Platelet aggregation and retinal microangiopathy in diabetes and hypertension.

Platelet aggregation studies were done in 10 cases of diabetes with and without retinopathy and 7 cases of hypertensive retinopathy with adenosine diphosphate (ADP) and adrenaline (ADR). It was observed that the rate and degree of aggregation was significantly increased in the retinopathy group both with ADP and ADR. A significant alteration in the latent period was found with ADP, whereas no such change was found with ADR. It is proposed that the increased platelet reactivity in retinal microangiopathy could be due to different mechanisms. Increased sensitivity of the platelets to ADP resulting in the rapid inductive phase of aggregation together with accelerated intrinsic ADP release in diabetic retinopathy may cause hyperaggregation of platelets. Hyperaggregation in hypertensive retinopathy, however, may occur due to accelerated ADP release only. Platelet metabolism supporting the release reaction is altered in both.     

C肽对糖尿病肾脏保护作用的研究进展

人体与动物实验研究显示,C肽对肾脏具有保护作用.在慢性肾功能不全的1型糖尿病患者中,残余胰岛功能在肾脏-胰腺联合移植时得以保存,可提高术后存活率,改善肾脏肥大和血管功能.C肽可以降低肾小球高滤过、尿蛋白排泄、尿钠消耗,减轻由此引起的肾纤维化,也可改善1型糖尿病引起的肾脏结构及功能的改变.研究显示,C肽发挥肾脏保护作用的机制可能与收缩入球小动脉、Na~+-K~+-ATP酶活性、细胞内的生化改变、炎性反应途径以及代谢调节等因素相关.     

C-peptide reserve in insulin-dependent diabetes

Summary Residual beta cell secretory capacity was assessed in short term (2 months to 2 years) and long term (5 to 8 years) insulin-dependent diabetics by measurement of serum C-peptide immunoreactivity during three provocative tests: glucose, tolbutamide, and glucagon. Minimal C-peptide secretion could be detected in only one out of seven long term diabetics by the stimulatory tests. All seven short-term diabetics responded to at least one provocative test of beta cell reserve, although these responses were blunted. The greatest C-peptide responses occurred after glucagon administration (mean increase 0.62 pmol/ml) in short-term responders. Patients who responded to one test did not necessarily respond to another stimulus. There was no correlation between basal C-peptide levels and the ability to provoke further C-peptide secretion by any of the three tests. C-peptide responses did not correlate with % Haemoglobin A_1c, mean fasting blood glucose levels, or mean blood glucose concentrations during an oral glucose tolerance test. The data indicate that stimulation tests are only useful in assessing endogenous beta cell reserve in patients with diabetes of less than 5 years duration. In diabetics of longer duration there is little insulin reserve above basal levels.     

C-peptide levels in transient neonatal diabetes

A baby boy with transient neonatal diabetes mellitus presenting with hyperglycaemia, glycosuria, and dehydration without ketonuria on the second day of life is reported. C-peptide levels were measured to aid in the assessment of insulin treatment. Very low levels were found for the first 5 months of life (less than 0.06 nmol/l). Thereafter insulin treatment was discontinued and the baby thrived showing normal growth and development at age 2 1/2 years.     

C-peptide and central nervous system complications in diabetes

Substantial evidence collected from clinical data and experimental studies has indicated that CNS is not spared from diabetes complications. Impairments in CNS function are well documented in both type 1 and type 2 diabetic patients as well as in various animal models of diabetes, in terms of alterations in cognition, neuropsychology, neurobehavior, electrophysiology, structure, neurochemistry and apoptotic activities. These data suggest that primary diabetic encephalopathy exists as a definable diabetic complication. The mechanisms underlying this CNS complication are not clear. Experimental studies have suggested that neuronal apoptosis may play an important role in neuronal loss and impaired cognitive function. In diabetes multiple factors are responsible for neuronal apoptosis, such as a perturbed IGF system, hyperglycemia and the aging process itself. Recent data suggest that insulin/C-peptide deficiency may exert an eminent role. Administration of C-peptide partially corrects the perturbed IGF system in the brain and prevents neuronal apoptosis in hippocampus of type 1 diabetes. In neuroblastoma SH-SY5Y cells C-peptide provides a dose-dependent stimulation on cell proliferation and an anti-apoptotic effect as well. These studies provide a basis for administration of C-peptide as a potentially effective therapy for type 1 diabetes.     

