| Home | Polyol pathway, neuropathy, myo-inositol, t2d, etc | Decreased collagen production with t2d, bone fragility, etc. | Low ascorbate is more significant than glycation in t2d | abnormalities of ascorbic acid metabolism and t2d | Ascorbate supplement recommended for t2d--2 grams | ascorbate polyol pathway abnormal metabolism et. | ascorbate deficiency reduced collagen polyol pathway | Insulin Resistance and Atherogenesis

recommended COLLAGEN, ASCORBATE (vitamin C)

Decreased collagen production with t2d, bone fragility, etc.

Merely decreased production of collagen can be pathogenic in that fresh replacement collagen is in short supply, which entails that older less functional collagen remains in use, such as in endothelial cells thus promoting endothelial dysfunction.  Other studies have shown that ascorbate enzyme for the synthesis of is affected through the polyol pathway --jk. 

Diabetes 1988 Apr; 37(4): 371-376.  ADA American diabetes Association


Decreased Collagen Production in Diabetic Rats


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 37C 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.


Since the advent of insulin therapy and the resulting marked reduction in acute metabolic complications, the major cause of diabetic morbidity and mortality has been the development of chronic complications. Subsequent observations have revealed that many of these complications are associated with a generalized defect in connective tissue metabolism, including poor wound healing (1), decreased bone mass and rate of formation (2), and thickening of the vascular basement membrane (3). Abnormalities in the connective tissue

of one organ may in fact be a signal of more generalized defects, which are seen in patients


in whom increased skin thickness was correlated with an increased incidence of retinopathy and neuropathy (4) and in the limited joint mobility syndrome, which was associated with an increased risk of microvascular disease (4,5). Because collagen is the most abundant protein

in mammals and the major protein component of connective tissues (6), the widespread


nature of connective tissue alterations in diabetes suggests that abnormalities in collagen metabolism may play a role.





…. magnitude and the specificity of changes in collagen production in diabetic animals demonstrate that collagen is more responsive to the altered conditions of diabetes than was previously suspected. Within 2 wks. after onset of diabetes, collagen production was decreased to ‐50% of that seen in tissues from control animals. In contrast, non‐collagen

protein production in the same tissue samples was no different from that in control. However, it could be demonstrated that in a subgroup of severely diabetic animals, non‐collagen protein production was reduced to 70% of control levels. Evidence for the specificity of the effect of diabetes on collagen, rather than total protein production was found when the relative rate of collagen production was compared in tissues from control and diabetic animals over a wide range of plasma glucose levels. With higher plasma glucose levels, there was a lower relative rate of collagen production in both cartilage (Fig. 1) and bone (Fig. 2) so that, at every level of hyperglycemia, collagen was decreased to a greater degree than non‐collagen protein production. Collagen is the most abundant protein in mammals, and distribution of collagen is ubiquitous (6). It provides tensile… addition to defects in collagen production, post‐ translational modifications of the collagen peptide have also been reported to occur in diabetes. Increased crosslinking of collagen occurs normally with aging, but it is accelerated in diabetic skin and tendon (18,19) and may lead to decreased solubility and increased accumulation of collagen in tissues through an increased half‐life. As shown for other proteins, non‐enzymatic glycosylation of collagen is also increased in diabetes (20), which may affect collagen metabolism by also changing the halflife of the collagen peptide. It is possible that these posttranslational modifications of collagen in diabetes may lead to excess collagen accumulation under conditions where there is decreased synthesis of collagen (7). Thus,

our studies, in combination with others, suggest the likelihood of more than one defect in


collagen metabolism in diabetes: 1) a decrease in collagen peptide production and 2) altered posttranslational modifications of collagen that may affect the long‐term turnover of tissue collagen. Diabetes mellitus is a complex disease, characterized by changes in metabolic substrates, hormones, and the general nutritional status. In our studies, we examined the correlation between collagen and noncollagen protein production and altered metabolic and nutritional Indices in diabetic animals. We found a significant negative correlation between collagen production and the degree of hyperglycemia, the duration of diabetes, and the amount of weight lost. Higher degrees of correlation were found when two factors were analyzed together for impact on collagen production. When duration of diabetes and the

amount of weight loss, or duration and hyperglycemia, were combined, there was a highly significant negative correlation with collagen production (P < .0001). Thus, although single metabolic or nutritional factors greatly influence collagen production, it is likely that combinations of these factors may be associated with a much more devastating impact on collagen production in diabetic animals. The mechanism of strength, organization, and integrity to the connective tissues (14); it plays a role in hemostasis through interaction with platelets (15); and it appears to participate in morphogenesis and differentiation during embryonic development (6). The potential implications of the rapid and marked drop in collagen production demonstrated in this study are, therefore, wide in range and may play a role in the chronic complication of diabetes. . . .


