Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although prospective randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between diabetic hyperglycemia and the development of secondary complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications. This hypothesis is supported by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals. Furthermore, exposure of endothelial cells to high glucose leads to augmented production of superoxide anion, which may quench nitric oxide, a potent endothelium-derived vasodilator that participates in the general homeostasis of the vasculature. In further support of the consequential injurious role of oxidative stress, many of the adverse effects of high glucose on endothelial functions, such as reduced endothelial-dependent relaxation and delayed cell replication, are reversed by antioxidants. A rational extension of this proposed role for oxidative stress is the suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status.

Oxidative Stress and Diabetic Vascular Complications

Background— Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-α, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione. Methods and Results— Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-α, and IL-18 levels rose (P<0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P<0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-α levels ...

Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans Role of Oxidative Stress

结节病易误诊,据王洪武等~([1])收集国内18篇关于此病误诊的文献,误诊率高达63.2%,当然有误诊就会有误治,如孙永昌等~([2])报道26例结节病在影像学检查诊断的第一印象中拟诊结核5例,其中就有2例完成规范的抗结核治疗,为此应引起临床对本病诊治的重视。

Sarcoidosis

Background: Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus The quality of the scientific evidence supporting the use of these assays varies substantially

Approach: An expert committee drafted evidence-based recommendations for the use of laboratory analysis in patients with diabetes An external panel of experts reviewed a draft of the guidelines, which were modified in response to the reviewers’ suggestions A revised draft was posted on the Internet and was presented at the AACC Annual Meeting in July, 2000 The recommendations were modified again in response to oral and written comments The guidelines were reviewed by the Professional Practice Committee of the American Diabetes Association

Content: Measurement of plasma glucose remains the sole diagnostic criterion for diabetes Monitoring of glycemic control is performed by the patients, who measure their own plasma or blood glucose with meters, and by laboratory analysis of glycated hemoglobin The potential roles of noninvasive glucose monitoring, genetic testing, autoantibodies, microalbumin, proinsulin, C-peptide, and other analytes are addressed

Summary: The guidelines provide specific recommendations based on published data or derived from expert consensus Several analytes are of minimal clinical value at the present time, and measurement of them is not recommended

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Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

Advanced glycation endproducts—role in pathology of diabetic complications

Objective This study evaluated the possibility of inhibiting protein glycosylation in vivo with vitamin E. Research Design and Methods Two groups of 10 insulin-requiring diabetic patients, matched for duration of disease and metabolic control, received daily vitamin E supplementation of 1200 and 600 mg, respectively, for 2 mo. A third group of 10 diabetic patients, matched for duration of disease and metabolic control, served as the control group and received placebo. Fasting plasma glucose, mean daily plasma glucose, fasting labile HbA 1 , and glycosylated proteins were measured in the basal state and after 1 and 2 mo of treatment. In addition, hyperglycemic clamp studies were performed in basal state and after 1 mo of vitamin E administration in all patients. Results Glycemic indices did not show any significant changes during the study, whereas fasting labile HbA, and glycosylated proteins decreased significantly after 1 and 2 mo in patients on vitamin E administration. Stable HbA 1 decreased after 2 mo. Mean glycemic incremental area in the hyperglycemic clamp procedure was similar before and after treatment, whereas a significant reduction in mean labile HbA 1 incremental area was found after vitamin E supplementation. A significant difference was also found in both fasting and incremental labile HbA 1 levels, stable HbA 1 , and glycosylated proteins between the two groups of diabetic patients on the two doses of vitamin E; the diabetic patients who received the higher dose of vitamin E showed the greater reduction. No significant changes in these parameters were observed in diabetic patients on placebo administration. Conclusions These results demonstrate that vitamin E administration may reduce protein glycosylation in diabetic subjects independently of changes in plasma glucose, an effect that may be due to the inhibition of labile glycosylation, the first step of the Maillard reaction. Long-term studies will help establish the usefulness of vitamin E administration for the prevention of diabetic complications.

Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic complications

1. In this study an acute anti-hypertensive effect of three anti-oxidant agents (vitamin C, thiopronine and glutathione) in hypertensive subjects and in both hypertensive and non-hypertensive diabetic patients is reported. 2. The anti-oxidants had no effect on blood pressure in healthy normal subjects at a dose of 6 mmol, but thiopronine and glutathione produced a significant hypotensive effect at a dose of 12 mmol. 3. These data suggest that anti-oxidants might have a dilatatory effect and that an imbalance of the nitric oxide-free radical interaction might facilitate the development of hypertension in humans.

