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The role of ubiquitin-proteasome system in the accelerated atherosclerotic progression of diabetic patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic diabetic and nondiabetic patients, as well as the effect of rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ activator, in diabetic plaques. Plaques were obtained from 46 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Diabetic patients received 8 mg rosiglitazone (n = 23) or placebo (n = 23) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLA-DR), ubiquitin, proteasome 20S activity, nuclear factor (NF)-κB, inhibitor of κB (IκB)-β, tumor necrosis factor (TNF)-α, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Compared with nondiabetic plaques, diabetic plaques had more macrophages, T-cells, and HLA-DR cells (P < 0.001); more ubiquitin, proteasome 20S activity (TNF-α), and NF-κB (P < 0.001); and more markers of oxidative stress (nitrotyrosine and O 2- production) and MMP-9 (P < 0.01), along with a lesser collagen content and IκB-β levels (P < 0.001). Compared with placebo-treated plaques, rosiglitazone-treated diabetic plaques presented less inflammatory cells (P < 0.01); less ubiquitin, proteasome 20S, TNF-α, and NF-κB (P < 0.01); less nitrotyrosine and superoxide anion production (P < 0.01); and greater collagen content (P < 0.01), indicating a more stable plaque phenotype. Similar findings were obtained in circulating monocytes obtained from the two groups of diabetic patients and cultured in the presence or absence of rosiglitazone (7.0 μmol/l). Ubiquitin-proteasome over-activity is associated with enhanced inflammatory reaction and NF-κB expression in diabetic plaques. The inhibition of ubiquitin-proteasome activity in atherosclerotic lesions of diabetic patients by rosiglitazone is associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by downregulating NF-κB-mediated inflammatory pathways. © 2006 by the American Diabetes Association.

The effect of rapid daily variation of glycemia and labile HbA1 on both antithrombin III (ATIII) activity and plasma concentration in ten insulin dependent diabetics has been evaluated. The variations of both plasma glucose and labile HbA1 were inversely correlated to the alterations of ATIII activity (r = -0.71 and r = -0.73, respectively, p less than 0.001), while no change in ATIII plasma concentration was present. These data suggest a direct role of glucose in determining rapid alteration of ATIII biologic activity, in vivo, in diabetes, probably mediated by labile non-enzymatic glycation.

The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)

Human plasma albumin was incubated in 25 mM/l glucose at 37 degrees C for up to sevent days. Aliquots of this mixture were also incubated with alpha-tocopherol (Vitamin E) at 2 mg/dl, 4 mg/dl and 8 mg/dl, respectively. Vitamin E inhibited protein glycation and, furthermore, shows a dose-dependent effect. This report suggests the possibility of using Vitamin E, at therapeutic doses, to obtain the inhibition of non-enzymatic glycation.

The serum concentrations of different glycosaminoglycan fractions have been studied in diabetic subjects without evidence of vascular complications and compared with those of age-and sex-matched normal subjects. Electrophoretic analysis of the various glycosaminoglycan fractions showed an increase in hyalunoric acid and heparin, and a decrease in heparan sulfate, chondroitin-4-sulfate and chondroitin-6-sulfate. Furthermore, the levels of glycosylated haemoglobin A1 were positively correlated with those of hyaluronic acid (r = 0.96, p. less than 0.001) and heparin (r = 0.45, p less than 0.01) in the diabetic group. The present data suggest thah a) in diabetics there is a shift in the metabolism of glycosaminoglycans towards a decreased sulfated glycosaminoglycans/hyaluronic acid ratio; and b) long-lasting hyperglycemia is correlated with the disturbances in the metabolism of glycosaminoglycans.

Dear Sir The hyperglycaemic effect of morphine has been a well recognized phenomenon throughout this century [1], but the mechanism of its action still remains unclear. Recent studies in the dog [2] and in man [3] suggest that both morphine and beta-endorphin increase the plasma levels of glucose, insulin and glucagon. These observations have led to the suggestion that the interference of the opioid peptides on carbohydrate metabolism may be through modifications of pancreatic hormone release. We have studied the effect of protracted morphine administration on carbohydrate metabolism in 27 male addicts (age range: 18-34 years, mean + SEM: 24 _+ 2.2 years) before narcotic withdrawal. The results were compared with those obtained in 46 healthy males matched for age (mean _+ SEM: 25 _+ 1.8 years) and weight. Carbohydrate metabolism was assessed by determining fasting plasma glucose (mean of three samples on three consecutive days) and glycosylated haemoglobin A1 (HbA0 (mean of two sampies) which represents a very useful index of the glycaemic control of the last 3-4 weeks [4]. Glycosylated haemoglobin A1 was determined according to the method of Welch and Boucher [5]. The intra- and inter-assay coefficients of variation for this method are 1.5% and 3%, respectively. The mean _+ SEM HbA1 level was 7.18 + 0.17% in addicts and 6.11 _+ 0.06% in control subjects, a difference which is statistically significant (p < 0.001). No significant difference was found in fasting plasma glucose (5.08 + 0.13 retool/1 in addicts versus 4.72 + 0.19 mmol/1 in control subjects). No significant correlation was found between fasting plasma glucose and HbA1 in addicts. Total haemoglobin was 15 _+ 0.2 g/dl in addicts and 14.3 + 0.4 g/dl in controls (NS) (Fig. 1).