Fasting plasma C-peptide,glucagon stimulated plasma C-peptide,and urinary C-peptide in relation to clinical type of diabetes

Summary Many patients with Type 2 (non-insulin-dependent) diabetes mellitus are treated with insulin in order to control hyperglycaemia. We studied fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and 24 h urinary C-peptide in relation to clinical type of diabetes in 132 insulin treated diabetic subjects. Patients were classified clinically as Type 1 (insulin-dependent) diabetic subjects in the presence of at least two of the following criteria: 1) significant ketonuria, 2) insulin treatment started within one year after diagnosis, 3) age of diagnosis 40 years, and 4) weight below 110% of ideal weight of the same age and sex. Eighty patients were classified as Type 1 and 52 as Type 2 diabetic subjects. A second classification of patients into 6 C-peptide classes was then performed. Class I consisted of patients without islet B-cell function. Class II-VI had preserved islet B-cell function and were separated according to the 20%, 40%, 60% and 80% C-peptide percentiles. The two classifications of patients were compared by calculating the prevalence of clinical Type 1 and Type 2 diabetes in each of the C-peptide classes. This analysis showed that patients with a fasting plasma C-peptide value <0.20 nmol/l, a glucagon stimulated plasma C-peptide value <0.32 nmol/l, and a urinary C-peptide value <3.1 nmol/l, or <0.54 nmol/mmol creatinine/24 h, or <5.4 nmol/24 h mainly were Type 1 diabetic patients; while patients with C-peptide levels above these values mainly were Type 2. At these limits the percentage, predictive value of positive tests as indicators of Type 2 diabetes were as follows: fasting C-peptide 83%, stimulated C-peptide 86%, and urinary C-peptide expressed as nmol/l 76%, as nmol/mmol creatinine/24 h 79%, and as nmol/24 h 78%. Similarly, the percentage predictive value of negative tests as indicators of Type 1 diabetes were as follows: fasting C-peptide 86%, stimulated C-peptide 88%, and urinary C-peptide expressed as nmol/l 79%, as nmol· mmol creatinine·24 h 81%, and as nmol/24 h 80%. If patients without detectable C-peptide were excluded, the predictive value of negative tests were as follows: fasting C-peptide 81%, stimulated C-peptide 88%, urinary C-peptide expressed as nmol/l 61%, as nmol/mmol creatinine/24 h 69%, and as nmol/24 h 64%. In conclusion, post glucagon C-peptide gives a good distinction between Type 1 and Type 2 diabetes mellitus in insulin treated diabetes while 24 h urinary C-peptide gives a less sensitive distinction between the clinical types of diabetes.     

Assay of C-peptide in diabetes in children and adolescents

Thirty eight children and adolescents aged 3 to 19 years with insulin-dependent diabetes had basal plasma C-peptide levels 50 to 70 p. 100 lower than comparable non-diabetic subjects. An appreciable residual fasting endogenic secretion greater than 1 ng/ml was found in half the patients during the first two years after the onset of diabetes. After this period, the concentrations were almost always lower than 1 ng/ml and in half the cases, at the lower limit of detection. In addition, it was difficult to stimulate C-peptide secretion by food or drugs. The effects of variations in blood glucose were made allowance for by using molar C-peptide/glucose ratio. This gives a better evaluation of the inverse relationship between residual pancreatic function and the duration of the diabetes and of the degree of residual beta-langerhans secretion to help obtain stable metabolic equilibrium.     

C-peptide secretion in calcific tropical pancreatic diabetes

Serum C-peptide levels were measured during a glucagon stimulation test in ten normal nonobese controls and 54 diabetic patients with recent onset of diabetes under 30 years of age. Diabetic patients were comprised of 13 CTPD, 23 IDDM, and 18 NIDDM. As similar to IDDM patients, serum C-peptide concentrations did not rise significantly (P greater than 0.05) in response to glucagon administration in CTPD-patients. Mean baseline and peak serum C-peptide concentrations in CTPD-patients were significantly lower (P less than 0.001) than the values in normal controls and NIDDM patients, but were significantly higher (P less than 0.05) than those in IDDM patients. We conclude that CTPD patients have partial C-peptide reserve, which may protect against ketosis and contribute to ketosis resistance in CTPD. Our results also suggest that CTPD patients require insulin treatment. Neither baseline nor peak C-peptide levels after glucagon could discriminate CTPD from IDDM and CTPD from NIDDM.     