Anti-oxidants show an anti-hypertensive effect in diabetic and hypertensive subjects

Study objective To evaluate the usefulness and safety of hydroxychloroquine in patients with decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. Design Prospective, randomized, placebo, double-blind 6-month trial. Patients Thirty-eight patients with noninsulin-dependent diabetes resistant to commonly used therapies (oral drugs, insulin, combination of insulin and oral drugs). Interventions Two study groups: one received insulin (n = 22) and the other, glibenclamide (n = 16). In each group, half of the patients were randomly allocated into two subgroups who continued the previous treatment but took either placebo tablets or hydroxychloroquine, 200 mg three times a day. The four subgroups were as follows: insulin and placebo (n = 11); insulin and hydroxychloroquine (n = 11); glibenclamide and placebo (n = 8); and glibenclamide and hydroxychloroquine (n = 8). Measurements and main results At 6 months, relevant and statistically significant improvement occurred in the 11 patients who received the insulin and hydroxychloroquine (glucose profile decrease, -11.7 mmol/L; 95% CI, -13.9 to -9.5, P = 0.001; glycated hemoglobin A1c decrease, -3.3%; 95% CI, -3.9 to -2.7, P = 0.001). No significant changes were seen in patients on placebo. The daily insulin dose in patients treated with the combined insulin and hydroxychloroquine therapy had to be reduced an average of 30%. No important side effects were detected. Conclusions Combining antidiabetic therapy with hydroxychloroquine in decompensated, treatment-refractory patients with noninsulin-dependent diabetes may help to break the vicious circle of hyperglycemia and lead to better management of the disease.

Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. A new job for an old drug?

the absence of bacteriuria or microscopic hematuria. In a preliminary study conducted on 54 diabetic outpatients, albuminuria was measured for each patient on both an overnight urine sample and a urine sample collected during consultation. A ratio of albumin to creatinine of >3 identified all patients with UAE >30 |xg/min (sensitivity 100%, specificity 92%). Moreover, a ratio of albumin to creatinine of ^1 was always associated with UAE <10 |xg/min (specificity 100%, sensitivity 50%). The relationship between UAE and the albumin-to-creatinine ratio in the group reference UAE of <30 |xg/min was not very close (r = .60, P < .001), but because of the 100% predictive value of the albumin-to-creatinine ratio ^1 measured on one urine sample, it appeared relevant to screen the patients for whom overnight urine samples were not necessary. To confirm the ratio of <1 determined retrospectively in the first study, UAE and the ratio of albumin to creatinine were measured 144 times on 133 diabetic subjects evaluated as outpatients or inpatients in a second study (Fig. 1). In 30 cases, UAE was >30 |xg/min (range 38-222 |xg/min); the correlation coefficient for the albumin-tocreatinine ratio in this reference group was r = .53 (P < .001). When the ratio of albumin to creatinine was >3, sensitivity and specificity were 90%. In 114 cases, UAE was <30 |xg/min (in 84 cases <10 |xg/min, in 30 cases between 10 and 30 |xg/min). In this group, the correlation coefficient between UAE in an overnight collection and the albumin-to-creatinine ratio was r = .57, P < .001. A ratio of albumin to creatinine of ^1 was always associated with UAE <10 |xg/min (specificity 100%, sensitivity 80%; Fig. 2). The second study, conducted on 144 evaluation pairs, confirmed that the predictive value of a ratio of albumin to creatinine of ^1 on one urine sample was 100%. All such patients had UAE <10 |xg/min in an overnight urine sample. The evaluation of albuminuria with one urine specimen collected during a consultation is recommended as a useful method of screening for incipient diabetic nephropathy. The test should be considered negative when the ratio of albumin to creatinine is < 1 . When the ratio is > 1 , it is necessary to collect an overnight sample of urine with results expressed in micrograms per minute to quantify the albuminuria. Mistakes due to improperly collected urine samples would be reduced as a result of the motivation of the patient after positive screening.

Does a common mechanism induce diverse complications of diabetes

Objective: To evaluate the effectiveness and safety of tolrestat, an aldose-reductase inhibitor, in patients with mild diabetic autonomic and peripheral neuropathy. Design: Randomized, placebo-cont...

Antonio Quatraro

Papers

Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic complications

Anti-oxidants show an anti-hypertensive effect in diabetic and hypertensive subjects

Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. A new job for an old drug?

Does a common mechanism induce diverse complications of diabetes

Tolrestat for Mild Diabetic Neuropathy: A 52-Week, Randomized, Placebo-Controlled Trial