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Islet Studies

β-Cell Failure in Diet-Induced Obese Mice Stratified According to Body Weight Gain: Secretory Dysfunction and Altered Islet Lipid Metabolism Without Steatosis or Reduced β-Cell Mass

  1. Marie-Line Peyot1,
  2. Emilie Pepin1,
  3. Julien Lamontagne1,
  4. Martin G. Latour1,
  5. Bader Zarrouki1,
  6. Roxane Lussier1,
  7. Marco Pineda1,
  8. Thomas L. Jetton2,
  9. S.R. Murthy Madiraju1,
  10. Erik Joly1 and
  11. Marc Prentki1,3
  1. 1Montreal Diabetes Research Center and CRCHUM, Montreal, QC, Canada;
  2. 2Diabetes and Metabolism, University of Vermont College of Medicine, Burlington, Vermont;
  3. 3Departments of Nutrition and Biochemistry, University of Montreal, Montreal, Quebec, Canada.
  1. Corresponding author: Marie-Line Peyot, marie-line.peyot{at}crchum.qc.ca.
Diabetes 2010 Sep; 59(9): 2178-2187. https://doi.org/10.2337/db09-1452
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  • FIG. 1.
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    FIG. 1.

    Body weight (BW), energy intake, and glycemia of C57Bl/6 mice fed normal diet (ND) or HFD for 8 weeks. DIO mice were classified after 7.5 weeks on HFD as LDR and HDR following body weight determinations. A: Distribution plots of body weight at 7.5 weeks of ND or HFD mice housed 3–4 per cage (ND, LDR, and HDR) or individually (NDi and DIOi). Encircled symbol corresponds to DIO mice excluded from the study. B: Fed glycemia and body weight of ND, LDR, and HDR mice after 7.5 weeks of dietary treatment. (C) Weight and (D) energy intake curves of ND, LDR, and HDR mice during 8 weeks of ND or HFD. D, inset: Mean of energy intake per week per group. A: Means ± SE of 52 mice for ND, LDR, and HDR, of 13 and 33 mice for NDi and DIOi, respectively. B and C: Means ± SE of 136, 117, and 148 mice for the ND, LDR, and HDR groups, respectively. D: Means ± SE of 13, 14, and 17 mice for the ND, LDR, and HDR groups, respectively. ND versus LDR or HDR, **P < 0.01, ***P < 0.001; LDR versus HDR, §P < 0.05, §§P < 0.01, §§§P < 0.001; one-way (B) or two-way ANOVA (C and D), Bonferroni post hoc test.

  • FIG. 2.
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    FIG. 2.

    DIO mice are insulin-resistant, are glucose-intolerant, and have defective first-phase GSIS. A and B: HIEC in 2-h–fasted anesthetized mice. A: Arterial glucose levels at time 0 of the clamp; B: glucose levels during the clamp. The dashed line corresponds to the clamped glucose value at ∼7.2 mmol/l. (C) Glucose infusion rate during the last 30 min of the 2-h HIEC (GIR) and (D) insulin sensitivity index (M/I) calculated as the glucose infusion rate (M) divided by the average insulinemia during the last 30 min of the clamp (I). M/I index is expressed as μmol · kg−1 · min−1 glucose infused per pmol/l insulin. E–I: IVGTT. Plasma glucose (E) and insulin (F) were measured at times 0, 3, 5, 15, 30, 45, and 60 min in response to a glucose challenge (i.v.; 0.5 g/kg) in 16-h overnight fasted anesthetized mice; (G) AUC of the 0–60 min glycemic responses; (H) first-phase insulin response to glucose (Glc) is the AUC of the 0–15 min insulinemic response; (I) second-phase insulin response to glucose is the AUC of the 15–60 min insulinemic response. Means ± SE of 5–8 animals per group. Normal diet (ND) versus LDR or HDR: *P < 0.05, **P < 0.01, ***P < 0.001; LDR versus HDR: §P < 0.05, §§P < 0.01, §§§P < 0.001; one-way (A, C, D, and G–I) or two-way ANOVA (B, E, and F), with Bonferroni post hoc test.

  • FIG. 3.
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    FIG. 3.

