DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet
Jun Shirakawa1, Tomoko Okuyama1, Mayu Kyohara1
1Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004 Japan.
Background:
Diabetes therapy that not only lowers glucose levels but also lengthens life spans is required. We previously demonstrated that DPP-4 inhibition ameliorated β cell apoptosis and adipose tissue inflammation in β cell-specific glucokinase haploinsufficient mice fed a diet containing a combination of sucrose and linoleic acid (SL).
Methods:
In this study, we investigated the effects of DPP-4 inhibition in obese diabetic db/db mice fed an SL diet or a control diet containing sucrose and oleic acid (SO). We also examined the effects of DPP-4 inhibition in IRS-1-deficient mice fed an SL or SO diet as a model of insulin resistance.
Results:
DPP-4 inhibition efficiently increases the active GLP-1 levels in db/db mice. Unexpectedly, the SL diet, but not the SO diet, markedly increases mortality in the db/db mice. DPP-4 inhibition reduces the early lethality in SL-fed db/db mice. DPP-4 inhibition improves glucose tolerance, β cell function, and adipose tissue inflammation in db/db mice fed either diet. No significant changes in glycemic control or β cell mass were observed in any of the IRS-1-deficient mouse groups.
Conclusions:
A diet containing a combination of sucrose and linoleic acid causes early lethality in obese diabetic db/db mice, but not in lean and insulin resistant IRS-1 knockout mice. DPP-4 inhibition has protective effects against the diet-induced lethality in db/db mice.
Insights
A diet high in sucrose and linoleic acid increases mortality in diabetic mice, but DPP-4 inhibition (dipeptidyl peptidase-4 inhibition) reduces this lethality and improves metabolic health.
Area of Science:
- Metabolic disease research
- Pharmacological interventions in diabetes
Background:
- Novel diabetes therapies are needed to improve glycemic control and longevity.
- Previous studies showed DPP-4 inhibition benefits beta cell function and reduces inflammation in specific mouse models.
Purpose of the Study:
- To investigate the impact of DPP-4 inhibition on obese diabetic mice (db/db) and insulin-resistant mice (IRS-1 deficient) fed diets with sucrose and linoleic acid (SL) or sucrose and oleic acid (SO).
Main Methods:
- Obese diabetic db/db mice and insulin-resistant IRS-1 deficient mice were fed either an SL or SO diet.
- The effects of DPP-4 inhibition were assessed in these models.
- Key parameters included mortality, glucose tolerance, beta cell function, and adipose tissue inflammation.
Main Results:
- The SL diet significantly increased mortality in db/db mice, while the SO diet did not.
- DPP-4 inhibition reduced early lethality in SL-fed db/db mice.
- DPP-4 inhibition improved glucose tolerance, beta cell function, and adipose tissue inflammation in db/db mice on both diets. No significant changes were noted in IRS-1 deficient mice.
Conclusions:
- A diet combining sucrose and linoleic acid induces premature death in obese diabetic mice, but not in lean, insulin-resistant mice.
- DPP-4 inhibition offers protection against diet-induced mortality in diabetic db/db mice.
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