Making insulin-deficient type 1 diabetic rodents thrive without insulin

Xinxin Yu, Byung Hyun Park, May-Yun Wang, Zhao Wang, Roger H Unger

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of β-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within ≈10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10-80 days without other treatment; normal physiological conditions lasted for ≈175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-γ-coactivator-1α may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.

Original languageEnglish (US)
Pages (from-to)14070-14075
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number37
DOIs
StatePublished - Sep 16 2008

Fingerprint

Rodentia
Insulin
Somatomedins
Leptin
Hyperglycemia
Skeletal Muscle
Phosphorylation
Somatomedin Receptors
Insulin Receptor Substrate Proteins
Cyclic AMP Response Element-Binding Protein
Terminally Ill
Ketosis
Peroxisome Proliferator-Activated Receptors
Gluconeogenesis
Liver
Glucagon
Type 1 Diabetes Mellitus
Phosphatidylinositol 3-Kinases
Up-Regulation
Muscles

Keywords

  • Glucagon suppression
  • Hyperglucagonemia
  • IGF-1 upregulation
  • Insulinomimetic
  • Leptin

ASJC Scopus subject areas

  • General

Cite this

Making insulin-deficient type 1 diabetic rodents thrive without insulin. / Yu, Xinxin; Park, Byung Hyun; Wang, May-Yun; Wang, Zhao; Unger, Roger H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 37, 16.09.2008, p. 14070-14075.

Research output: Contribution to journalArticle

@article{4d808fefc3c94f33be6f74c8e9cb152e,
title = "Making insulin-deficient type 1 diabetic rodents thrive without insulin",
abstract = "Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of β-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within ≈10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10-80 days without other treatment; normal physiological conditions lasted for ≈175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-γ-coactivator-1α may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.",
keywords = "Glucagon suppression, Hyperglucagonemia, IGF-1 upregulation, Insulinomimetic, Leptin",
author = "Xinxin Yu and Park, {Byung Hyun} and May-Yun Wang and Zhao Wang and Unger, {Roger H}",
year = "2008",
month = "9",
day = "16",
doi = "10.1073/pnas.0806993105",
language = "English (US)",
volume = "105",
pages = "14070--14075",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "37",

}

TY - JOUR

T1 - Making insulin-deficient type 1 diabetic rodents thrive without insulin

AU - Yu, Xinxin

AU - Park, Byung Hyun

AU - Wang, May-Yun

AU - Wang, Zhao

AU - Unger, Roger H

PY - 2008/9/16

Y1 - 2008/9/16

N2 - Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of β-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within ≈10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10-80 days without other treatment; normal physiological conditions lasted for ≈175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-γ-coactivator-1α may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.

AB - Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of β-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within ≈10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10-80 days without other treatment; normal physiological conditions lasted for ≈175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-γ-coactivator-1α may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.

KW - Glucagon suppression

KW - Hyperglucagonemia

KW - IGF-1 upregulation

KW - Insulinomimetic

KW - Leptin

UR - http://www.scopus.com/inward/record.url?scp=52949140814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52949140814&partnerID=8YFLogxK

U2 - 10.1073/pnas.0806993105

DO - 10.1073/pnas.0806993105

M3 - Article

C2 - 18779578

AN - SCOPUS:52949140814

VL - 105

SP - 14070

EP - 14075

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 37

ER -