The Metabolic Syndrome and Microvascular Complications in a Murine Model of Type 2 Diabetes

Abstract

To define the components of the metabolic syndrome that contribute to diabetic polyneuropathy (DPN) in type 2 diabetes mellitus (T2DM), we treated the BKS db/db mouse, an established murine model of T2DM and the metabolic syndrome, with the thiazolidinedione class drug pioglitazone. Pioglitazone treatment of BKS db/db mice produced a significant weight gain, restored glycemic control, and normalized measures of serum oxidative stress and triglycerides but had no effect on LDLs or total cholesterol. Moreover, although pioglitazone treatment normalized renal function, it had no effect on measures of large myelinated nerve fibers, specifically sural or sciatic nerve conduction velocities, but significantly improved measures of small unmyelinated nerve fiber architecture and function. Analyses of gene expression arrays of large myelinated sciatic nerves from pioglitazone-treated animals revealed an unanticipated increase in genes related to adipogenesis, adipokine signaling, and lipoprotein signaling, which likely contributed to the blunted therapeutic response. Similar analyses of dorsal root ganglion neurons revealed a salutary effect of pioglitazone on pathways related to defense and cytokine production. These data suggest differential susceptibility of small and large nerve fibers to specific metabolic impairments associated with T2DM and provide the basis for discussion of new treatment paradigms for individuals with T2DM and DPN.

Transcriptional networks of murine diabetic peripheral neuropathy and nephropathy: common and distinct gene expression patterns

“…Network-based comparisons also identified enriched functions and signalling pathways related to cell survival, proliferation, migration, blood vessel development, VEGFR3 endothelial signalling and angiopoietin signalling in both DN and DPN. While not new to our knowledge base, these categories provide reassurance for the long-standing idea that DPN and DN are ‘microvascular’ complications [28]. …”

An Update On Rodent Model Studies In Diabetic Neuropathy: A Brief Communication

“…These murine data support that this network of metabolic impairments activates detrimental feed-forward cycles of local and systemic oxidative stress and dysregulated energy homeostasis with local mitochondrial dysfunction and inflammation, thus resulting in neural injury and DPN. Corroborating this idea, there are some clinical studies showing that dyslipidemiais strongly correlated with DPN [2,87] and that lowering cholesterol, not glycemia, is significantly associated with decreasing lower-extremity amputations among patients with diabetes [2,88].…”

“…These findings along with similar results in several large clinical trials in patients with T2DM and DPN collectively suggest that treatment of the metabolic syndrome as a whole and not just hyperglycemia is required to effectively target DPN in T2DM. [2] …”

“…[1,2,11,14] Type 2 diabetes mellitus (T2DM) accounts for 95% of diagnosed diabetes, [2,3] and its complications, including heart disease and stroke, result in significant morbidity and mortality, representing the first and fourth most common causes of death, respectively, in the U.S. [2,3] Diabetes mellitus (DM) is the most common metabolic disease with a high prevalence rate in human society that eventually leads to the peripheral nervous system complications in a great number of patients. It is a chronic metabolic disorder that leads to long-term complications affecting some sites such as heart, kidney, retina, vessels and peripheral nerves.…”

“…[15] The best predictor of T2DM macrovascular complications is the preceding presence of microvascular complications, particularly diabetic polyneuropathy (DPN) and diabetic nephropathy (DN). [2] DPN consists of demyelization and axonal degeneration of peripheral nerves, [16], leading to slowing of nerve conduction velocity and reduction of the amplitude of the compound muscle and sensory nerve action potentials. [16,23] These features of diabetic polyneuropathy are observed in human diabetes [16,24] and in experimentally induced diabetic animals.…”