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. 2008 Sep 16;105(37):14070-5.
doi: 10.1073/pnas.0806993105. Epub 2008 Sep 8.

Making insulin-deficient type 1 diabetic rodents thrive without insulin

Xinxin Yu  1 , Byung-Hyun Park, May-Yun Wang, Zhao V Wang, Roger H Unger
Affiliations

Making insulin-deficient type 1 diabetic rodents thrive without insulin

Xinxin Yu et al. Proc Natl Acad Sci U S A. .

Abstract

Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of beta-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within approximately 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 approximately 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-gamma-coactivator-1alpha 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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Hyperleptinemia reverses abnormalities of uncontrolled autoimmune diabetes in the absence of insulin. Comparison of mean (± SEM) leptin levels (A), blood glucose levels (B), body weight and food intake (shaded dark area = Adv-leptin) (C), and plasma glucagon levels (D) in diabetic NOD mice after either treatment with Adv-leptin (■) (n = 9) or injection of Adv-β-gal (□) as a control (n = 6). Plasma glucagon levels of diabetic NOD mice were obtained 30 days after treatment with Adv-leptin (■) (n = 9) or injection of Adv-β-gal (□) (n = 6). Glucagon levels of prediabetic NOD mice (n = 6) are also displayed (formula image). *, P < 0.01.
Fig. 2.
Fig. 2.
Hyperleptinemia reverses abnormalities of uncontrolled chemical diabetes in the absence of insulin. Comparisons of mean (± SEM) leptin levels (A), plasma glucose levels (B), and body weight (C) in untreated streptozotocin (STZ)-diabetic rats on an unrestricted diet (○) (n = 5), or untreated streptozotocin (STZ)-diabetic rats pair-fed with leptinized rats (△) (n = 3), and in streptozotocin (STZ)-diabetic rats treated with Adv-leptin (■) (n = 6). (D) Blood glucose levels in untreated alloxan-diabetic rats (○) (n = 5) or rats treated with Adv-leptin (■) (n = 6).
Fig. 3.
Fig. 3.
Hyperleptinemia reverses abnormalities of uncontrolled diabetes induced by a double dose of STZ. (A) Comparison of mean (± SEM) blood glucose levels treated with Adv-leptin (■) (n = 5) or untreated double-dose STZ-diabetic rats (○) (n = 5). (B) Morphometric comparison of insulin-positive cells (mean ± SEM) in pancreata of 4 untreated diabetic rats, 5 Adv-leptin-treated STZ-diabetic rats, and 3 normal nondiabetic controls. (C) Plasma glucagon levels 30 days after treatment (*, P < 0.01).
Fig. 4.
Fig. 4.
Hyperleptinemia activates liver STAT-3 and down-regulates proteins of gluconeogenesis, while limiting postprandial hyperglycemia. Comparisons (mean ± SEM) of relevant signal transcription factors for leptin and glucagon and their gluconeogenic targets in livers of untreated diabetic rats (□) (n = 4), double-dose STZ-diabetic rats 3 days after Adv-leptin treatment (■) (n = 5), and 3 h after insulin treatment (formula image) (n = 3). (A) Immunoblotting for P-STAT-3 and total STAT-3 (Upper), and immunoblotting for P-CREB and total CREB (Lower). Results are in densitometric units. (B) mRNA of phosphoenolpyruvate carboxykinase (PEPCK) and peroxisome proliferator-activated receptor coactivator-1 (PGC-1α). (C) Postprandial rise above fasting levels in blood glucose of untreated STZ rats (□), Adv-leptin-treated STZ rats (■), and nondiabetic rats (formula image).
Fig. 5.
Fig. 5.
Hyperleptinemia increases plasma IGF-1 and IGF-1 action on skeletal muscle, while restoring linear growth in severely insulin-deficient rats. Comparisons of plasma IGF-1 (A) and liver IGF-1 mRNA (B) 30 days after treatment and phosphorylated IGF-1 receptor (P-IGF-1R) in skeletal muscle (C) 3 days after treatment (densitometric units) in untreated (□) (n = 4) and Adv-leptin-treated (■) (n = 4) double-dose-STZ-diabetic rats. (D) Appearance of a nondiabetic normal lean wild-type Zucker Diabetic Fatty (+/+) rat, a double-dose-STZ-diabetic littermate treated with Adv-leptin, and an untreated diabetic littermate. Note that, although both the leptinized and the untreated diabetic rats are slimmer than the nondiabetic wild-type control, the length of the leptinized rat is almost normal. Thus, the growth inhibition caused by insulin deficiency was corrected without insulin replacement.
See this image and copyright information in PMC

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