Serum Type I Collagen Propeptide and Severity of Alcoholic Liver Disease

We assessed the relationship of serum type I collagen propeptide concentrations with various severity indices of alcoholic liver disease, including clinical and morphological severity, the amount of alcohol consumption, and the serum levels of other components of connective tissue. The serum concentration of the carboxyterminal propeptide of type I procollagen (PICP) was measured with a new radioimmunoassay that is devoid of a crossreaction caused by type III procollagen-derived fragments. A significant correlation was found between serum PICP and the Combined Clinical and Laboratory Index (CCLI) (rs = 0.58, p < 0.001) and the Combined Morphological Index (CMI) (rs = 0.57, p < 0.01). However, PICP was elevated less frequently than serum type III collagen propeptide (PIIINP), type IV collagen or laminin, and the correlations with the latter three parameter with both the CCLI (PIIINP: rs = 0.80, type IV collagen: rs = 0.80; and laminin: rs = 0.81) or CMI (PIIINP: rs = 0.75, type IV collagen: rs = 0.72; and laminin rs = 0.61) were all stronger than that of PICP. Furthermore, although during a follow-up period of 6 months, the mild or moderately drinking patients had a significant decrease in PIIINP and the heavily drinking patients had no improvement. PICP was, however, found to improve in both the mild and heavy drinkers. These results point to differences in handling of type I and type III collagen propeptides in alcoholic liver disease. The latter appears to be a more sensitive indicator of disease severity, presence of alcoholic hepatitis, and the amount of alcohol intake.     

Serum basement membrane and type III procollagen-related antigens in primary biliary cirrhosis

A characteristic histological lesion in early primary biliary cirrhosis (PBC) is disruption of the basement membrane around small bile ducts, which at later stages of the disease is followed by fibrosis. To assess the significance of serum basement membrane- and type III procollagen-related antigens in reflecting such processes, we have measured radioimmunologically the concentrations of serum laminin, type IV collagen and the aminoterminal propeptide of type III procollagen in 22 patients with PBC, classified into four stages according to liver histology. The mean laminin concentration in PBC patients was twice that of the healthy control subjects. Increased concentrations were observed in all patients with stage III or IV of the disease and also in 60% (6/10) of the patients, with early stages (I or II). Elevated serum type IV collagen concentrations were found only in four patients, all in the late, fibrotic stages of the disease. The basement membrane protein changes in serum were in accordance with immunohistochemical findings obtained with the antibodies against these proteins. Neither of these serum parameters emerged, however, as a significant predictive factor for survival. The changes in serum aminoterminal propeptide of type III procollagen resembled those in laminin P1. Moreover, the propeptide was also significant as a predictive factor for survival.     

Immunohistochemical study of basement membrane proteins and type III procollagen in myelofibrosis

In this study the distribution of type IV collagen in the marrow is compared with that of laminin, another basement membrane protein. In addition, incompletely processed type III procollagen is identified with specific antibodies. In normal bone marrow the distribution of the type III procollagen antigen closely resembles that of reticulin staining. In all the myelofibrotic samples, representing both early and advanced disease, the fibrous tissue stains heavily for this antigen. Thus type III procollagen which has not completely lost its aminoterminal propeptide is a genuine component of the extracellular matrix fibres in human bone marrow. Laminin is found with type IV collagen in continuous basement membranes in arterial walls, whereas only discontinuous strips of staining are seen along the sinusoids in normal marrow. In myelofibrosis the dilated or obliterated sinusoids have thickened or continuous basement membranes, visible with both stainings. Neovascularization also increases the extent of basement membrane staining in fibrotic marrow. With respect of these antigens, there is no difference between primary and secondary myelofibrosis. These changes warrant the use of serum antigens related to type IV collagen and to type III procollagen as markers for developing myelofibrosis.     