    Isolated islets from DIO mice show defective glucose-, KCl-, and arginine-induced insulin release. Insulin secretion was measured in freshly isolated islets from normal diet (ND), LDR, and HDR mice. Group of 10 islets were incubated 1 h in KRBH at 3, 8, or 16 mmol/l glucose (G; A and D) ± 0.25 mmol/l palmitate/0.5% d-BSA (Pal; B and D) or 3 mmol/l glucose ± 35 mmol/l KCl (C) ± Pal (C). Means ± SE are of 14–16 determinations from islets of 21–22 animals per group in five (A, B, and D) and three (C) separate experiments. E–H: Insulin secretion by islets perifused at 3 mmol/l glucose (3G) or 16 mmol/l glucose (16G) with or without 10 mmol/l arginine (Arg). AUC for insulin over the first 15 min (F) and from 15–60 min (G) following glucose concentration increased from 3 to 16 mmol/l. AUC for maximal insulin secretion was determined from 60–80 min after arginine injection (H). Means ± SE are of six normal diet, seven LDR, and seven HDR. Insulin release in the media was determined after the 1-h incubation or at the different time points of the perifusion experiment. *P < 0.05, **P < 0.01, ***P < 0.001 normal diet versus LDR or HDR; #P < 0.05, ##P < 0.01, ###P < 0.001 versus 3 mmol/l glucose (A) plus palmitate (B) or plus KCl (C) or versus the value in absence of palmitate (D) for the same group (normal diet, LDR, HDR); one-way ANOVA–Bonferroni multiple comparison test.

  • FIG. 4.
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    FIG. 4.

    β-Cell mass and proliferation, islet cell cytosolic free calcium, ATP, proinsulin, insulin and protein contents, and glucose metabolism of DIO mice. (A) β-Cell mass and (B) proliferation as indicated by the number of Ki-67 positive β-cells/islet. Means ± SE of six animals for normal diet (ND) and LDR and seven for HDR. Normal diet versus LDR or HDR, *P < 0.05. One-way ANOVA with Dunnett post hoc test. (C) Protein, (D and E) insulin expressed per islet (D) or per islet protein content (E), and (F) total islet proinsulin contents. Means ± SE of 83, 35, and 9 animals per group for (C), (D and E), and (F), respectively. Normal diet versus LDR or HDR, *P < 0.05, **P < 0.01, and ***P < 0.001; LDR versus HDR, §§P < 0.01. One-way ANOVA with Bonferroni post hoc test. Glucose utilization (G) and oxidation (H) were measured in islets incubated in KRBH at 3, 8, and 16 mmol/l glucose (G) with d-[U-14C]glucose and d-[5-3H]glucose. Means ± SE of 13–15 determinations from islets of 9 normal diet, 8 LDR, and 10 HDR mice in three separate experiments. ###P < 0.001 versus 3 mmol/l glucose for the same group. One-way ANOVA–Bonferroni multiple comparison test. I: Total ATP content was determined in islets incubated for 15 min in KRBH at 3 or 16 mmol/l glucose (G). Means ± SE of 13–15 determinations from islets of 9 normal diet, 9 LDR, and 9 HDR mice in three separate experiments. #P < 0.05 versus 3 mmol/l glucose for the same group. One-way ANOVA–Bonferroni multiple comparison test. J: Cytosolic free calcium was measured by confocal microscopy using Fluo-4 AM dye in dispersed-islet cells of normal diet, LDR, and HDR mice. Cells were perifused for 3 min at 3 mmol/l glucose, then at 16 mmol/l glucose for 10 min, and finally at 3 mmol/l glucose + 35 mmol/l KCl for 2 min. Fluorescence level is expressed in arbitrary units. For clarity purposes, only the mean of six independent experiments from six mice per group is represented. Of note, SE was no more than 15% at all times. One-way ANOVA with repeated measures, Tukey post test. ***P < 0.001 normal diet versus LDR and §§§P < 0.001 LDR versus HDR.

  • FIG. 5.
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    FIG. 5.

