Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice - PubMed (original) (raw)

. 2011 Sep;60(9):2265-73.

doi: 10.2337/db10-1795. Epub 2011 Aug 1.

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Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice

Masaki Naito et al. Diabetes. 2011 Sep.

Abstract

Objective: The aim of the current study was to evaluate the long-term effects of leptin on glucose metabolism, diabetes complications, and life span in an insulin-dependent diabetes model, the Akita mouse.

Research design and methods: We cross-mated Akita mice with leptin-expressing transgenic (LepTg) mice to produce Akita mice with physiological hyperleptinemia (LepTg:Akita). Metabolic parameters were monitored for 10 months. Pair-fed studies and glucose and insulin tolerance tests were performed. The pancreata and kidneys were analyzed histologically. The plasma levels and pancreatic contents of insulin and glucagon, the plasma levels of lipids and a marker of oxidative stress, and urinary albumin excretion were measured. Survival rates were calculated.

Results: Akita mice began to exhibit severe hyperglycemia and hyperphagia as early as weaning. LepTg:Akita mice exhibited normoglycemia after an extended fast even at 10 months of age. The 6-h fasting blood glucose levels in LepTg:Akita mice remained about half the level of Akita mice throughout the study. Food intake in LepTg:Akita mice was suppressed to a level comparable to that in WT mice, but pair feeding did not affect blood glucose levels in Akita mice. LepTg:Akita mice maintained insulin hypersensitivity and displayed better glucose tolerance than did Akita mice throughout the follow-up. LepTg:Akita mice had normal levels of plasma glucagon, a marker of oxidative stress, and urinary albumin excretion rates. All of the LepTg:Akita mice survived for >12 months, the median mortality time of Akita mice.

Conclusions: These results indicate that leptin is therapeutically useful in the long-term treatment of insulin-deficient diabetes.

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Figures

FIG. 1.

FIG. 1.

Time course of changes in plasma leptin, blood glucose, HbA1c, body weight, and food intake. A: Plasma leptin levels of WT, LepTg, Akita, and LepTg:Akita mice at 8 and 28 weeks of age (n ≥4 in each group). B: Sixteen-hour fasting blood glucose levels of WT, LepTg, Akita, and LepTg:Akita mice at 8, 18, and 43 weeks of age (n ≥4 in each group). C: Time course of 6-h fasting blood glucose concentrations of WT (◇), LepTg (♦), Akita (○), and LepTg:Akita (●) mice (n ≥11 in each group, except n = 5 for data of 40 weeks of age). Since the glucometer has a detection limit up to 600 mg/dL, values above the detection limit were treated as 601 mg/dL. Dashed line indicates detection limit of 600 mg/dL. The numbers along the curves indicate the percent of samples above detection limit. D: Time course of glycated hemoglobin (HbA1c) levels of WT (◇), LepTg (♦), Akita (○), and LepTg:Akita (●) mice (n ≥4 in each group). Since the analyzer has a detection limit up to 14%, values above the detection limit were treated as 14.1%. Dashed line indicates detection limit of 14%. The numbers along the curves indicate the percent of samples above detection limit. E: Time course of body weight changes of WT (◇), LepTg (♦), Akita (○), and LepTg:Akita (●) mice (n ≥ 11 in each group, except n = 5 for data of 40 weeks of age). F: Time course of 24-h food intake of WT (◇), LepTg (♦), Akita (○), and LepTg:Akita (●) mice (n ≥ 11 in each group, except n = 4 for data of 40 weeks of age). G: Body weight of Akita, pair-fed Akita, and LepTg:Akita mice at the end of 3 weeks of pair feeding (n = 4 in each group). H: Six-hour fasting blood glucose concentrations of Akita, pair-fed Akita, and LepTg:Akita mice at the end of 3 weeks of pair feeding (n = 4 in each group). Data are expressed as means ± SE. In A_–_F, †P < 0.05, ††P < 0.01 for WT vs. LepTg, §P < 0.05, §§P < 0.01 for WT vs. Akita, ‡P < 0.05, ‡‡P < 0.01 for WT vs. LepTg:Akita, ¶¶P < 0.01 for LepTg vs. Akita, ★★P < 0.01 for LepTg vs. LepTg:Akita, *P < 0.05, and **P < 0.01 for Akita vs. LepTg:Akita. In G and H, ##P < 0.01 for Akita vs. pair-fed Akita and **P < 0.01 for LepTg:Akita vs. pair-fed Akita.

FIG. 2.

FIG. 2.