Serum type IV collagen in various liver diseases in comparison with serum 7S collagen,laminin, and type III procollagen peptide

The clinical significance of the immunoreactive triple helical domain of type IV collagen in serum was evaluated in 73 healthy controls and 161 patients with various biopsy-proven liver diseases. Although serum levels of type III procollagen peptide were increased in all liver diseases, those of type IV collagen, 7S collagen, and laminin were principally increased in chronic liver diseases associated with hepatic fibrogenesis/fibrosis. In both non-alcoholic and alcoholic liver diseases, 7S collagen was increased in serum, while type IV collagen and laminin in serum were particularly increased in alcoholic liver diseases and in hepatocellular carcinoma, in which latter the sensitivity was greater for type IV collagen than for laminin. Gel filtration analysis in Sephacryl S-400 revealed type IV collagen in serum to be a single molecular form with a molecular weight that correspond to type IV collagen, whereas 7S collagen was recognized as several heterogeneous macromolecules. These findings indicate that serum type IV collagen is derived from the type IV protocollagen pool, and is a sensitive marker for the fibrogenetic process in hepatic basement membranes.     

Serum markers for type IV collagen and type III procollagen in the myelofibrosis-osteomyelosclerosis syndrome and other chronic myeloproliferative disorders

Myelofibrosis is characterized by excessive deposition of interstitial and basement membrane collagens in the bone marrow. In this study, specific radioimmunoassays for the aminoterminal propeptide of type III procollagen and for the 7S collagen domain of type IV (basement membrane) collagen were used to determine how this accumulation is reflected in serum. Of the 41 patients with chronic myeloproliferative disorders studied, the highest levels of both parameters were found in idiopathic myelofibrosis and in chronic myelogenous leukaemia associated with bone marrow fibrosis. Increasing degrees of bone marrow fibrosis were accompanied by increasing serum concentrations of both markers, except for osteomyelosclerosis, where notably low values were seen. Pathologically high values of one or both parameters were also found in a few patients with polycythaemia vera or a transitional myeloproliferative disorder. The antigens related to type III procollagen and type IV collagen correlated significantly with each other and with the leucocyte count. These parameters should provide noninvasive means for following the accumulation of interstitial and basement membrane collagens in the bone marrow.     

Serum laminin and portal pressure in alcoholic cirrhosis. A study of 39 patients

A correlation between serum laminin, a glycoprotein found in basement membranes, and hepatic wedge pressure has previously been reported in a small number of patients with various liver diseases. To study this relationship in patients with alcoholic cirrhosis, we measured the wedge hepatic pressure and venous gradient, in comparison with serum concentrations of laminin and collagen metabolism products: N-terminal peptide of type III procollagen, collagen type I, and collagen type III in 39 patients. A statistically significant correlation was observed between serum laminin and wedged hepatic pressure (r = 0.529; p less than 10(-3] or hepatic venous gradient (r = 0.482; p = 0.002). By contrast, no statistically significant correlation was found between hemodynamic parameters and serum concentrations of N-terminal peptide of type III procollagen, collagen type I or collagen type III. These results suggest that, in patients with alcoholic cirrhosis, portal pressure may be estimated by serum concentration of laminin, and that perisinusoidal fibrosis, especially basement membrane thickening, may play an important role in the pathogenesis of portal hypertension in these patients.     

Biochemical markers of type III and I collagen: association with retinopathy and neuropathy in type 1 diabetic subjects.

AIMS: Connective tissue alterations may contribute to the development of diabetic long-term complications in eyes, kidneys and peripheral nerves. Collagen deposition may be increased in micro- and macrovascular disease in diabetic subjects. We tested whether biochemical markers of type III and I collagen metabolism are associated with retinopathy and neuropathy in Type 1 diabetes. METHODS: A total of 28 patients, mean age 43.4 +/- 9.5 (sd) and duration of diabetes 25.2 +/- 9.7 years, were studied. Stereoscopic colour fundus photographs were taken for assessment of retinopathy which was classified as no, background or proliferative. Concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in serum and urinary excretion of cross-linked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) into urine were measured. RESULTS: Average serum PIIINP was higher in subjects with proliferative (3.2 +/- 1.1 microg/l) than without proliferative retinopathy (2.5 +/- 0.6 microg/l) (P = 0.03). Average serum PICP was higher in subjects without retinopathy (181.7 +/- 19.5 microg/l) than in subjects with background retinopathy (132.1 +/- 42.7 microg/l) (P = 0.02). Concentrations of other collagen markers were not different in subjects with or without retinopathy. No association between collagen markers and neuropathy was found. CONCLUSIONS: The increased synthesis of type III collagen, reflecting deposition of matrix and basement membrane connective tissue, may be involved in the pathogenesis of proliferative retinopathy in Type 1 diabetic subjects. On the other hand, we observed decreased synthesis of Type I collagen, which can result in weakened vascular integrity in subjects with retinopathy.     

