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Effects of carbohydrate quality and amount on plasma lactate: results from the OmniCarb trial.
Hu JR, Wu Y, Sacks FM, Appel LJ, Miller Iii ER, Young JH, Juraschek SP
(2020) BMJ Open Diabetes Res Care 8:
Show Abstract · Added September 14, 2020
INTRODUCTION - Plasma lactate is a marker of non-oxidative glucose metabolism associated with progression to diabetes. We examined the effect of carbohydrate quality (glycemic index (GI)) and amount (%kcal) on plasma lactate. We hypothesized that low GI (≤45 (g)) versus high (≥65 (G)) and low %kcal from carbohydrate (40% kcal (c)) versus high (58% kcal (C)) each would reduce lactate levels.
RESEARCH DESIGN AND METHODS - We measured lactate in OmniCarb, a randomized, cross-over trial of four diets in overweight/obese adults without diabetes or cardiovascular disease (N=163). The four diets were high carbohydrate+high GI (CG, reference), high carbohydrate+low GI (Cg), low carbohydrate+high GI (cG), and low carbohydrate+low GI (cg). Participants (N=163) consumed each of the four diets over a 5-week period, separated by 2-week washout periods. Plasma lactate levels were measured at baseline, during which the participants consumed their own diets, and after each 5-week period.
RESULTS - Baseline plasma lactate was 1.2 mmol/L. In the setting of high carbohydrate amount, reducing GI lowered plasma lactate non-significantly by 0.08 mmol/L (Cg vs CG: 95% CI -0.16 to 0.00; p=0.06). In the setting of high GI, reducing carbohydrate amount lowered plasma lactate by 0.10 mmol/L (cG vs CG: 95% CI -0.19 to -0.02; p=0.02). The combined effect of reducing GI and carbohydrate proportion in the diet (cg vs CG) was similar (cg vs CG: -0.08; 95% CI -0.16 to 0.00; p=0.04). All four diets reduced plasma lactate compared with baseline.
CONCLUSIONS - Compared with a diet with high GI and high carbohydrate amount, diets with low GI and/or low carbohydrate amount reduced plasma lactate. Whether this change in lactate leads to long-term change in glucose metabolism needs to be examined.
TRIAL REGISTRATION NUMBER - NCT00608049.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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0 MeSH Terms
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
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.
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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
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
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The Peripheral Peril: Injected Insulin Induces Insulin Insensitivity in Type 1 Diabetes.
Gregory JM, Cherrington AD, Moore DJ
(2020) Diabetes 69: 837-847
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.
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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.
1 Communities
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16 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.
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27 MeSH Terms
Increased proportion of time in hybrid closed-loop "Auto Mode" is associated with improved glycaemic control for adolescent and young patients with adult type 1 diabetes using the MiniMed 670G insulin pump.
Duffus SH, Ta'ani ZA, Slaughter JC, Niswender KD, Gregory JM
(2020) Diabetes Obes Metab 22: 688-693
Show Abstract · Added November 12, 2019
The Medtronic MiniMed 670G system delivers insulin to patients with type 1 diabetes mellitus (T1DM) using either its hybrid closed-loop (HCL) "Auto Mode" feature or an open-loop mode. In this retrospective, cross-sectional analysis, we quantified the association between time in Auto Mode and both haemoglobin A1c (HbA1c) and time in range (TIR, sensor glucose 70-180 mg/dL) among 96 paediatric and young adult patients with T1DM. The median percentage time in Auto Mode was 38.5% (interquartile range 0%-64%). The percentage time in Auto Mode significantly correlated with HbA1c after adjustment for covariables (β = -0.008, P = 0.014). Each daily 3.4-h increase in Auto Mode time was associated with a 0.1% decrease in HbA1c. Auto Mode time was also correlated with TIR after adjustment for covariables (β = 0.14, P = 0.02): for each daily 8.6-h increase in Auto Mode time, TIR increased by 5%. While Auto Mode use was low, increased time in Auto Mode was associated with a significantly lower HbA1c and increased TIR. These findings emphasize the importance of identifying strategies to improve the ease of use of HCL systems.
© 2019 John Wiley & Sons Ltd.
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Metabolite Profiles of Incident Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program.
Chen ZZ, Liu J, Morningstar J, Heckman-Stoddard BM, Lee CG, Dagogo-Jack S, Ferguson JF, Hamman RF, Knowler WC, Mather KJ, Perreault L, Florez JC, Wang TJ, Clish C, Temprosa M, Gerszten RE, Diabetes Prevention Program Research Group
(2019) Diabetes 68: 2337-2349
MeSH Terms: Adult, Aged, Biomarkers, Cytosine, Diabetes Mellitus, Type 2, Female, Humans, Incidence, Life Style, Male, Metabolome, Middle Aged, Risk Factors
Show Abstract · Added March 3, 2020
Novel biomarkers of type 2 diabetes (T2D) and response to preventative treatment in individuals with similar clinical risk may highlight metabolic pathways that are important in disease development. We profiled 331 metabolites in 2,015 baseline plasma samples from the Diabetes Prevention Program (DPP). Cox models were used to determine associations between metabolites and incident T2D, as well as whether associations differed by treatment group (i.e., lifestyle [ILS], metformin [MET], or placebo [PLA]), over an average of 3.2 years of follow-up. We found 69 metabolites associated with incident T2D regardless of treatment randomization. In particular, cytosine was novel and associated with the lowest risk. In an exploratory analysis, 35 baseline metabolite associations with incident T2D differed across the treatment groups. Stratification by baseline levels of several of these metabolites, including specific phospholipids and AMP, modified the effect that ILS or MET had on diabetes development. Our findings highlight novel markers of diabetes risk and preventative treatment effect in individuals who are clinically at high risk and motivate further studies to validate these interactions.
