Abstract
ABSTRACTDiabetes mellitus (DM) is one of most common chronic diseases with an increasing incidence in most countries. Diabetic neuropathy (DN) is one of the earliest and main complications of diabetic patients, which is characterized by progressive, distal-to-proximal degeneration of peripheral nerves. The cellular and molecular mechanisms that trigger DN are highly complex, heterogeneous and not completely known. Animal models have constituted a valuable tool for understanding diabetes pathophysiology; however, the temporal course of DN progression in animal models of type 2 diabetes (T2DM) is not completely understood. In this work, we characterized the onset and progression of DN in BKS diabetic (db/db) mice, including the main functional and histological features observed in the human disease. We demonstrated that diabetic animals display progressive sensory loss and electrophysiological impairments in the early-to-mid phases of the disease. Furthermore, we detected an early decrease in intraepidermal nerve fiber (IENF) density in 18-week-old diabetic mice, which is highly associated with sensory loss and constitutes a reliable marker of DN. Other common histological parameters of DN – like Schwann cells apoptosis and infiltration of CD3+ cells in the sciatic nerve – were altered in mid-to-late phases of the disease. Our results support the general consensus that DN evolves from initial functional to late structural changes. This work aimed to characterize the progression of DN in a reliable animal model sharing the main human disease features, which is necessary to assess new therapies for this complex disease. Finally, we also aimed to identify an effective temporal window where these potential treatments could be successfully applied.
Highlights
Diabetes mellitus (DM) is one of most common chronic diseases, reaching epidemic level with approximately 425 million patients worldwide (International Diabetes Federation, 2017)
Glycemia, body weight and biochemical parameters through diabetes development Previously, it has been described that db/db mice developed obesity from four weeks and hyperglycemia from four to eight weeks of age (Sullivan et al, 2007; Wang et al, 2014; O’Brien et al, 2014)
Our results indicates that diabetic mice displayed a significant decrease in intraepidermal nerve fiber (IENF) density from 18 weeks of age compared to its littermates, and these differences worsened in 26- and 32-week-old diabetic mice, evidencing progressive impairments that correlate with disease evolution (Fig. 2)
Summary
Diabetes mellitus (DM) is one of most common chronic diseases, reaching epidemic level with approximately 425 million patients worldwide (International Diabetes Federation, 2017). T2DM is the most common form of DM, which accounts for at least 90% of all cases, and its incidence is increasing in most countries. One of the earliest and main complications in diabetic patients is diabetic neuropathy (DN), occurring in approximately 60% of DM cases (type 1 and 2) (Vincent and Feldman, 2004). According to NIH’s Diabetic Complications Consortium (DiaComp), DN diagnosis requires: (i) evaluation of sensory loss, (ii) nerve conduction velocity test, and (iii) identification of fiber anatomical defects, as reduction of intraepidermal nerve fiber (IENF) density or fiber myelination studies
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