An inverse relationship between markers of fibrogenesis and collagen degradation in patients with or without alcoholic liver disease

OBJECTIVES: Excessive deposition of collagen leading to cirrhosis is a major complication of alcohol abuse. However, the mechanisms behind the accumulation of the extracellular matrix proteins are poorly understood. METHODS: We measured serum markers of collagen degradation (beta-CTx), fibrogenesis (PINP, PIIINP), and pro- and anti-inflammatory cytokines from 84 male heavy drinkers, who were either with (N = 52) or without (N = 32) clinical or histological signs of alcoholic liver disease (ALD), and from 20 healthy nonalcoholic controls. RESULTS: Serum beta-CTx levels in ALD patients were significantly lower than in healthy controls or in the alcoholics without liver disease, while PINP and PIIINP, reflecting type I and type III collagen synthesis, respectively, were significantly increased. The alcoholics without liver disease showed values, that were not significantly different from those of healthy controls. Serum beta-CTx correlated negatively with serum PIIINP and proinflammatory cytokines (IL-2, IL-6, IL-8, TNF-alpha), and positively with anti-inflammatory cytokines (IL-1, TGF-beta), whereas serum PIIINP correlated positively with these proinflammatory cytokines and negatively with the anti-inflammatory cytokines. Calculation of PIIINP/beta-CTx ratio was found to yield an excellent sensitivity (94%) and specificity (98%) in differentiating the alcoholics with liver disease. CONCLUSION: The present findings indicate a positive relationship between markers of collagen biosynthesis and proinflammatory cytokines, and a negative relationship between these markers and a marker of collagen degradation and anti-inflammatory cytokines, suggesting that a disturbed balance in these cellular responses may facilitate fibrogenesis and play a pivotal role in the pathogenesis of ALD. These findings should also be implicated in the development of noninvasive tools for discriminating individuals at risk for fibrogenesis.     

Serum aminoterminal type III procollagen peptide and the 7S domain of type IV collagen in patients with alcohol abuse. Relation to ultrastructural fibrosis in the acinar zone 3 and to serum hyaluronan

Serum concentrations of the aminoterminal propeptide of type III procollagen and of the 7S domain of type IV collagen, presumed to reflect fibrotic activity in liver tissue, and of the glycosamonoglycan hyaluronan, were obtained from 40 alcohol abusers, at the time of liver biopsy. The serological results were related to morphological findings in liver tissue, i.e. no fibrosis, fibrosis without cirrhosis, micronodular cirrhosis and macronodular cirrhosis, and to ultrastructural indications of perisinusoidal fibrosis in the acinar zone 3. All patients with fibrosis and cirrhosis on light microscopy had elevated serum levels of the type III procollagen peptide as well as of the 7S domain of type IV collagen. However, due to a considerable overlap between the groups, no relations could be demonstrated to the severity of the fibrosis, supporting the assumption that these serological markers reflect the current fibrotic activity and not the amount of fibrotic tissue previously deposited. Among patients without fibrosis on light microscopy, a relation between the propeptide levels and ultrastructural perisinusoidal zone 3 fibrosis was observed, suggesting that type III procollagen peptide may be valuable in detecting very early liver fibrosis. A positive correlation was demonstrated between the serum concentrations of type III procollagen peptide and hyaluronan. As hyaluronan is degraded in the liver endothelial cells, it is suggested that the liver is involved, not only in the synthesis, but also in the degradation of the propeptide.     

