Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes

Chaparro, Rodolfo; Konigshofer, Yves; Beilhack, Georg F.; Shizuru, Judith A.; McDevitt, Hugh O.; Chien, Yueh‐hsiu

doi:10.1073/pnas.0604317103

Cited by 64 publications

(55 citation statements)

References 45 publications

(42 reference statements)

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“…3. Gene studies of autoimmune-prone NOD/SCID and non-autoimmuneprone C57BL/6 mice suggest that, in the absence of hyperglycemia and β-cell destruction, the NOD genetic background may predispose to diabetic complications, including insulin resistance [57].…”

Section: Discussionmentioning

confidence: 99%

Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

Coulaud¹,

Durant²,

Homo‐Delarche³

2010

Rev Diabet Stud

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■ AbstractBACKGROUND: Unlike other strains, spontaneously type 1 non-obese diabetic (NOD) mice experience transient hyperinsulinemia after weaning. The same applies for NOD/SCID mice, which lack functional lymphocytes, and unlike NOD mice, do not develop insulitis and diabetes like NOD mice. AIMS: Given that β-cell stimulation is a natural feature of gestation, we hypothesized that glucose homeostasis is disturbed in gestate pre-diabetic NOD and non-diabetic NOD/SCID mice, which may accelerate the onset of diabetes and increase diabetes prevalence. METHODS: During gestation and postpartum, mice were analyzed under basal feed conditions, and following glucose injection (1 g/kg, i.p.) after overnight fast, using glucose tolerance test (GTT). Glycemia, corticosteronemia, blood and pancreatic insulin, glucagon levels, islet size, and islet morphology were evaluated. Glycemia and mortality were assessed after successive gestations in NOD mice mated for the first time at 2 different ages. RESULTS: 1. Basal glucagonemia rose markedly in first-gestation fed NOD mice. 2. β-cell hyperactivity was present earlier in first-gestation non-diabetic fasted NOD and NOD/SCID mice than in age-matched C57BL/6 mice, assessed by increased insulin/glucose ratio after GTT. 3. Overnight fasting increased corticosteronemia rapidly and sharply in pre-diabetic gestate NOD and NOD/SCID mice. 4. Islet size increased in non-diabetic gestate NOD mice compared with C57BL/6 mice. 5. Successive gestations accelerated diabetes onset, and contributed to increased mortality in NOD mice. CONCLUSIONS: First-gestation prediabetic NOD and non-diabetic NOD/SCID mice exhibited β-cell hyperactivity and deregulation of glucagon and/or corticosterone secretion. This amplified normally occurring insulin resistance, further exhausted maternal β-cells, and accelerated diabetes in NOD mice.

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Section: Discussionmentioning

confidence: 99%

Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

Coulaud¹,

Durant²,

Homo‐Delarche³

2010

Rev Diabet Stud

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“…As an insulin-resistant state in NOD mice exists in new-onset T1DM (7,17), we analyzed the effect of AAT treatment on the sensitivity of NOD mice to insulin-driven disposal of blood glucose. After an i.p.…”

Section: Aat Treatment Alters the Balance Of Immunity And Inflammatiomentioning

confidence: 99%

“…In addition, islets are sensitive to proinflammatory cytokines (12)(13)(14)(15). Adverse inflammation in muscle and fat causes faulty insulin signaling and insulin resistance (16) in type 2 diabetes mellitus (13) and, as recently shown, T1DM (7,17). Hence, we have tested the hypothesis that treatment with AAT, an acutephase reactant with known antiinflammatory and antiapoptotic effects (18)(19)(20)(21) including effects on islets (21,22), is effective in NOD mice with overt new-onset T1DM.…”

mentioning

confidence: 99%

Curative and β cell regenerative effects of α1-antitrypsin treatment in autoimmune diabetic NOD mice

