Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
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Pentosidine is an advanced glycosylation end product and protein cross-link that results from the reaction of pentoses with proteins. Recent data indicate that long-term glycation of proteins with glucose also leads to pentosidine formation through sugar fragmentation. In this study, the relationship between the severity of diabetic complications and pentosidine formation was investigated in collagen from skin-punch biopsies from 25 nondiabetic control subjects and 41 IDDM patients with diabetes duration greater than 17 yr. Pentosidine was significantly elevated in all IDDM patients versus control subjects (P less than 0.0001). It correlated strongly with age (P less than 0.0001) and weakly with duration (P less than 0.082). Age-adjusted pentosidine levels were highest in grade 2 (severe) versus grade 1 and 0 complication in all four parameters tested (retinopathy, proteinuria, arterial stiffness, and joint stiffness). Significant differences were found for retinopathy (P less than 0.014) and joint stiffness (P less than 0.041). The highest degree of association was with the cumulative grade of individual complication (P less than 0.005), determined by summing indexes of all four parameters. Pentosidine also was significantly elevated in the serum of IDDM patients compared with control subjects (P less than 0.0001), but levels were not significantly correlated with age, diabetes duration, complication, or skin collagen pentosidine (P greater than 0.05). A high correlation between pentosidine levels and long-wave collagen-linked fluorescence also was observed, suggesting that pentosidine is a generalized marker of accelerated tissue modification by the advanced glycosylation/Maillard reaction, which is enhanced in IDDM patients with severe complications.
Diabetes 1992 Oct
PMID:Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM. 139 2

Collagen undergoes progressive browning with age and diabetes characterized by yellowing, fluorescence, and cross-linking. The present research was undertaken in order to investigate the nature of the collagen-linked fluorescence. Human collagen was exhaustively cleaved into peptides by enzymatic digestion. Upon purification, a highly fluorescent chromophore was identified and purified from old human collagen. Structure elucidation revealed the presence of an imidazo [4,5-b] pyridinium-type structure acting as a cross-link between arginine, lysine, and a pentose. This advanced glycosylation end-product and protein cross-link results from the reaction of pentoses with proteins and was named pentosidine. Further work indicated that long-term glycosylation of proteins with hexoses also leads to pentosidine formation through sugar fragmentation. The proposed mechanism of pentosidine formation involves the dehydration of the pentose-derived Amadori compound to form an intermediate which is attacked under base catalysis by the guanido group of arginine. The strict requirement for the Amadori rearrangement is uncertain. However, oxidation is definitely involved since pentosidine is not formed in the absence of oxygen. Five-carbon sugars contributing to pentosidine formation could be formed from larger sugars by oxidative fragmentation or from trioses, tetroses, and ketoses by condensation and/or reverse aldol reactions. Pentosidine increases exponentially in human skin at autopsy. Mean age-adjusted skin levels were significantly increased in subjects with uremia and especially in type 1 diabetics with uremia vs. controls. In skin biopsy, levels were significantly elevated in all diabetic (type 1) vs. control subjects. The highest degree of association was with the cumulative grade of diabetic complication (retinopathy, nephropathy, arterial stiffness, and joint stiffness). Pentosidine also forms in various proteins other than collagen, although to a much lesser extent. In blood, pentosidine is mainly associated with plasma proteins and is highly elevated during uremia. In the lens, it is associated with both water-soluble and -insoluble protein fractions and is especially elevated during brunescent cataract formation. The origin of pentosidine in vivo is uncertain. Evidence suggests that the pentoses are the most reactive sugars in pentosidine formation in vitro; however, the origin and importance of free pentoses in vivo, especially during the diabetic state, are not certain. Possible origins include hemolysis and/or a defect in the primary pentose metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Metab Rev 1991 Dec
PMID:Pentosidine: a molecular marker for the cumulative damage to proteins in diabetes, aging, and uremia. 181 79

Nonenzymatic glycosylation (glycation) of collagen was measured by boronate affinity chromatography in skin biopsies from 41 type I diabetics with mean duration of diabetes of 25 yr (range 20-40 yr) and from 25 age-matched controls. Mean level of Amadori products was significantly increased in diabetic [7.85 +/- 1.78 (SD) nmol/mg collagen] versus control subjects [3.34 +/- 1.06 (SD) nmol/mg collagen, P less than .001] but did not correlate with age, diabetes duration, or severity of retinopathy, nephropathy, arterial stiffness, and joint stiffness. Similarly, mean collagen content per biopsies was 42% increased in diabetic versus control subjects (P less than .001) but did not correlate with age, diabetes duration, or severity of complications. A weak but positive correlation between glycohemoglobin level and glycation of skin collagen was observed. These results indicate that Amadori products cannot explain by themselves the pathogenesis of diabetic complications unless individual tissue response to glycation is different in subjects with and without complication. They do not exclude a role for the late stages of the Maillard reaction, nonenzymatic browning, in the formation of some of these complications.
Diabetes 1986 Aug
PMID:Glycation of skin collagen in type I diabetes mellitus. Correlation with long-term complications. 373 33

