because it could link improvements in liver glucose metabolism after RYGB with increased insulin responsiveness also seen after surgery.
0 Communities
2 Members
0 Resources
17 MeSH Terms