    Altered lipid partitioning, lipolysis, and glycerolipid/fatty acid cycling in DIO islets. A: Islet triglyceride content. Means ± SE of 10–12 animals per group. B: Glycerol release, as an index of lipolysis, was determined in islets incubated for 3 h in KRBH at 3 and 16 mmol/l glucose (G). Means ± SE of 19–20 determinations from islets of 17–18 mice per group in four separate experiments. Islets were incubated in KRBH at 3 and 16 mmol/l glucose with [9,10-3H]palmitate to assess (C) FFA oxidation, (D) total intracellular labeled NEFA, and (E) fatty acid (FA) esterification (esterif.) into triglycerides (TG) and (F) cholesterol esters (CE). Means ± SE of 9–12 determinations from islets of 14–18 mice per group in three (C) or four (D–F) separate experiments. (G) Total cholesterol (TC) and free cholesterol (FC) fractions extracted from normal diet (ND), LDR, and HDR islets. Means ± SE of 10–15 animals per group. LDR or HDR versus normal diet: *P < 0.05, **P < 0.01, ***P < 0.001; LDR versus HDR: §P < 0.05; #P < 0.05, ##P < 0.01, ###P < 0.001 versus 3 mmol/l glucose for the same islet group. One-way ANOVA–Bonferroni multiple comparison test.

  • FIG. 6.
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    FIG. 6.

    Model depicting the possible mechanisms of β-cell failure to compensate for insulin resistance in HDR mice. In normal mice, an elevation of glucose leads to an increase in ATP/ADP ratio and intracellular Ca2+ and a decrease in fatty acid oxidation that allows long-chain-acyl-CoA (fatty acid-CoA) availability for glycerolipid/fatty acid (GL/FA) cycling, which produces lipid signaling molecules (LSMs), such as diacylglycerol, necessary for insulin secretion. Enhanced GL/FA cycling is an “on” signal for insulin secretion that contributes to the amplification arm of GSIS. Enhanced fat oxidation is an “off” signal for insulin secretion because it removes molecules from the cycle (46). In HDR mice, to adapt to the elevation of circulating FFA and postprandial glucose and to prevent β-cell glucolipotoxicity and steatosis, fatty acid esterification processes and lipolysis are simultaneously decreased in association with enhanced FFA oxidation. The increase in fatty acid oxidation, in parallel to depleting LSM, reduces fatty acid-CoA availability for cholesterol ester (CE) synthesis, contributing with elevated blood cholesterol to free cholesterol accumulation and β-cell dysfunction with reduced secretion. Besides the amplification arm of GSIS, the classical triggering ATP/Ca2+ pathway is also affected in HDR versus LDR mice due to reduced glucose-stimulated ATP production and a lack of compensatory increase in the rise in Ca2+ promoted by high glucose. GPR40 activation by FFA may contribute to maintain high level of secretion and hyperinsulinemia. However, in the absence of insufficient insulin secretion for the demand due to the marked insulin resistance, HDR mice become hyperglycemic. Black arrows indicate a difference between DIO group (LDR and HDR) and normal diet group. Striped arrows indicate a difference between HDR and LDR groups.

Tables

  • Figures
  • TABLE 1

    Metabolic parameters of C57Bl/6 mice fed with normal diet or HFD for 8 weeks

    FedFasted
    Normal dietLDRHDRNormal dietLDRHDR
    Weight gain (g)8.5 ± 0.2 (62)15.5 ± 0.2*** (60)20.4 ± 0.2***,§§§ (72)5.5 ± 1.0 (5)16.9 ± 0.6*** (5)21.0 ± 0.3***,§§ (5)
    Insulin (pmol/l)252 ± 24 (59)266 ± 20 (58)658 ± 54***,§§§ (67)133 ± 87 (5)338 ± 84 (5)503 ± 40* (5)
    ProIns (pmol/l)18.5 ± 2.3 (8)23.7 ± 1.9 (9)31.8 ± 4.0* (9)NDNDND
    ProIns/Ins (%)7.8 ± 1.3 (8)9.4 ± 1.4 (9)5.5 ± 0.9§ (9)NDNDND
    FFA (mmol/l)0.60 ± 0.04 (33)0.55 ± 0.03 (33)0.58 ± 0.03 (38)0.77 ± 0.06 (5)1.12 ± 0.06 (5)1.58 ± 0.30* (5)
    TG (mmol/l)0.41 ± 0.02 (33)0.32 ± 0.01*** (34)0.33 ± 0.01*** (38)0.36 ± 0.04 (5)0.40 ± 0.04 (5)0.39 ± 0.03 (5)
    TC (mmol/l)1.50 ± 0.07 (8)1.90 ± 0.14 (8)2.58 ± 0.21***,§ (8)NDNDND
    • Data are means ± SE of n animals as indicated in parentheses. Plasma triglyceride (TG), FFAs, TC, proinsulin (ProIns), and insulin (Ins) were determined in anesthetized overnight fasted and/or fed male mice on a high-fat diet (LDR and HDR) or normal diet for 8 weeks. Delta body weight represents the weight gain of mice since the introduction of diets (normal diet or HFD) at 6 weeks of age. LDR or HDR versus normal diet:

