Individual volumes in the series Frontiers in Animal Diabetes Research provide basic researchers as well as clinical investigators with in-depth coverage of basic experimental diabetes research. Each volume will be topic oriented with timely and liberally referenced reviews. The book provides a valuable reference source for basic researchers as well as clinical investigators, graduate students and research fellows in the areas of diabetology, endocrinology, physiology, and pharmacology.

It is well known that C-peptide fulfills an important function in the synthesis of insulin. After cleavage of proinsulin in the pancreatic β-cells, the 31-amino acid C-peptide is secreted into the portal circulation in equimolar concentrations with insulin. After its discovery in 1967 (1), it was believed that C-peptide might exert physiological effects similar to those of insulin. However, no influence on glucose or lipid metabolism could be demonstrated, and C-peptide was subsequently regarded as a waste product of insulin synthesis. Nevertheless, it was found to be useful as an indicator of β-cell function, and since the mid-1970s, C-peptide has been used as a surrogate marker for monitoring the course of type 1 and type 2 diabetes and determining the effects of interventions designed to preserve and improve residual β-cell function. Several studies demonstrate that patients with type 1 diabetes who show a degree of remaining β-cell activity are considerably less prone to develop microvascular complications than those who are totally C-peptide deficient (2). The possibility that C-peptide may exert direct effects of its own was reevaluated in the early 1990s. A series of studies was undertaken involving administration of the peptide to patients with type 1 diabetes, who lack C-peptide. This approach gave positive results, and it became apparent that replacement of C-peptide in physiological concentrations resulted in significant improvements in several diabetes-induced functional abnormalities (3–7). These surprising findings prompted a renewed interest in C-peptide physiology, and during the past 15 years, a steadily increasing number of reports on new aspects of C-peptide physiology have emerged. The information available today includes studies of the peptide’s interaction with cell membranes and its intracellular signaling properties (8). In vivo studies in animal models of type 1 diabetes have defined a beneficial influence of C-peptide on diabetes-induced functional and structural …

Diabetic neuropathy is a common complication of diabetes. While multiple pathways are implicated in the pathophysiology of diabetic neuropathy, there are no specific treatments and no means to predict diabetic neuropathy onset or progression. Here, we identify gene expression signatures related to diabetic neuropathy and develop computational classification models of diabetic neuropathy progression. Microarray experiments were performed on 50 samples of human sural nerves collected during a 52-week clinical trial. A series of bioinformatics analyses identified differentially expressed genes and their networks and biological pathways potentially responsible for the progression of diabetic neuropathy. We identified 532 differentially expressed genes between patient samples with progressing or non-progressing diabetic neuropathy, and found these were functionally enriched in pathways involving inflammatory responses and lipid metabolism. A literature-derived co-citation network of the differentially expressed genes revealed gene subnetworks centred on apolipoprotein E, jun, leptin, serpin peptidase inhibitor E type 1 and peroxisome proliferator-activated receptor gamma. The differentially expressed genes were used to classify a test set of patients with regard to diabetic neuropathy progression. Ridge regression models containing 14 differentially expressed genes correctly classified the progression status of 92% of patients (P < 0.001). To our knowledge, this is the first study to identify transcriptional changes associated with diabetic neuropathy progression in human sural nerve biopsies and describe their potential utility in classifying diabetic neuropathy. Our results identifying the unique gene signature of patients with progressive diabetic neuropathy will facilitate the development of new mechanism-based diagnostics and therapies.

It is indeed encouraging to see the rapid accumulation of new data on the pathophysiological role of C-peptide and the clinical benefits of its replacement in type 1 diabetic patients. It is also a pleasure to acknowledge an increasing number of investigators and clinicians joining the field.

Gray and white matter structural deficits may accompany type 1 diabetes. Earlier experimental studies have demonstrated neuronal deficits associated with impaired neurotrophic support, inflammation and oxidative stress. In this study we demonstrate in two patients with histories of poorly controlled type 1 diabetes and fatal brain edema of ketoacidosis neuronal deficits associated with a decreased presence of insulin and IGF-1 receptors and accumulation of nitrotyrosin in neurons of affected areas and the choroid plexus. The findings add support to the suggested genesis of T1DM encephalopathy due to compromised neurotrophic protection, oxidative stress, inflammation and neuronal deficits, as demonstrated in T1DM encephalopathy in the BB/Wor-rat.