Nonenzymatically glycosylated proteins gradually form fluorescent cross-linked protein adducts--a process termed "browning." The rate of this reaction increases with the glucose concentration. Assaying for the presence of browning products in long-lived proteins should therefore provide information on long-term metabolic control. We measured collagen-linked fluorescence typical for nonenzymatic browning in skin-biopsy specimens from 41 subjects with longstanding Type I diabetes and from 25 controls. Fluorescence correlated with age and (weakly) with the duration of diabetes. Mean age-adjusted fluorescence values were twice as high in diabetic subjects as in control subjects (P less than 0.0001) and increased with the severity of retinopathy, nephropathy, and arterial and joint stiffness. The correlation was significant for retinopathy (r = 0.42; P less than 0.01), arterial stiffness (r = 0.41; P less than 0.01), joint stiffness (r = 0.34; P less than 0.05), and the sum of all complications (r = 0.47; P less than 0.01). Fluorescence also correlated with systolic (r = 0.42; P less than 0.01) and diastolic (r = 0.36; P less than 0.05) blood pressures. If one can assume that the fluorescence results from a browning product of glucose, our data suggest that there is an overall correlation between the severity of diabetic complications and cumulative glycemia over many years.
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PMID:Relation between complications of type I diabetes mellitus and collagen-linked fluorescence. 394 67

Limited joint mobility (LJM) has been described in juvenile diabetic patients by Rosenbloom et al.; similar abnormalities are also present in adult diabetes. This modification may be associated with a high risk of microvascular complications. We tested the use of a goniometer in measuring subclinical joint limitation in 50 adult diabetic patients without overt, i.e., clinically evident, LJM as described by these authors. This diabetic population was compared with 118 nondiabetic adult controls. We found significant changes in hand mobility between the two groups for wrist flexion and extension of the 3rd and 5th fingers (P less than 0.001). Age was correlated to wrist flexion, wrist extension, and proximal interphalangeal flexion of the little finger. Wrist extension correlated with duration of diabetes (r = -0.37, P less than 0.01). Heavy manual activities significantly limited all motions except wrist and 5th finger metacarpophalangeal flexion. Early systematic examination by goniometry may prove to be a sensitive, quantitative, and inexpensive way of detecting joint stiffness at an early stage.
Diabetes Care
PMID:Quantification of early subclinical limited joint mobility in diabetes mellitus. 404 98

We examined 204 persons with insulin-dependent diabetes mellitus (IDDM), aged 7-23 yr, and 336 of their first-degree relatives, to determine whether there is a genetic component to the development of limited joint mobility. Simple and multiplex pedigrees with IDDM were studied along with normal controls. Only 1 of 90 normal controls had joint stiffness. Among 225 nondiabetic parents of children with IDDM, 7 (3%) had joint limitation, compared with 42 (21%) of children and youth with IDDM. Only 1 of 108 nondiabetic siblings of diabetic probands had limitation. Three parents had adult-onset diabetes and all had limited joint mobility. None of the 8 nondiabetic relatives with joint limitation had diabetic probands with joint involvement; 5 of these 8 tested were negative for islet cell auto-antibodies. There were 11 IDDM multiplex families with at least one member having joint limitation. The concordance rate for limited joint mobility of persons with diabetes for more than 5 yr who were over 12 yr of age was 56%, not different from the 48% frequency in patients with IDDM who met these age and duration criteria. Thus, evidence that limited joint mobility is a metabolic consequence of diabetes includes the virtual absence of limitation among first-degree relatives of probands, including probands with joint stiffness, and that the frequency of joint involvement is not increased in first-degree relatives of patients with IDDM. Furthermore, two brothers with pancreatic hypoplasia and a non-HLA-associated form of IDDM were affected with limited joint mobility. Nonetheless, the expression of this complication must be influenced by host factors, since not all persons with IDDM develop it, and those who do have variable ages of onset without correlation to control measures.
Diabetes Care
PMID:Limited joint mobility in childhood diabetes: family studies. 661 14

Diabetes mellitus is known to involve a wide range of musculoskeletal disorders including tendon contracture, tenosynovitis, joint stiffness, and osteoporosis. Recent studies with experimentally induced models of diabetes show that insulin therapy mitigates such alterations. These data are from relatively short-term experiments. This manuscript reports the results of tensile failure experiments on the canine patella-patellar tendon-tibia complex from a group of juvenile diabetic animals that received insulin therapy. The duration of the disease was 4-9 yr. The stiffness of the diabetic preparations in a physiological range of loading was approximately 13% greater than controls (P < 0.05). On the other hand, the strength of the tendon preparation from the diabetic population was not different from controls, but the mode of structural failure for controls was by substance and avulsion fractures while the diabetics failed by tensile fracture of the patella.
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PMID:Changes in the mechanical properties of patellar tendon preparations of spontaneously diabetic dogs under long-term insulin therapy. 808 66