Koulmanda¹,

Bhasin

Hoffman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

154

161

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Invasive insulitis is a destructive T cell-dependent autoimmune process directed against insulin-producing ␤ cells that is central to the pathogenesis of type 1 diabetes mellitus (T1DM) in humans and the clinically relevant nonobese diabetic (NOD) mouse model. Few therapies have succeeded in restoring long-term, drug-free euglycemia and immune tolerance to ␤ cells in overtly diabetic NOD mice, and none have demonstrably enabled enlargement of the functional ␤ cell mass. Recent studies have emphasized the impact of inflammatory cytokines on the commitment of antigen-activated T cells to various effector or regulatory T cell phenotypes and insulin resistance and defective insulin signaling. Hence, we tested the hypothesis that inflammatory mechanisms trigger insulitis, insulin resistance, faulty insulin signaling, and the loss of immune tolerance to islets. We demonstrate that treatment with ␣1-antitrypsin (AAT), an agent that dampens inflammation, does not directly inhibit T cell activation, ablates invasive insulitis, and restores euglycemia, immune tolerance to ␤ cells, normal insulin signaling, and insulin responsiveness in NOD mice with recent-onset T1DM through favorable changes in the inflammation milieu. Indeed, the functional mass of ␤ cells expands in AAT-treated diabetic NOD mice.autoimmunity ͉ type 1 diabetes ͉ inflammation A destructive T cell-dependent autoimmune process directed against insulin-producing ␤ cells causes type 1 diabetes mellitus (T1DM) in humans and the nonobese diabetic (NOD) mouse model (1, 2). Although many therapeutic interventions, including viral-mediated gene transfer of human ␣1-antitrypsin (AAT) (3), can prevent T1DM or resolve the T cell-rich, ␤ cell-invasive insulitis lesion in prediabetic hosts, surprisingly few therapies have succeeded in restoring long-term drug-free euglycemia and immune tolerance to ␤ cells in overtly diabetic NOD mice (4-8). Although each of these successful therapies directly targets T cells, each bears an element that may dampen proinflammatory responses or their consequences upon target tissues.Inflammatory cytokines direct the commitment of antigenactivated CD4 ϩ T cells to specific effector or Foxp3ϩ regulatory phenotypes (9-11). In addition, islets are sensitive to proinflammatory cytokines (12-15). Adverse inflammation in muscle and fat causes faulty insulin signaling and insulin resistance (16) in type 2 diabetes mellitus (13) and, as recently shown, T1DM (7,17). Hence, we have tested the hypothesis that treatment with AAT, an acutephase reactant with known antiinflammatory and antiapoptotic effects (18-21) including effects on islets (21,22), is effective in NOD mice with overt new-onset T1DM. In short, we are probing the hypothesis that inflammatory mechanisms trigger T1DM. Results AAT Does Not Inhibit T Cell Activation.Purified carboxyfluorescein diacetate succinmidyl ester (CFSE)-labeled C57BL/6 mouse T cells were stimulated with plate-bound anti-CD3 plus soluble anti-CD28 mAbs. AAT did not impair T cell proliferation or acquisition of an ...

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“…Far more challenging is the restoration of a euglycemic state in mice with frank T1DM (2). To date, only short-term treatments with anti-CD3 mAb (3)(4)(5), polyclonal antilymphocyte serum plus exendin-4 (6), or infusion of islet-specific regulatory T cells (7) has proven effective in restoring, in the long term, a euglycemic state in at least 50% of treated new-onset diabetic NOD mice in the absence of islet transplantation. Yet, the excellent results achieved with anti-CD3 treatment in diabetic NOD mice have served as the basis for initiating successful clinical trials of anti-CD3 mAb in humans with T1DM (8,9).…”

mentioning

confidence: 99%

Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts

Koulmanda

Budo

Bonner-Weir

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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In nonobese diabetic (NOD) mice with overt new-onset type 1 diabetes mellitus (T1DM), short-term treatment with a ''tripletherapy'' regimen [rapamycin plus agonist IL-2-related and antagonist-type, mutant IL-15-related Ig fusion proteins (IL-2.Ig and mutIL-15.Ig)] halts autoimmune destruction of insulinproducing beta cells and restores both euglycemia and immune tolerance to beta cells. Increases in the mass of insulin-producing beta cells or circulating insulin levels were not linked to the restoration of euglycemia. Instead, the restoration of euglycemia was linked to relief from an inflammatory state that impaired the host's response to insulin. Both restoration of immune tolerance to beta cells and relief from the adverse metabolic effects of an inflammatory state in insulin-sensitive tissues appear essential for permanent restoration of normoglycemia in this T1DM model. Thus, this triple-therapy regimen, possessing both toleranceinducing and select antiinflammatory properties, may represent a prototype for therapies able to restore euglycemia and selftolerance in T1DM.autoimmunity ͉ diabetes ͉ NOD mice ͉ tolerance ͉ transplantation

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Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes

Abstract: authors note that in Fig. 2, the ''myosin VI'' labels should be replaced with ''vinculin'' in D and with ''R-Tfn'' in E. The corrected figure and its legend appear below. In addition, the portion of the

Cited by 64 publications

References 45 publications

Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

Glucose Homeostasis in Pre-diabetic NOD and Lymphocyte-Deficient NOD/SCID Mice During Gestation

Curative and β cell regenerative effects of α1-antitrypsin treatment in autoimmune diabetic NOD mice

Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts

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