A functional arterial spasm, revealed by reduced post-ischemic response, is present in diabetic subjects with no overt evidence of vascular damage. The administration of three different antioxidant agents, vitamin C, thiopronine and glutathione, produces an increase of basal blood flow in both diabetic and normal subjects, and ameliorates significantly the vascular functional response in diabetes. These data suggest that free radicals may play a role in the regulation of arterial resistance in humans, and that a de-regulation of their action may be involved in the development of arterial dysfunction in diabetes.

Data on fibrinolysis in diabetes mellitus are still unclear, as is the role of hyperglycaemia on this topic and the possibility of any therapeutic intervention. In this study we examined fibrinopeptide A, tissue plasminogen activator and plasminogen activator inhibitor plasma levels in Type 1 diabetic patients compared to matched healthy normal controls, and the effect of induced hyperglycaemia on these parameters. At the same time the effect of a glycosaminoglycan, Sulodexide, administration during hyperglycaemia was evaluated. Fibrinopeptide A and plasminogen activator inhibitor were increased while tissue plasminogen activator was decreased in Type 1 diabetic patients, in the basal state. Induced hyperglycaemia increases fibrinopeptide A formation and tissue plasminogen activator concentrations, while it decreases plasminogen activator inhibitor levels more in normal subjects than in diabetic patients. Sulodexide consistently reduces this phenomenon. This study shows an altered fibrinolytic response to increased thrombin activation in Type 1 diabetic patients and suggests that the administration of the glycosaminoglycan, Sulodexide, may help to reduce this phenomenon.

Alteration of antithrombin III (ATIII) activity, glycemia level dependent, exists in diabetes mellitus. In this study the ability of a low molecular weight heparin (LMWH) (Fluxum, Alfa-Wassermann S.p.A., Bologna, Italy), as well as unfractioned héparin, to preserve ATIII activity from glucose-induced alterations, both in vitro and in vivo, is reported. The subcutaneous and intravenous LMWH and heparin administration increases basal depressed ATIII activity in diabetic patients. Heparin shows an equivalent effect on both anti-IIa and anti-Xa activity of ATIII, while LMWH is more effective in preserving the anti-Xa activity. Similarity, heparin preserves ATIII activity from hyperglycemia-induced alterations, during hyperglycemic clamp, and LMWH infusion is able to preserve a significant amount of anti-Xa activity from glucose-induced alterations. Since diabetic patients show a high incidence of thrombotic accidents, LMWH appears to be a promising innovation for the prevention of diabetic thrombophylia.

To evaluate the status of ano-rectal complex in diabetic patients, 20 patients with no fecal incontinence and/or local ano-rectal disorders and 18 normal subjects underwent to: 1) ano-rectal manometry; 2) defecography; and 3) rectal sensation tests. In all subjects, the five classic cardiovascular reflexes tests were performed to detect autonomic neuropathy. No significant difference between diabetic patients and controls was found in length, maximum resting pressure and strength of phasic external anal sphincter or anal canal at ano-rectal manometry; similarly, no significant difference between diabetic and normal subjects was found by the same technique in threshold and amplitude of ano-rectal inhibitory reflex. Ano-rectal angle of diabetic patients was not significantly different from normals both at resting and during straining at defecographic study. By rectal sensation testing, it was possible to demonstrate a significant difference between diabetic and normal subjects in perception of rectal distension (87.5 +/- 27.5 vs 39.2 +/- 6.5 ml, p less than 0.05; mean +/- SEM) and of stimulus of defecation (147.0 +/- 56.3 vs 52.9 +/- 18.5 ml, p less than 0.001) but not in perception of maximum tolerable volume (343.5 +/- 69.9 vs 322.0 +/- 48.5 ml, p = NS). No relationship was found between these results and the score of autonomic neuropathy and/or duration of diabetic disease. These data suggest that an early involvement of only sensory parasympathetic fibers of ano-rectal complex occurs in diabetic patients without gastrointestinal symptoms.