Basement membrane peptides as markers of liver disease in chronic hepatitis C

BACKGROUND/AIM: Chronic hepatitis C is characterised by slow progression to liver fibrosis. In liver fibrosis, basement membrane components are increasingly deposited around the vessels and in the portal tracts. Serum assays can measure the two major components of the basement membrane, type IV collagen and laminin. The aim of this study was to determine whether serum levels of type IV collagen and laminin are related to severity of liver injury in chronic hepatitis C. METHODS: Thirty-seven patients with chronic hepatitis C (CHC) and five healthy controls were studied. Serum type IV collagen was measured by a one-step sandwich EIA kit (Fuji, Japan) and serum laminin was measured by RIA (CIS, UK). Liver biopsies in patients with CHC were scored using a previously described grading and staging system. Liver biopsy scores were compared to serum levels of laminin, type IV collagen and alanine aminotransferase (ALT). Receiver operating characteristic (ROC) analysis was used to compare the ability of the assays to detect advanced liver injury. RESULTS: The median serum concentration of type IV collagen was 127.1 ng/ml (range 17.7 to 317.4) in CHC patients compared to a median of 61.3 ng/ml (range 11.5 to 102.3) in controls, p=0.006. The median serum concentration of laminin was 1.12 U/ml (range 0.74 to 2.46) in CHC compared to a median of 0.87 U/ml (range 0.83 to 1.06) in controls, p=0.07. Both serum type IV collagen and laminin were significantly correlated with the fibrotic stage and also with the necroinflammatory injury scores- histological activity index, portal inflammation and periportal hepatitis. Serum ALT was significantly correlated with portal inflammation. Using ROC analysis, the area under the curve for type IV collagen and laminin was 0.83 (p=0.001) and 0.82 (p=0.0017), respectively, while the area under the curve for ALT was 0.54 (p=0.1). CONCLUSIONS: Serum assays of basement membrane peptides are accurate non-invasive markers of liver fibrosis and liver inflammation in chronic hepatitis C. These markers are superior to serum ALT in reflecting liver injury and they have high specificity and sensitivity in detecting advanced liver disease in chronic hepatitis C.     

Extracellular matrix in normal and fibrotic human lungs

Polyclonal affinity-purified antibodies to human collagen types I, III, and IV, and laminin were used to compare the extracellular matrix (ECM) in 10 normal and 32 abnormal lungs by indirect immunofluorescence. In normal lungs, type IV collagen and laminin codistributed in a uniform linear pattern along the epithelial and endothelial basement membranes. Type III collagen was found within the alveolar septa and interstitium in an interrupted ribbonlike pattern and was aggregated at the entrance rings of the alveoli. Type I collagen was distributed irregularly within the alveolar wall and was less prominent than type III collagen. In patients with pulmonary disease not characterized by interstitial fibrosis (n = 15), the distribution of ECM components studied was essentially normal. In pulmonary disease in which interstitial fibrosis was the characteristic feature, such as idiopathic pulmonary fibrosis (IPF) and adult respiratory distress syndrome (ARDS) (n = 17), collagen types I and III accumulated in the expanded interstitium. Type III collagen was initially predominant in the thickened alveolar septa and interstitium, whereas type I collagen appeared to be the principal collagen at later stages in the disease course. The basement membrane was disrupted early in the disease course with invasion of the alveolar spaces by interstitial collagens similar in type to those present in the adjacent interstitium.     

Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin.

