Objective: To evaluate mechanisms underlying diabetic neuropathy (DN) progression using indices of sural nerve morphometry obtained from two identical randomized placebo-controlled clinical trials. Research Design and Methods: Sural nerve myelinated fiber density (MFD), nerve conduction velocities, vibration perception thresholds, clinical symptom scores and a visual analogue scale for pain were analyzed in participants with DN. A loss of ≥ 500 fibers/mm 2 in sural nerve MFD over 52 weeks was defined as progressing DN and a MFD loss of ≤ 100 fibers/mm 2 during the same time interval as non-progressing DN. The progressing and non-progressing cohorts were matched for baseline characteristics using an O9Brien rank sum and baseline MFD. Results: At 52 weeks, the progressing cohort demonstrated a 25% decrease (p Conclusions: In this cohort of participants with mild/moderate DN, elevated triglycerides correlated with MFD loss independent of disease duration, age, diabetes control or other variables. These data support the evolving concept that hyperlipidemia is instrumental in the progression of DN.

https://diabetes.diabetesjournals.org/content/diabetes/58/7/1634.full.pdf

Elevated triglycerides correlate with progression of diabetic neuropathy

Diabetic neuropathies (DNs) are one of the most prevalent chronic complications of diabetes and a major cause of disability, high mortality, and poor quality of life. Given the complex anatomy of the peripheral nervous system and types of fiber dysfunction, DNs have a wide spectrum of clinical manifestations. The treatment of DNs continues to be challenging, likely due to the complex pathogenesis that involves an array of systemic and cellular imbalances in glucose and lipids metabolism. These lead to the activation of various biochemical pathways, including increased oxidative/nitrosative stress, activation of the polyol and protein kinase C pathways, activation of polyADP ribosylation, and activation of genes involved in neuronal damage, cyclooxygenase-2 activation, endothelial dysfunction, altered Na(+)/K(+)-ATPase pump function, impaired C-peptide-related signaling pathways, endoplasmic reticulum stress, and low-grade inflammation. This review summarizes current evidence regarding the role of low-grade inflammation as a potential therapeutic target for DNs.

/pdf/inflammation-as-a-therapeutic-target-for-diabetic-18k27ky7qs.pdf

Inflammation as a Therapeutic Target for Diabetic Neuropathies.

OBJECTIVE —To examine the association of stage of change with diet and exercise behaviors in response to a lifestyle intervention for Native Hawaiians (NHs). RESEARCH DESIGN AND METHODS —A family (‘ohana) support lifestyle intervention was compared with a standard intervention in NHs with or at risk for diabetes in two rural communities in Hawaii ( n = 147). Stage of change, as a hypothesized mediator of behavior change, and dietary and exercise behaviors were measured at baseline and at 1 year postintervention. RESULTS —Stage of change was significantly associated with positive dietary and exercise behaviors. NHs receiving the ‘ohana support (OS) intervention were more likely to advance from pre-action to action/maintenance for fat intake and physical activity than the group who received the standard intervention. Participants in the OS group who advanced from pre-action to action/maintenance showed more improvement in fat intake and physical activity than those in the standard group. CONCLUSIONS —These initial findings suggest that stage of change is an important factor in mediating lifestyle behavior changes in persons with or at risk for diabetes and merits further study among minority populations at high risk for diabetes.

/pdf/mediators-of-lifestyle-behavior-change-in-native-hawaiians-56760kislp.pdf

Mediators of Lifestyle Behavior Change in Native Hawaiians: Initial findings from the Native Hawaiian Diabetes Intervention Program

Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic nephropathy (DN), resulting in chronic kidney disease and potential organ failure. There is evidence for a heritable genetic susceptibility to DN, but despite intensive research efforts the causative genes remain elusive. Recently, genome-wide association studies have discovered several novel genetic variants associated with DN. The identification of such variants may potentially allow for early identification of at risk patients. Here we review the current understanding of the key molecular mechanisms and genetic architecture of DN, and discuss the merits of employing an integrative approach to incorporate datasets from multiple sources (genetics, transcriptomics, epigenetic, proteomic) in order to fully elucidate the genetic elements contributing to this serious complication of diabetes.

https://www.mdpi.com/2073-4425/4/4/596/pdf

The Genetics of Diabetic Nephropathy

Progress in developing treatments for diabetic neuropathy is slowed by our limited understanding of how disturbances in metabolic substrates - glucose and fatty acids - produce nerve injury. In this review, we present the current oxidative stress hypothesis and experimental data that support it. We identify weaknesses in our understanding of diabetes-disordered metabolism in the neurovascular unit, that is, in critical cell types of the microvascular endothelium, peripheral sensory neurons, and supporting Schwann cells. Greater understanding of peripheral nervous system bioenergetics may provide insight into new drug therapies or improvements in dietary interventions in diabetes or even pre-diabetes.

/pdf/bioenergetics-in-diabetic-neuropathy-what-we-need-to-know-2lgkoldqf7.pdf

Chrisholm Dj

Papers

The Diabetes Control and Complications Trial (DCCT). A milestone in diabetes management.