Metabolism of AA is abnormal in diabetes, and reduced plasma and tissue concentrations of this vitamin have been reported (1‐4). AA has many important functions and is essential for the maintenance of health. It is a cofactor regulating the activity of proline hydroxylase (EC, which catalyzes the formation of hydroxyproline, an amino acid specific for collagen and required for its structural stability (6). AA deficiency may therefore be responsible for some of the collagen abnormalities in diabetes, e.g., impaired wound healing

(11), decreased production of granulation tissue (12), and reduced proline hydroxylase activity


(13). We reported previously that decreased proline hydroxylase activity in the granulation tissue of diabetic animals can be normalized by dietary supplementation of AA (4). AA is also important in regulating the intracellular redox state and scavenging free, radicals (5). Taking these factors into consideration, the deficiency of AA in diabetes is potentially of great relevance in the pathogenesis of some diabetic complications.

Nutritional and Hormonal Regulation of Articular Collagen Production in Diabetic Animals

1.       Guillermo E UmpierrezSteven GoldsteinLawrence S Phillips and,  Robert G Spanheimer



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.]



Endocrinology and Metabolism   Volume 37, Issue 3September 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



Osteoporosis International February 2010Volume 21, Issue 2pp 195–214

Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus


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.

http://www.sciencedirect.com/science/article/pii/002604959190165S Metabolism

Volume 40, Issue 2, February 1991, Pages 146-149

Reduced mononuclear leukocyte ascorbic acid content in adults with insulin-dependent diabetes mellitus consuming adequate dietary vitamin C



Several recent studies suggest that vitamin C (ascorbic acid [AA]) status may be altered in insulin-dependent diabetes mellitus (IDDM). We measured the AA content of mononuclear leukocytes (MM-AA) as an indicator of tissue vitamin C status in adults with IDDM and nondiabetic adults matched for age and sex. Dietary vitamin C intake and plasma AA were analyzed to ensure that vitamin C availability was adequate. Dietary vitamin C intakes were above recommendations and were not different between the groups. MN-AA was reduced by 33% on average (P < .05) in adults with IDDM (1.75 μg/mg total protein [TP]) when compared with nondiabetics (2.60 μg/mg TP). When MN-AA is indexed to the dietary vitamin C intake (MN-AA100 mgdiet C), the storage deficit in adults with IDDM averages 50% (P < .05). This observation suggests an impaired tissue AA storage in adults with IDDM and supports the theory that intracellular scurvy contributes to the chronic degenerative complications of the disease.





Nutr Rev (1996) 54 (7): 193-202.  July 1, 1996

Increase the Requirement Does Diabetes Mellitus for Vitamin C?



This paper reviews the scientific evidence regarding the vitamin C status of people with diabetes mellitus and whether they might have increased dietary vitamin C requirements. English language articles published from 1935 to the present that either compare ascorbic acid concentrations of persons with and without diabetes mellitus or assess the impact of vitamin C supplementation on various health outcomes among persons with diabetes mellitus were examined. Most studies have found people with diabetes mellitus to have at least 30% lower circulating ascorbic acid concentrations than people without diabetes mellitus. Vitamin C supplementation had little impact on blood glucose concentrations, but was found to lower cellular sorbitol concentrations and to reduce capillary fragility. Much of the past research in this area has been methodologically weak. To further understand the relation of ascorbic acid and diabetes mellitus, randomized clinical trials of ascorbic acid supplementation should be a high priority for research..