GTTs and ITTs. A: GTTs of WT (◇), LepTg (♦), Akita (open circles), and LepTg:Akita (closed circles) mice at 8 and 16 weeks of age. Blood glucose levels are shown at indicated times after glucose injections (1 g/kg body wt i.p.; n ≥4 in each group). B: ITTs of WT (◇), LepTg (♦), Akita (○), and LepTg:Akita (●) mice at 8, 18, and 28 weeks of age. Percent changes in blood glucose levels are shown at indicated times after injection of insulin (0.5 units/kg body wt i.p.; n ≥ 4 in each group). Dashed line indicates detection limit of 600 mg/dL. Data are expressed as means ± SE. §P < 0.05, §§P < 0.01 for WT vs. Akita, ‡P < 0.05, ‡‡P < 0.01 for WT vs. LepTg:Akita, ★P < 0.05, ★★P < 0.01 for LepTg vs. LepTg:Akita, *P < 0.05, and **P < 0.01 for Akita vs. LepTg:Akita.

FIG. 3.

FIG. 3.

Glucose-stimulated insulin secretion, plasma glucagon levels, and pancreatic hormone contents. A: Plasma insulin (open bars) and glucose (black lines) concentrations after glucose (3 g/kg i.p.) injection in WT, LepTg, Akita, and LepTg:Akita mice at 8 weeks of age (n ≥4 in each group). B: Plasma glucagon concentration in ad libitum–fed WT, LepTg, Akita, and LepTg:Akita mice at 22 weeks of age (n ≥4 in each group). C and D: Pancreatic insulin (C) and glucagon (D) content measured in acid-ethanol extracts of homogenized pancreas from WT, LepTg, Akita, and LepTg:Akita mice at 18 weeks of age (n ≥5 in each group). E: Double immunofluorescent stainings against insulin (green) and glucagon (red) in pancreatic sections from WT, LepTg, Akita, and LepTg:Akita mice at the age of 18 weeks. Scale bar indicates 50 μm. F: α-Cell and β-cell areas per islet in WT, LepTg, Akita, and LepTg:Akita mice at 18 weeks of age (n ≥ 4in each group). Data are expressed as means ± SE. ††P < 0.01 for WT vs. LepTg, §§P < 0.01 for WT vs. Akita, ‡P < 0.05, ‡‡P < 0.01 for WT vs. LepTg:Akita, ¶P < 0.05, ¶¶P < 0.01 for LepTg vs. Akita, ★P < 0.05, ★★P < 0.01 for LepTg vs. LepTg:Akita, *P < 0.05, and **P < 0.01 for Akita vs. LepTg:Akita. (A high-quality digital representation of this figure is available in the online issue.)

FIG. 4.

FIG. 4.

Plasma levels of TG, NEFA, β-hydroxybutyrate, and TBARS. A and B: Fasting plasma levels of TG (A) and NEFA (B) concentrations in WT, LepTg, Akita, and LepTg:Akita mice at 18 weeks of age (n ≥4 in each group). C: Fasting plasma levels of β-hydroxybutyrate concentrations in WT, LepTg, Akita, and LepTg:Akita mice at 11 weeks of age (n ≥4 in each group). D: Fasting plasma levels of TBARS concentrations in WT, LepTg, Akita, and LepTg:Akita mice at 18 weeks of age (n ≥4 in each group). Data are expressed as means ± SE. §§P < 0.01 for WT vs. Akita, ‡P < 0.05, ‡‡P < 0.01 for WT vs. LepTg:Akita, ¶P < 0.05, ¶¶P < 0.01 for LepTg vs. Akita, ★★P < 0.01 for LepTg vs. LepTg:Akita, and *P < 0.05 for Akita vs. LepTg:Akita.

FIG. 5.

FIG. 5.

Urinary albumin excretion and histology of glomeruli. A: Time course of urinary albumin excretion of WT (◇), LepTg (♦), Akita (○), and LepTg:Akita (●). Data are expressed as means ± SE (n ≥4 in each group). §§P < 0.01 for WT vs. Akita, ¶¶P < 0.01 for LepTg vs. Akita, ★P < 0.01 for LepTg vs. LepTg:Akita, *P < 0.05, and **P < 0.01 for Akita vs. LepTg:Akita. B: PAS-staining of representative glomeruli from WT, LepTg, Akita, and LepTg:Akita mice at 22 weeks of age. Scale bar indicates 50 μm. (A high-quality color representation of this figure is available in the online issue.)

FIG. 6.

FIG. 6.

Survival rates. Survival curves of Akita (dotted line) and LepTg:Akita (solid line) mice (n ≥11 in each group). Survival rate of Akita mice markedly decreased relative to LepTg:Akita mice (P < 0.01) and was ∼50% at 52 weeks of age.

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