Desensitization of the insulin receptor by antireceptor antibodies in vivo is blocked by treatment of mice with beta-adrenergic agonists.

Elias, Dana; Rapoport, Micha J.; Cohen, Irun R.; Shechter, Yoram

doi:10.1172/jci113546

“…Their presence in mice was associated with peripheral insulin resistance due to down regulation and desensitization of the insulin receptor (19). Hence these anti-idiotypic antibodies could contribute to the diabetic process.…”

mentioning

confidence: 99%

Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein.

Elias

¹

,

Markovits

²

,

Reshef

³

et al. 1990

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

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Insulin-dependent diabetes mellitus is caused by autoimmune destruction of the insulin-producing beta cells of the pancreas. The results described here indicate that a beta-cell target antigen in non-obese diabetic (NOD/Lt) mice is a molecule cross-reactive with the 65-kDa heat shock protein (hsp65) of Mycobacterium tuberculosis. The onset of beta-cell destruction is associated with the spontaneous development of anti-hsp65 T lymphocytes. Subsequently hsp65 cross-reactive antigen becomes detectable in the sera of the prediabetic mice and some weeks later anti-hsp65 antibodies, anti-insulin antibodies, and anti-idiotypic antibodies to insulin antibodies become detectable. The hsp65-cross-reactive antigen, the autoantibodies, and the T-cell reactivity then decline with the development of overt insulin-dependent diabetes. The importance of hsp65 in the pathogenesis of insulin-dependent diabetes was confirmed by the ability of clones of anti-hsp65 T cells to cause insulitis and hyperglycemia in young NOD/Lt mice.Moreover, hsp65 antigen could be used either to induce diabetes or to vaccinate against diabetes, depending on the form of its administration to prediabetic NOD/Lt mice. Other antigens such as the 70-kDa heat shock protein (hsp7O) had no effect on the development of diabetes.Type 1 or insulin-dependent diabetes mellitus (IDDM) is caused in most cases by autoimmune destruction of the insulin-producing beta cells resident in the islets of the pancreas (1). It is thought that once the autoimmune process takes root, it progresses relentlessly without causing symptoms until the number of beta cells irreversibly destroyed is so large, perhaps 90% of the beta-cell mass, that the individual suffers a derangement in glucose homeostasis and requires an exogenous supply of insulin to sustain life.The non-obese diabetic (NOD/Lt) mouse is a useful experimental model of IDDM (1). NOD/Lt mice spontaneously develop inflammation of the islets, insulitis, beginning at 4-6 weeks of age which progresses to overt IDDM at 4-5 months of age. Autoimmune T lymphocytes would seem to be the cause of beta-cell destruction because IDDM can be adoptively transferred to very young prediabetic NOD/Lt mice with T lymphocytes from older mice (2).Identification of target antigens recognized in the pathogenesis of IDDM is important for at least two reasons: specific antigens would facilitate the early diagnosis of preclinical IDDM and they might be used to abort the destructive autoimmune process through modification of the autoimmune response. For example, copolymer 1 (COP 1), a synthetic peptide immunologically cross-reactive with myelin basic protein has been used to alter the course of multiple sclerosis (3).We now show that a beta-cell antigen cross-reactive with a 65-kDa heat shock protein (hsp65) of Mycobacterium tuberculosis, termed hsp65 cross-reactive (hsp65-CR) antigen, is involved in the pathogenesis of NOD/Lt mouse IDDM. MATERIALS AND METHODSMice. The breeding nucleus of NOD/Lt mice was a gift of E. Leiter (Jackson Laborat...

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“…Nevertheless, IDDM is generally attributed to central destruction of the insulin-producing p-cells (18), whereas the anti-DM-id has been shown to cause desensitization of peripheral insulin receptors (3,19). How then might the anti-DM-id contribute to IDDM?…”

Section: Discussionmentioning

confidence: 99%

Insulin-Mimicking Anti-Idiotypic Antibodies in Development of Spontaneous Autoimmune Diabetes in BB/E Rats

Elias

¹

,

Bone

²

,

Baird

³

et al. 1990

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BB/E rats spontaneously develop a form of autoimmune diabetes resembling insulin-dependent diabetes mellitus (IDDM) in humans. IDDM results from central destruction of the insulin-producing beta-cells of the pancreatic islets. Herein, we report that the outbreak of IDDM in BB/E rats is preceded by the spontaneous development of an anti-idiotypic antibody to a particular antibody to insulin made by the rats. This anti-idiotype, designated anti-DM-id, behaves as an antibody to the insulin-hormone receptor. Thus, a spontaneous anti-idiotypic antibody network whose products can affect the peripheral utilization of insulin seems to accompany the central destruction of beta-cells in developing IDDM.

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Membrane Receptor–Linked Disease States

Nebes

¹

,

Wall

²

1998

Comprehensive Physiology

0

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The sections in this article are: Genetic Disorders of Receptor and Effector Molecules Types of Receptor Clinical Disorders C Proteins Receptors and Oncogenes Antibodies Against Receptors and Autoimmune Disorders Seven‐Transmembrane‐Receptor/G Protein–Coupled Disorders Thyroid‐Stimulating Hormone Receptor/Toxic Thyroid Hyperplasia/Thyroid‐Stimulating Hormone Resistance Luteinizing Hormone Receptor/Precocious Puberty/ Leydig Cell Hypoplasia Adrenocorticotropic Hormone Receptor/Familial Glucocorticoid Deficiency Arginine Vasopressin/Nephrogenic Diabetes Insipidus Rhodopsin/Retinifis Pigmentosa Parathyroid Hormone/Parathyroid Hormone–Related Peptide Receptor/Jansen‐Type Metaphyseal Chondrodysplasia β3‐Adrenergic Receptor/Obesity Growth Hormone–Releasing Hormone Receptor Somatostatin Receptor Mutations of G Proteins Gα s Mutations/Albright Hereditary Osteodystrophy Single‐Transmembrane‐Receptor–Coupled Diseases Insulin Receptor/Leprechaunism/Rabson‐Mendenhall Syndrome/Type A Insulin Resistance Growth Hormone Receptor/Laron Dwarfism Insulin‐Like Growth Factor‐1 Receptor Four‐Transmembrane‐Segment Receptor Diseases Gamma‐Aminobutyric Acid and Serotonin Receptors Acetylcholine Receptor/Slow‐Channel Syndrome Abnormal Recognition, Regulation, and Signaling Pathways Receptor‐Specific Cross‐Over Disease Hyperprolactinemia Syndrome Trophoblastic Tumors/Human Chorionic Gonadotropin Non‐Islet Cell Neoplasms/Type II Insulin‐Like Growth Factor Oncogenic Receptor Defects Thyroid‐Stimulating Hormone Receptor/ Thyroid Adenomas Gα s Mutations/McCune‐Albright Syndrome Disorders of Ras and Ras ‐Like Proto‐oncogenes Antireceptor Antibodies and Autoimmune Disease Effect of Antireceptor Antibodies Thyroid‐Stimulating Hormone Receptor Antibodies and Graves' Disease Thyroid Growth–Stimulating Antibodies Insulin Receptor Antibodies β‐Adrenergic Receptor Antibodies Myasthenia Gravis Other Receptor Antibodies

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Desensitization of the insulin receptor by antireceptor antibodies in vivo is blocked by treatment of mice with beta-adrenergic agonists.

Cited by 7 publications

References 56 publications

Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein.

Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein.

Insulin-Mimicking Anti-Idiotypic Antibodies in Development of Spontaneous Autoimmune Diabetes in BB/E Rats

Membrane Receptor–Linked Disease States

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