Specific antibodies to collagen type IV, laminin, and fibronectin were used to localise these proteins by indirect immunofluorescence in frozen sections of normal and fibrotic liver. In normal livers distinct staining was found in basement membranes of blood and lymph vessels, of bile ducts and ductules and around nerve axons. Positive reactions for type IV collagen and fibronectin were also observed in the perisinusoidal space, while hepatocytes and most of the interstitial matrix of portal fields remained unstained. Liver specimens obtained from patients with alcoholic liver disease (fatty liver, hepatitis or cirrhosis) and chronic active hepatitis showed a more intense reaction with the antibodies in the perisnusoidal space including now distinct staining for laminin. These patterns were particularly prominent at borders between fibrotic septa and remnants of parenchyma or pseudolobules. Strong reactions were also found for type IV collagen and fibronectin in the periportal interstitium and in large fibrotic areas. The findings support previous electron-microscopical and chemical evidence for increased basement membrane production in human liver fibrosis and demonstrate that this may involve different proteins and occur at different anatomical sites.     

Hepatic fibrosis in rats produced by carbon tetrachloride and dimethylnitrosamine: observations suggesting immunoassays of serum for the 7S fragment of type IV collagen are a more sensitive index of liver damage than immunoassays for the NH2-terminal propeptide of type III procollagen.

Liver fibrosis was induced in rats both with carbon tetrachloride and dimethylnitrosamine. Assays were performed on steady-state levels of messenger RNAs in the liver for several collagens and basement membrane components. The results indicated marked increases in the steady-state levels of messenger RNA for type I collagen, type III collagen, type IV collagen and the B2 component of laminin. In the same animals, immunoassays were performed for serum levels of the N-terminal propeptide of type III procollagen and the 7S fragment of type IV collagen. The results demonstrated an increase in the serum levels of 7S fragment that occurred early and closely paralleled the increase in the steady-state levels of messenger RNA for the alpha 1(IV) chain of type IV collagen. In contrast, no significant increase was seen in the serum levels of the N-propeptide of type III procollagen. The results suggest that immunoassays for 7S fragment of type IV collagen in serum are a more sensitive index for liver cell damage and fibrosis than assays for the N-propeptide of type III procollagen. The results suggest that greater attention should be paid to assays of 7S fragments in assessing hepatic fibrosis in man.     

Liver fibrosis and extracellular matrix

Liver fibrosis and extracellular matrix play a central role in liver function impairment. Little information is available on the dynamic aspects and the natural history of fibroplasia, even if there is growing evidence that extracellular matrix accumulation (collagen I, III, IV, fibronectin, laminin, proteoglycans, etc.) is not to be considered only a passive structural support for damaged hepatic tissue, but may actively modulate liver cell behaviour. Clinicians need to date liver fibrosis and to monitor connective tissue synthesis and degradation, but attempts to develop reliable serological markers for collagen metabolism are hampered by the absence of a well defined golden standard to validate them. Nevertheless, serum type III aminoterminal procollagen peptide, at the moment, seems to be the most acceptable parameter of fibrogenesis. The data concerning the mechanisms of collagen production-degradation are becoming so precise and numerous that even if they have not, to date, led to 'routine' advantages for patients, they will end up becoming important tools in the clinical practice and management of liver fibrosis.     

Schistosoma mansoni infection in a recently exposed community in Senegal: lack of correlation between liver morphology in ultrasound and connective tissue metabolites in serum

Summary Four hundred and seventy villagers of Ndombo, a village with recently established intensive transmission of Schistosoma mansoni in the Senegal River Basin, were enrolled in a study with the intention to assess hepatosplenic morbidity. All patients were examined parasitologically and by ultrasound. Hepatic fibrosis serum markers were determined in 153 adult patients (aminoterminal propeptide of procollagen type III, hyaluronan and laminin). By ultrasound, about 60% of the patients showed early stages of hepatic involvement, 3% of the patients unequivocally showed severe hepatosplenic pathology (grade 3 according to the Managil classification), whereas in another study performed in the same village 3 years earlier, no patients with severe hepatosplenic pathology had been found. No correlation between the aminoterminal propeptide of procollagen type III, hyaluronan or laminin and the ultrasound findings could be established. These hepatic fibrosis serum markers do not seem to be a sensitive method to detect early hepatic fibrosis in schistosomiasis.     

