recommended COLLAGEN, ASCORBATE (vitamin C)

abnormalities of ascorbic acid metabolism and t2d

Diabetes 1988 Apr; 37(4): 371-376.  ADA American diabetes Association http://diabetes.diabetesjournals.org/content/37/4/371.short Decreased Collagen Production in Diabetic Rats Abstract Many of the chronic complications of diabetes mellitus involve defects in the connective tissue such as poor wound healing, diminished bone formation, and decreased linear growth. Because collagen is the major protein component of these connective tissues, we examined collagen production in diabetic rats as a probe of this generalized defect in connective tissue metabolism. Doses of streptozocin ranging from 35 to 300 mg/kg were used to induce diabetes of graded metabolic severity in rats. Parietal bone or articular cartilage was removed and incubated at 37°C with 5 μCi L-[5-3H]proline for 2 h, and collagen and noncollagen protein production were quantitated after separation with purified bacterial collagenase. Within 2 wk after induction of diabetes, collagen production was significantly reduced in bone and cartilage from diabetic rats to 52% (P < .01) and 51% (P < .01) of control (buffer-injected) levels, respectively. In contrast, noncollagen protein production in bone and cartilage from diabetic animals was no different from in tissue from control rats. The correlation between collagen relative to total protein production (relative rate) and the degree of hyperglycemia was highly significant for both bone (r = −.77, P < .001) and cartilage (r = −.87, P < .001). Other factors found to correlate with altered collagen production were the duration of diabetes and the amount of weight loss. Thus, diabetes is associated with a marked decrease in collagen production, which was seen early after induction of diabetes and was specific when compared with noncollagen protein production. Cumulative effects of these marked changes in collagen production may contribute to the chronic connective tissue complications in diabetes. Copyright © 1988 by the American Diabetes Association ^^^^^^ Endothelia dysfunction is the starting point for atherogenesis and the subsequent ischemic events.  Insulin resistance explains the association of diabetes with such events, and why TOFI people are also at high risk. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ http://diabetes.diabetesjournals.org/content/38/6/758.long?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Diabetes_TrendMD_0 Diabetes 1989 Jun; 38(6): 758-763.  Nutritional and Hormonal Regulation of Articular Collagen Production in Diabetic Animals 1.       Guillermo E Umpierrez, Steven Goldstein,  Lawrence S Phillips and,  Robert G Spanheimer   Abstract Although changes in collagen production probably play a major role in the connective tissue defects of diabetes, we do not know to what extent these changes are attributable to hormonal/metabolic versus nutritional alterations. To study collagen production as influenced separately by nutrition versus hormonal/metabolic factors, rats were given 50 mg/kg i.v. streptozocin (STZ) (mild weight-gaining diabetes) or 100 mg/kg STZ (severe weight-losing diabetes) and compared with nondiabetic food-restricted rats to match weight changes in diabetic animals. Articular cartilage was incubated with [3H]proline, and uptake of [3H]proline into both collagen and non-collagen proteins was determined with purified bacterial collagenase. Collagen decreased to 49% in mildly diabetic rats and 16% in severely diabetic rats, compared with control rats fed ad libitum and decreased to 85 and 73%, respectively, in food-restricted rats (both P < .01 vs. diabetes). Diabetes induced a greater defect in collagen production than food restriction and a greater decrease in collagen than non-collagen protein production within each group, suggesting a specific effect on collagen   {this is caused by the reduction in ascorbate].  With comparable levels of metabolic severity (glucose, β-hydroxybutyrate), diabetic animals that lost weight produced significantly less collagen than animals that gained weight, suggesting separate mechanisms. Quantitation of the impact of undernutrition on collagen production in diabetes demonstrated that ∼31 to 32% of the defect was due to undernutrition, leaving ∼68–69% of the defect due to the diabetic state. Multivariate analysis of metabolic (glucose, β-hydroxybutyrate), hormonal (insulin, insulin-like growth factor I [IGF-I]), and nutritional (weight change) factors revealed that altered collagen production was correlated only with the degree of weight change (P <.01) in food-restricted animals; reduced collagen production was correlated only with circulating IGF-I (P <.01) in diabetic animals [as expected given less food and lower ascorbate. Rats are a poor model since they produce some of their ascorbate.] ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ http://www.sciencedirect.com/science/article/pii/S0889852908000327   Endocrinology and Metabolism   Volume 37, Issue 3, September 2008, Pages 685-711 An Integrated View of Insulin Resistance and Endothelial Dysfunction Endothelial dysfunction and insulin resistance are frequently comorbid states. Vasodilator actions of insulin are mediated by phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways that stimulate production of nitric oxide from vascular endothelium. This helps to couple metabolic and hemodynamic homeostasis under healthy conditions. In pathologic states, shared causal factors, including glucotoxicity, lipotoxicity, and inflammation selectively impair PI3K-dependent insulin signaling pathways that contribute to reciprocal relationships between insulin resistance and endothelial dysfunction. This article discusses the implications of pathway-selective insulin resistance in vascular endothelium, interactions between endothelial dysfunction and insulin resistance, and therapeutic interventions that may simultaneously improve both metabolic and cardiovascular physiology in insulin-resistant conditions

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ https://link.springer.com/article/10.1007%2Fs00198-009-1066-z?LI=true Osteoporosis International February 2010, Volume 21, Issue 2, pp 195–214 Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus Abstract Collagen cross-linking, a major post-translational modification of collagen, plays important roles in the biological and biomechanical features of bone. Collagen cross-links can be divided into lysyl hydroxylase and lysyl oxidase-mediated enzymatic immature divalent cross-links, mature trivalent pyridinoline and pyrrole cross-links, and glycation- or oxidation-induced non-enzymatic cross-links (advanced glycation end products) such as glucosepane and pentosidine. These types of cross-links differ in the mechanism of formation and in function. Material properties of newly synthesized collagen matrix may differ in tissue maturity and senescence from older matrix in terms of cross-link formation. Additionally, newly synthesized matrix in osteoporotic patients or diabetic patients may not necessarily be as well-made as age-matched healthy subjects. Data have accumulated that collagen cross-link formation affects not only the mineralization process but also microdamage formation. Consequently, collagen cross-linking is thought to affect the mechanical properties of bone. Furthermore, recent basic and clinical investigations of collagen cross-links seem to face a new era. For instance, serum or urine pentosidine levels are now being used to estimate future fracture risk in osteoporosis and diabetes. In this review, we describe age-related changes in collagen cross-links in bone and abnormalities of cross-links in osteoporosis and diabetes that have been reported in the literature.       Couldn’t find IR and ascorbate, though there were articles on collagen and diabetes   ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ http://www.sciencedirect.com/science/article/pii/S0889852908000297 Endocrinology and Metabolism Volume 37, Issue 3, September 2008, Pages 603-621 Insulin Resistance and Atherosclerosis         Abstract      Insulin resistance characterizes type 2 diabetes and the metabolic syndrome, disorders associated with an increased risk of death due to macrovascular disease. In the past few decades, research from both the basic science and clinical arenas has enabled evidence-based use of therapeutic modalities such as statins and angiotensin-converting enzyme inhibitors to reduce cardiovascular (CV) mortality in insulin-resistant patients. Recently, promising drugs such as the thiazolidinediones have come under scrutiny for possible deleterious CV effects. Ongoing research has broadened our understanding of the pathophysiology of atherosclerosis, implicating detrimental effects of inflammation and the cellular stress response on the vasculature. In this review, we address current thinking that is shaping our molecular understanding of insulin resistance and atherosclerosis.

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