Reversing Neuronal Klotho Dysfunction-Mediated Diabetic Neuropathy Through 16:8 Intermittent Fasting

Area of Science:

• Endocrinology
• Metabolism
• Gerontology

Background:

• Type 1 diabetes mellitus (T1DM) management relies on insulin, but effective strategies for reversing associated diabetic neuropathy (DN) and improving glucose metabolism, especially in diverse age groups, are needed.
• The anti-aging gene Klotho plays a role in regulating signaling pathways crucial for glucose metabolism and mitigating DN.
• Investigating novel therapeutic approaches like intermittent fasting (IF) is essential for T1DM and DN management.

Purpose of the Study:

• To evaluate the efficacy of 16:8 intermittent fasting (168if) protocols in young and elderly diabetic mice with T1DM.
• To determine if 168if is age-dependent and its effects on Klotho-related signaling molecules.
• To assess the potential of 168if for drug reduction and alleviating neuropathic pain in T1DM.

Main Methods:

• Five 16:8 intermittent fasting (168if) protocols with varied timing were applied to young and elderly diabetic mice.
• Assessment of blood glucose levels, neuropathic pain indicators (thermal hyperalgesia, mechanical allodynia), and Klotho-related signaling molecules (Klotho, PKCε, FGFR1, NF-κB).
• Evaluation of mortality rates in elderly diabetic mice undergoing the DNf (early-stage T1DM onset) 168if protocol.

Main Results:

• Early-stage 168if (DNf protocol) effectively reduced blood glucose in both young and elderly diabetic mice.
• The DNf protocol increased mortality risk in elderly diabetic mice, rendering it unsuitable for this population.
• Young mice on the DNf protocol showed reduced neuropathic pain, reversed Klotho downregulation, and normalized PKCε, FGFR1, and NF-κB expression.

Conclusions:

• 16:8 intermittent fasting is effective for blood glucose control and relieving neuropathic pain in young T1DM patients when initiated early.
• The DNf protocol is not suitable for elderly diabetic mice due to increased mortality risk.
• Klotho-related signaling pathways are significantly modulated by early-stage 168if, offering a potential non-pharmacological approach for T1DM and DN management in younger individuals.