Serum aminoterminal type III procollagen peptide and the 7S domain of type IV collagen in patients with alcohol abuse Relation to ultrastructural fibrosis in the acinar zone 3 and to serum hyaluronan

ABSTRACT— Serum concentrations of the aminoterminal propeptide of type III procollagen and of the 7S domain of type IV collagen, presumed to reflect fibrotic activity in liver tissue, and of the glycosamonoglycan hyaluronan, were obtained from 40 alcohol abusers, at the time of liver biopsy. The serological results were related to morphological findings in liver tissue, i.e. no fibrosis, fibrosis without cirrhosis, micronodular cirrhosis and macronodular cirrhosis, and to ultrastructural indications of perisinusoidal fibrosis in the acinar zone 3. All patients with fibrosis and cirrhosis on light microscopy had elevated serum levels of the type III procollagen peptide as well as of the 7S domain of type IV collagen. However, due to a considerable overlap between the groups, no relations could be demonstrated to the severity of the fibrosis, supporting the assumption that these serological markers reflect the current fibrotic activity and not the amount of fibrotic tissue previously deposited. Among patients without fibrosis on light microscopy, a relation between the propeptide levels and ultrastructural perisinusoidal zone 3 fibrosis was observed, suggesting that type III procollagen peptide may be valuable in detecting very early liver fibrosis. A positive correlation was demonstrated between the serum concentrations of type III procollagen peptide and hyaluronan. As hyaluronan is degraded in the liver endothelial cells, it is suggested that the liver is involved, not only in the synthesis, but also in the degradation of the propeptide.     

Serum concentrations of N-terminal propeptide of type III procollagen and laminin in the outflow of fibrotic livers compared with liver-distal regions

The immunoreactive serum concentrations of the basement membrane glycoprotein laminin, including its split product (pepsin-resistant fragment P1), and of the aminoterminal propeptide of type III procollagen, were measured in liver outflow (hepatic vein) and in liver-distal venous (renal vein) and arterial (femoral artery) regions in liver cirrhotic and fibrotic patients (n = 40). In the majority of patients with liver fibrosis and cirrhosis (0.52 to 0.69) the relatively highest concentrations of laminin (2.09 U/ml, p less than 0.05) and of procollagen propeptide (28.5 ng/ml, p less than 0.001) were found in the hepatic vein. No significant correlations were observed between the concentrations of the two biomatrix proteins in either region of the circulation, but a highly positive statistical correlation (r = 0.9425) was found between the level of laminin in the hepatic vein of cirrhotic subjects and portal venous pressure. The respective correlations were lower for laminin measured in the renal vein and the femoral artery. The concentration of procollagen propeptide was statistically not related to the portal venous pressure.     

Cardiac microinjury measured by troponin T predicts collagen metabolism in adults aged >=65 years with heart failure

BACKGROUND: Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition. METHODS AND RESULTS: Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74±6 years; 52% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P<0.001) and aminoterminal propeptide of procollagen III (β=0.12, P=0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions- Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.     

Dupuytren's disease in type I diabetic subjects: investigation of biochemical markers of type III and I collagen

OBJECTIVE: To clarify whether biochemical markers of collagen type III and I metabolism show alterations in type I diabetic subjects with Dupuytren's disease (DD) compared to those without DD. METHODS: DD was assessed in a total of 28 type I diabetic subjects, mean age 43.4 +/- 9.5 (SD) and duration of diabetes 25.2 +/- 9.7 years. Concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in serum and excretion of cross-linked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) into urine were measured. RESULTS: The prevalence of DD was 32% (9 of 28 diabetic subjects). Average serum ICTP was 2.7 +/- 0.8 micrograms/l in subjects without DD and 3.6 +/- 1.2 micrograms/l with DD (p = 0.0276). No significant association between other collagen markers and DD was found. The reference intervals of PIIINP and ICTP were exceeded only in 1 and 2 subjects, respectively, and they both had DD. CONCLUSION: The degradation of type I collagen might be increased in diabetic subjects with DD. The overall implication was that synthesis or degradation of type III and I collagen in diabetic subjects with DD did not differ enough from those without DD to reflect changes in the biochemical markers of type III and I collagen.