© 2019 by the American Diabetes Association.
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13 MeSH Terms
Aerobic exercise training improves hepatic and muscle insulin sensitivity, but reduces splanchnic glucose uptake in obese humans with type 2 diabetes.
Gregory JM, Muldowney JA, Engelhardt BG, Tyree R, Marks-Shulman P, Silver HJ, Donahue EP, Edgerton DS, Winnick JJ
(2019) Nutr Diabetes 9: 25
MeSH Terms: Adult, Diabetes Mellitus, Type 2, Exercise, Female, Glucose, Glucose Clamp Technique, Glucose Tolerance Test, Humans, Insulin Resistance, Liver, Male, Middle Aged, Muscle, Skeletal, Obesity
Show Abstract · Added September 3, 2019
BACKGROUND - Aerobic exercise training is known to have beneficial effects on whole-body glucose metabolism in people with type 2 diabetes (T2D). The responses of the liver to such training are less well understood. The purpose of this study was to determine the effect of aerobic exercise training on splanchnic glucose uptake (SGU) and insulin-mediated suppression of endogenous glucose production (EGP) in obese subjects with T2D.
METHODS - Participants included 11 obese humans with T2D, who underwent 15 ± 2 weeks of aerobic exercise training (AEX; n = 6) or remained sedentary for 15 ± 1 weeks (SED; n = 5). After an initial screening visit, each subject underwent an oral glucose load clamp and an isoglycemic/two-step (20 and 40 mU/m/min) hyperinsulinemic clamp (ISO-clamp) to assess SGU and insulin-mediated suppression of EGP, respectively. After the intervention period, both tests were repeated.
RESULTS - In AEX, the ability of insulin to suppress EGP was improved during both the low (69 ± 9 and 80 ± 6% suppression; pre-post, respectively; p < 0.05) and high (67 ± 6 and 82 ± 4% suppression, respectively; p < 0.05) insulin infusion periods. Despite markedly improved muscle insulin sensitivity, SGU was reduced in AEX after training (22.9 ± 3.3 and 9.1 ± 6.0 g pre-post in AEX, respectively; p < 0.05).
CONCLUSIONS - In obese T2D subjects, exercise training improves whole-body glucose metabolism, in part, by improving insulin-mediated suppression of EGP and enhancing muscle glucose uptake, which occur despite reduced SGU during an oral glucose challenge.
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14 MeSH Terms
Fibrotic Encapsulation Is the Dominant Source of Continuous Glucose Monitor Delays.
McClatchey PM, McClain ES, Williams IM, Malabanan CM, James FD, Lord PC, Gregory JM, Cliffel DE, Wasserman DH
(2019) Diabetes 68: 1892-1901
MeSH Terms: Animals, Blood Glucose, Blood Glucose Self-Monitoring, Equipment Failure, Fibrosis, Mice, Subcutaneous Fat
Show Abstract · Added August 11, 2019
Continuous glucose monitor (CGM) readings are delayed relative to blood glucose, and this delay is usually attributed to the latency of interstitial glucose levels. However, CGM-independent data suggest rapid equilibration of interstitial glucose. This study sought to determine the loci of CGM delays. Electrical current was measured directly from CGM electrodes to define sensor kinetics in the absence of smoothing algorithms. CGMs were implanted in mice, and sensor versus blood glucose responses were measured after an intravenous glucose challenge. Dispersion of a fluorescent glucose analog (2-NBDG) into the CGM microenvironment was observed in vivo using intravital microscopy. Tissue deposited on the sensor and nonimplanted subcutaneous adipose tissue was then collected for histological analysis. The time to half-maximum CGM response in vitro was 35 ± 2 s. In vivo, CGMs took 24 ± 7 min to reach maximum current versus 2 ± 1 min to maximum blood glucose ( = 0.0017). 2-NBDG took 21 ± 7 min to reach maximum fluorescence at the sensor versus 6 ± 6 min in adipose tissue ( = 0.0011). Collagen content was closely correlated with 2-NBDG latency ( = 0.96, = 0.0004). Diffusion of glucose into the tissue deposited on a CGM is substantially delayed relative to interstitial fluid. A CGM that resists fibrous encapsulation would better approximate real-time deviations in blood glucose.
© 2019 by the American Diabetes Association.
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7 MeSH Terms