The Review of Diabetic Studies,2009,6,3,136-137.DOI:10.1900/RDS.2009.6.136Published:November 2009Type:Review Article Authors:Anders AF Sima, and John Wahren Author(s) affiliations:Anders A.F. Sima1,2 and John Wahren3 1Department of Pathology, Wayne State University, Detroit, MI, USA. 2Department of Neurology, Wayne State University, Detroit, MI, USA. 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Abstract:It is well accepted that the connecting peptide (C-peptide) of proinsulin is a critical element in the biosynthesis of insulin. It facilitates the proinsulin molecule’s proper folding. Following cleavage of proinsulin, the two resultant peptides are stored in secretory granules in the beta-cells and eventually co-released into the circulation in equal concentrations. The possibility that Cpeptide may possess biological activity on its own was a consideration at the time of its discovery in 1968. However, no detectable influence on glucose metabolism in humans, or on lipolysis of isolated fat cells, could be observed. Consequently, the focus on C-peptide as a bioactive peptide diminished, and instead, interest centered on its usefulness as a marker of insulin secretion. In the early 1990s, direct C-peptide effects were re-evaluated in a new setting. Several studies were undertaken involving administration of the peptide to type 1 diabetes patients, who otherwise lacked C-peptide. This approach gave positive results. It emerged that replacement of physiological concentrations of C-peptide in this patient group resulted in significant improvements of diabetes-induced abnormalities in peripheral nerves and kidney functions. In addition, C-peptide was found to significantly augment the blood flow in skeletal muscle, myocardium, skin, and the kidney. Read more... Keywords:NilView:PDF (31.64 KB)

We investigated mechanisms underlying progressive axonal dysfunction and structural deficits in type 1 BB/Wor-rats from 1 week to 10 month diabetes duration. Motor and sensory conduction velocities were decreased after 4 and 6 weeks of diabetes and declined further over the remaining 9 months. Myelinated sural nerve fibers showed progressive deficits in fiber numbers and sizes. Structural deficits in unmyelinated axonal size were evident at 2 month and deficits in number were present at 4 mo. These changes were preceded by decreased availability of insulin, C-peptide and IGF-1 and decreased expression of neurofilaments andβ-III-tubulin. Upregulation of phosphorylating stress kinases like Cdk5, p-GSK-3β, and p42/44 resulted in increased phosphorylation of neurofilaments. Increasing activity of p-GSK-3βcorrelated with increasing phosphorylation of NFH, whereas decreasing Cdk5 correlated with diminishing phosphorylation of NFM. The data suggest that impaired neurotrophic support results in sequentially impaired synthesis and postranslational modifications of neuroskeletal proteins, resulting in progressive deficits in axonal function, maturation and size.

Encephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neuro-behavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide. Here we examined whether contributing factors such as activation of innate immune mediators are responsive to C-peptide replacement. Seven-month diabetic BB/Wor-rats and those treated with full C-peptide replacement were compared to age-matched control rats. Hippocampi of diabetic rats showed upregulation of RAGE and NF-kappaB, the former being localized to proliferating astrocytes. These changes were associated with increased expression of TNF-alpha, IL-1beta, IL-2 and IL-6 in hippocampi of diabetic rats. Full C-peptide replacement, which did not induce hyperglycemia, resulted in significant prevention of upregulation of RAGE expression, activation of NF-kappaB and activation of pro-inflammatory factors. In conclusion, impaired insulin activity is associated with upregulation of RAGE and pro-inflammatory factors, and these are likely to contribute to previously described oxidative and apoptotic neuronal cell death. Replacement of insulinomimetic C-peptide significantly prevents this cascade of events.

Diabetic encephalopathy is a recently recognized complication in type 1 diabetes. In this review, we summarize a series of experimental results obtained longitudinally in the spontaneously type 1 diabetic BB/Wor-rat, and bringing out the beneficial effects of C-peptide replacement. It is increasingly clear that lack of insulin and C-peptide, and perturbations of their signaling cascades in type 1 diabetes are detrimental to the regulation of neurotrophic factors and their receptors. Other consequences of such deficits and perturbations are innate inflammatory responses with effects on synaptogenesis, neurite degeneration, and early behavioral abnormalities. Replacement of C-peptide, which does not effect hyperglycemia, has beneficial effects on a variety of pro-apoptotic stressors, oxidative stressors, and finally on apoptosis. Eventually, this cascade of events leads to neuronal loss and decreased densities of white matter myelinating cells, with more profound deficits in behavioral and cognitive function. Such changes are likely to underlie gray and white matter atrophy in type 1 diabetes, and are significantly prevented by full C-peptide replacement. Present data demonstrate that C-peptide replacement has beneficial effects on numerous sequential and partly interrelated pathogenetic mechanisms, resulting in prevention of neuronal and oligodendroglial cell loss, with significant prevention of neurobehavioral and cognitive functions.