    • *P < 0.05,

    • **P < 0.01,

    • ***P < 0.001; HDR versus LDR:

    • §P < 0.05,

    • §§P < 0.01,

    • §§§P < 0.001. One-way ANOVA–Bonferroni multiple comparison test. ND, not determined.

  • TABLE 2

    Summary of the metabolic and islet β-cell parameters obtained in C57Bl/6 male mice fed a high-fat diet for 8 weeks

    LDRHDR
    Metabolic parameters
        Weight gain↑↑↑
        Insulin resistance↑↑↑
        Insulinemia(↑)↑↑
        Proinsulinemia/insulinemia⇆⇆
        OGTT glucose tolerance(↓)↓
        ivGTT glucose tolerance(↓)↓
        ivGTT/1st-phase GSIS↓↓↓
        ivGTT/2nd-phase GSIS⇆⇆
        Fasting FFA(↑)↑
        Fed total cholesterol(↑)↑
        Fed glycemia↑↑↑
        2-h–fasted glycemia(↑)↑
        6-h–fasted glycemia↑↑↑
        16-h–fasted glycemia⇆(↑)
        ivGTT, 1 h glucose⇆↑
        OGTT, 2 h glucose(↑)↑
    Islet β-cell parameters
        β-Cell mass(↑)↑
        β-Cell proliferation(↑)↑
        Protein content/islet↑↑↑
        Insulin content/islet⇆⇆
        Proinsulin content/islet protein⇆⇆
        Glucose-induced insulin secretion↓↓↓
        KCl-induced insulin secretion↓↓
        Glucose usage/oxidation⇆⇆
        TG content⇆⇆
        Free cholesterol content⇆↑
        Glucose-stimulated lipolysis↓↓
        Glucose effect on NEFA content(↓)↓
        Glucose effect on FA esterif. in TG↓↓
        FA esterification in CE↓↓↓
        FA oxidation⇆↑
        Glucose-induced ATP↓↓
        Glucose-induced Ca2+↑⇆
        KCl-induced Ca2+⇆⇆
    • Horizontal arrow, unchanged versus normal diet–fed animals; arrows in parentheses indicate a clear trend that did not reach statistical significance. FA, fatty acid; TG, triglyceride.

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β-Cell Failure in Diet-Induced Obese Mice Stratified According to Body Weight Gain: Secretory Dysfunction and Altered Islet Lipid Metabolism Without Steatosis or Reduced β-Cell Mass
Marie-Line Peyot, Emilie Pepin, Julien Lamontagne, Martin G. Latour, Bader Zarrouki, Roxane Lussier, Marco Pineda, Thomas L. Jetton, S.R. Murthy Madiraju, Erik Joly, Marc Prentki
Diabetes Sep 2010, 59 (9) 2178-2187; DOI: 10.2337/db09-1452

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β-Cell Failure in Diet-Induced Obese Mice Stratified According to Body Weight Gain: Secretory Dysfunction and Altered Islet Lipid Metabolism Without Steatosis or Reduced β-Cell Mass
Marie-Line Peyot, Emilie Pepin, Julien Lamontagne, Martin G. Latour, Bader Zarrouki, Roxane Lussier, Marco Pineda, Thomas L. Jetton, S.R. Murthy Madiraju, Erik Joly, Marc Prentki
Diabetes Sep 2010, 59 (9) 2178-2187; DOI: 10.2337/db09-1452
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