Endocrinology and Metabolism Volume 37, Issue 3September 2008, Pages 603-621

Insulin Resistance and Atherosclerosis

5.     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.


https://www.researchgate.net/profile/Susan_Mclennan3/publication/20320496_Deficiency_of_Ascorbic_Acid_in_Experimental_Diabetes_Relationship_With_Collagen_and_Polyol_Pathway_Abnormalities/links/5729272108ae057b0a03405d.pdf  FULL
Deficiency of Ascorbic Acid in Experimental Diabetes: Relationship With Collagen and Polyol Pathway Abnormalities

1. Diabetes 1988 Mar; 37(3): 359-361 -- Address correspondence and reprint requests to Dr. D.K. Yue, Department of Medicine, The University of Sydney, Sydney, NSW, Australia 2006.
The plasma and tissue concentration of ascorbic acid (AA) is reduced in diabetes. This study was designed to investigate the mechanism and significance of this phenomenon. The low plasma AA concentration of diabetic rats can be normalized by dietary AA supplement (20&#8211;40 mg/day), a dosage approximately equal to the maximal synthetic rate of this substance in the rats. Treatment of diabetic rats with this regime prevented the decrease in activity of granulation tissue prolyl hydroxylase (PRLase), an AA-dependent enzyme required for maintaining the normal properties of collagen. The decreased plasma AA concentration and granulation tissue PRLase activity in diabetes can also be normalized by the aldose reductase inhibitor tolrestat. We conclude that in diabetic animals there is a true deficiency of AA that may be responsible for some of the changes of collagen observed in diabetes. Treatment with AA or an aldose reductase inhibitor may prevent some of the diabetic complications with underlying collagen abnormalities.
From Full

The interaction between AA and collagen biosynthesis is complex, but a major factor is the ability of AA to maintain in vivo the enzyme PRLase in its active state (5,6). This enzyme catalyzes the hydroxylation of proline to form hydroxyproline, an amino acid required for the stability of the collagen molecule (9). We and others have previously observed a reduction of PRLase activity in the tissues of diabetic animals (10,11). Results herein showed that this phenomenon is a manifestation of AA depletion, which suggests a true deficiency of AA in diabetes and that its supplementation should be considered in the treatment of diabetic patients. This has the potential of preventing the abnormal synthesis and biomechanical properties of collagen in diabetes. Because AA has many other important biochemical actions, including the scavenging of free radicals (4), its therapeutic usage in diabetes has even wider implications&#8230;. The pattern of changes in AA metabolism is very similar in diabetic rats and humans, although rats can synthesize AA, whereas humans must rely on exogenous sources.
How aldose reductase inhibition leads to normalization of plasma AA is uncertain but may be related to the ability of this class of substance to raise the tissue concentration of reduced glutathione, which is required for the recycling of dehydroascorbate to AA by both enzymatic and nonenzymatic mechanisms (12,13). The urinary excretion of AA and myo-inositol is increased in experimental diabetes, and aldose reductase inhibition could also affect the metabolism of AA at this level.
This study confirms the low AA level in diabetes and reveals its relationship with the abnormalities of collagen and the polyol pathway. The depletion of AA in diabetes may not be a harmless phenomenon, and further studies are required to evaluate the need of treating diabetic patients with this vitamin.
It is known that aboriginal peoples serum glucose level averages in the bottom 10% of Swedes. Possible the present through glycation, hydration induced by glucose, or other mechanism such as defects in the use of ascorbate in the polyol pathway is causative of not just diabetic comorbidities but also those on the high fructose Western diet. That those on a very low carb diet do much better than those on the standard carb recommended diet, is another link to the effect of polyol pathway defects in pathologies associated with T2D. SOMETHING IS AMISS BUT POSSIBLE TODAYS TECHNOLOGY GIVEN THE COMPLEXITY AND POSSIBILITY OF MULTIPLE CAUSAL FACTORS MAKE A SIMPLE SOLUTION IMPOSSIBLE.

Acceleration of Fructose Mediated Collagen Glycation
http://journals.sagepub.com/doi/abs/10.1177/030006058901700307 Journal of Interna Medical Research May 1, 1989
The effect of fructose on the formation of advanced Maillard reaction products which show fluorescence and have crosslinking was investigated. Type I collagen was added to various concentrations of glucose and fructose which were then incubated at 37C for 4 weeks. The level of furosine and the fluorescence intensity both increased in direct proportion to glucose and fructose levels and to the duration of incubation. Incubation with fructose produced less furosine but more intense fluorescence than incubation with glucose. Furthermore, collagen was significantly less
soluble after incubation with fructose than after incubation with glucose. These results suggest that in the polyol pathway plays an important role in the formation of advanced Maillard products

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