A randomized controlled study of 19 patients with diabetes mellitus (10 men, 9 women) was undertaken to determine the effects of home exercise therapy on joint mobility and plantar pressures. Of the 19 subjects, 9 subjects performed unsupervised active and passive range-of-motion exercises of the joints in their feet. Each subject was evaluated for joint stiffness and peak plantar pressures at the beginning and conclusion of the study. After only 1 month of therapy, a statistically significant average decrease of 4.2% in peak plantar pressures was noted in the subjects performing the range-of-motion exercises. In the control group, an average increase of 4.4% in peak plantar pressures was noted. Although the joint mobility data revealed no statistically significant differences between the groups, there was a trend for a decrease in joint stiffness in the treatment group. The results of this study demonstrate that an unsupervised range-of-motion exercise program can reduce peak plantar pressures in the diabetic foot. Given that high plantar pressures have been linked to diabetic neuropathic ulceration, it may be possible to reduce the risk of such ulceration with this therapy.
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PMID:The effects of range-of-motion therapy on the plantar pressures of patients with diabetes mellitus. 1238 97

The majority of plantar ulcers in the diabetic population occur in the forefoot. Peripheral neuropathy has been related to the occurrence of ulcers. Long-term diabetes results in the joints becoming passively stiffer. This static stiffness may translate to dynamic joint stiffness in the lower extremities during gait. Therefore, the purpose of this investigation was to demonstrate differences in ankle and knee joint stiffness between diabetic individuals with and without peripheral neuropathy during gait. Diabetic subjects with and without peripheral neuropathy were compared. Subjects were monitored during normal walking with three-dimensional motion analysis and a force plate. Neuropathic subjects had higher ankle stiffness (0.236 N.m/deg) during 65 to 80% of stance when compared with non-neuropathic subjects (-0.113 N.m/deg). Neuropathic subjects showed a different pattern in ankle stiffness compared with non-neuropathic subjects. Neuropathic subjects demonstrated a consistent level of ankle stiffness, whereas non-neuropathic subjects showed varying levels of stiffness. Neuropathic subjects demonstrated lower knee stiffness (0.015 N.m/deg) compared with non-neuropathic subjects (0.075 N.m/deg) during 50 to 65% of stance. The differences in patterns of ankle and knee joint stiffness between groups appear to be related to changes in timing of peak ankle dorsiflexion during stance, with the neuropathic group reaching peak dorsiflexion later than the non-neuropathic subjects. This may partially relate to the changes in plantar pressures beneath the metatarsal heads present in individuals with neuropathy.
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PMID:Diabetic neuropathy is related to joint stiffness during late stance phase. 1808 23

Limited joint mobility is frequently observed in elderly people and in patients suffering from diabetes, who represent a growing segment of the population of western countries. Our review wishes to offer the state of art about this interesting topic, which may have important clinical implications, leading to impairment of both basic and instrumental activities of daily living. The main causes of a reduced range of motion are degenerative joint diseases and increased stiffness of collagen tissue. The main biochemical abnormality, common to aging and diabetes, is the non-enzymatic glycosilation of collagen, with advanced glycation end product (AGE) formation, which in turn leads to an increase of collagen cross-links. The most extensive accumulation of AGEs occurs in tissues that contain proteins with low turnover, such as the collagen in the extracellular matrix of articular capsule, ligaments and muscle-tendon units. The increase in collagen cross-linking alters the mechanical properties of these tissues with a decrease in elasticity and tensile strength, and an increase in mechanical stiffness. Besides this, AGEs react with specific cell surface receptors (RAGEs). The engagement of the ligand by RAGEs triggers cell-specific signalling, resulting in enhanced generation of reactive oxygen species and sustained up-regulation of pro-inflammatory mediators and adhesion molecules. An appropriate control of the glucose levels and a diet rich in antioxidant agents are recommended in patients with diabetes. Stretching and strengthening programmes are widely used, in order to prevent and to reduce joint stiffness, but the improvements with physiotherapy are little and short-lasting. Several drugs, which can interfere with AGE formation and removal, or with the cellular effects of AGEs, are under study (among them pyridoxamine, an active form of Vitamin B6, AGE-breaker compounds, glucosamine, rutin and derivatives, soluble RAGE isoforms, and statins). In experimental animal models, these drugs are effective in reducing diabetic complications due to AGE formation; however, further study is necessary before their extensive use in the clinical setting.
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PMID:Limited joint mobility in diabetes and ageing: recent advances in pathogenesis and therapy. 2124 49


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