Diabetic neuropathy (DPN) is a dynamic condition affecting both type 1 and type 2 diabetic subjects. It can be divided into an early and reversible metabolic phase of nerve dysfunction. This is caused by hyperglycemia-induced activation of the polyol-pathway, redox imbalances as well as by insulin/C-peptide deficiencies resulting in impaired neural Na+/K+-ATPase activity and impairment of endoneurial blood flow. Superimposed on these metabolic abnormalities, progressive structural changes evolve which become increasingly resistant to therapeutic interventions. These affect both unmyelinated and myelinated fiber populations and consist of axonal atrophy, degeneration, and loss occurring in a dying-back fashion. The underlying mechanisms include impaired neurotrophic support including perturbed insulin/C-peptide signaling, resulting in suppressed expression of neuroskeletal protein genes, and aberrant phosphorylation of these axonal building blocks. Both the early metabolic and later occurring molecular abnormalities underlying the structural abnormalities are more severely affected in type 1 DPN relating to insulin and C-peptide deficiencies, which are not present in type 2 diabetes. This distinction between the two forms of DPN also underlies nodal and paranodal degeneration unique to both human and experimental type 1 DPN. Impaired insulin action affects the expression of nodal and paranodal adhesive molecules and their post-translational modifications. Such aberrations result in disruption of the paranodal barrier function with decreased nodal Na+-channels densities and worsening of the nerve conduction defect in type 1 DPN. In conclusion, major differences exist between type 1 and type 2 DPN, which can be directly related to the absence and presence of insulin action.

Autorzy zbadali dzialanie terapeutyczne peptydu Cw ustalonej neuropatii nocyceptywnej u szczurowBB/Wor z cukrzycą typu 1. Oceniono nocyceptywnąfunkcje nerwow, morfometrie niezmielinizowanychwlokien nerwu lydkowego i zwoju korzenia grzbietowego(DRG), zawartośc peptydu nocyceptywnegooraz ekspresje czynnikow neurotroficznych i ichreceptorow. Peptyd C podawano w dawce substytucyjnejdrogą pompy osmotycznej w ciąglym wlewielub raz dziennie w iniekcji podskornej. Szczuryz cukrzycą leczono od 4.-7. miesiąca trwania cukrzycyi porownywano z nieleczonymi szczurami z grupykontrolnej w tym samym okresie choroby. Peptyd Cpodawany przez pompe osmotyczną, lecz nie w iniekcjachpodskornych, zmniejszyl hiperalgezje i cukrzycozaleznąredukcje liczby wlokien niezmielinizowanych(p < 0,01) oraz średnią wielkośc aksonow(p < 0,05) w nerwie lydkowym. Ekspresja receptoraczynnika wzrostu nerwu (NGF) o duzym podobienstwie(NGFR-TrkA) w DRG zmniejszyla sie znamienniew 4. miesiącu (p < 0,01). Ekspresja receptorowinsulinowego oraz IGF-1 w DGR i NFG w nerwie kulszowym zmniejszyla sie znamiennie w 7. miesiącuu szczurow z cukrzycą (odpowiednio: p < 0,01,p < 0,05 i p < 0,005). Podawanie przez pompe osmotycznązapobieglo spadkowi ekspresji NGFR-TrkA,receptora insulinowego (p < 0,05) i IGF-IR (p < 0,005)w DRG oraz zwiekszylo zawartośc NGF (p < 0,05)w nerwie kulszowym. Natomiast peptyd C podawanydrogą podskorną wplynąl jedynie w niewielkimstopniu na morfometryczne i molekularne zmianyu szczurow z cukrzycą. Stwierdzono, ze peptyd C korzystniewplywa na cukrzycową neuropatie nocyceptywną;aby uzyskac efekt optymalny, nalezy utrzymywacfizjologiczne stezenie peptydu C w ciągu dnia.

Diabetic polyneuropathy (DPN) is the most common late complication of diabetes mellitus. The underlying pathogenesis is multifaceted, with partly interrelated mechanisms that display a dynamic course. The mechanisms underlying DPN in type 1 and type 2 diabetes mellitus show overlaps or may differ. The differences are mainly due to insulin deficiency in type 1 diabetes which exacerbates the abnormalities caused by hyperglycaemia.

Our previous work demonstrated that the sterol response element binding proteins (SREBP)-1 and SREBP-2, which are the key regulators of storage lipid and cholesterol metabolism respectively, are highly expressed in Schwann cells of adult peripheral nerves. In order to evaluate the role of Schwann cell SREBPs in myelination and functioning of peripheral nerves we have determined their expression during development, after fasting and refeeding, and in a rodent model of diabetes. Our results show that SREBP-1c and SREBP-2, unlike SREBP-1a, are the major forms of SREBPs present in peripheral nerves. The expression profile of SREBP-2 follows the expression of genes involved in cholesterol biosynthesis, while SREBP-1c is co-expressed with genes involved in storage lipid metabolism. In addition, the expression of SREBP-1c in the endoneurial compartment of peripheral nerves depends on nutritional status and is disturbed in type 1 diabetes. In line with this, insulin elevates the expression of SREBP-1c in primary cultured Schwann cells by activating the SREBP-1c promoter. Taken together, these findings reveal that SREBP-1c expression in Schwann cells responds to metabolic stimuli including insulin and that this response is affected in type 1 diabetes mellitus. This suggests that disturbed SREBP-1c regulated lipid metabolism may contribute to the pathophysiology of diabetic peripheral neuropathy.