Relation between the serum level of C-peptide and risk factors for coronary heart disease and diabetic microangiopathy in patients with type-2 diabetes mellitus.

Syndrome X is used to describe a constellation of factors that lead to coronary heart disease (CHD): hypertension, hyperinsulinemia, impaired glucose tolerance, and an abnormality in lipid metabolism. We investigated the relationship between serum levels of C-peptide immunoreactivity (CPR) and diabetic complications in 256 patients with type-2 diabetes mellitus. The serum level of CPR was measured by radioimmunoassay (RIA). Diabetic patients were divided into 3 groups according to the serum level of CPR as follows: low CPR (n = 19, <0.7 ng/ml), normal CPR (n = 174, 0.7 to 2.2 ng/ml) and high CPR (n = 63, >2.2 ng/ml). The body mass index (BMI) and the serum level of triglycerides were significantly higher in the high CPR group (P < 0.05, respectively) compared with normal CPR group. The prevalence of hypertension was significantly higher in the high CPR group than in the other 2 groups (low CPR: 16%, normal CPR: 28%, high CPR: 38%). The frequency of the number of patients receiving insulin therapy was greater in the low CPR group than in the other 2 groups, (low CPR: 58%, normal CPR: 15%, high CPR: 11%). The serum CPR level was significantly lower in patients with than without proliferative retinopathy or macroalbuminuria. Our conclusion is that the present data suggest that an increased serum level of CPR is associated with obesity, elevated serum triglycerides, and hypertension in patients with type-2 diabetes mellitus. A low CPR level leading to hyperglycemia is associated with the progression of diabetic microangiopathies, such as retinopathy and nephropathy.     

Renal and retinal microangiopathy after 15 years of follow-up study in a sample of Type 1 diabetes mellitus patients

PURPOSE: In the present study, the objective is to determine the epidemiological risk factors in the appearance of diabetic retinopathy and nephropathy in 112 Type 1 diabetic patients after 15 years. METHODS: A 15-year follow-up study was done in a cohort of 112 consecutive Type 1 (IDDM) diabetes mellitus patients without diabetic retinopathy or nephropathy at enrolment in 1990. We studied the incidence of diabetic retinopathy and/or microalbuminuria. The epidemiological risk factors included in the study were gender, diabetes duration, HbA(1c) levels, arterial hypertension, levels of triglycerides and fractions of cholesterol (HDL-cholesterol and LDL-cholesterol). RESULTS: The incidence of diabetic retinopathy was 55.40% at the end of study; the risk factors associated were duration of diabetes mellitus (P<.001), high levels of HbA(1c) (P=.009), presence of arterial hypertension (P=.007) and high levels of LDL-cholesterol (P=.002). The incidence of microalbuminuria was 41.07% and that of overt nephropathy, 19.60%; the risk factors associated were high levels of HbA(1c) (P<.001) and presence of arterial hypertension (P=.023). At the end of study, four groups of patients were formed: patients without microalbuminuria or retinopathy, patients with microalbuminuria only, patients with retinopathy only and patients with retinopathy and microalbuminuria. From the results of the discriminate analysis, we may assume that for the development of retinal lesions only, in the diabetes mellitus, the duration of the disease, the high levels of HbA(1c) and the arterial hypertension are most important, and for the development of renal and retinal lesion simultaneously, the important factor is poor control of glycemia measured by levels of HbA(1c) and arterial hypertension. CONCLUSIONS: In conclusion, microalbuminuria correlated well with severe forms of diabetic retinopathy, and at the end of the study, two groups of patients had been configured: the first group had developed only diabetic retinopathy, and the second, their patients with diabetic retinopathy together with renal lesion (microalbuminuria). For the first group, the duration of diabetes mellitus was the most important risk factor, and for the second group, the levels of HbA(1c) and blood pressure were the most important.     

HLA-types,C-peptide and insulin antibodies in juvenile diabetes

Summary HLA-types were determined in 102 juvenile diabetics. HLA-B8 was found in 39 patients (RR 2.64; p < 0.01) and HLA-BW15 in 32 patients (RR 1.33; n.s.). HLA-B7 was found in 14 patients (RR 0.40; p < 0.05). There were no correlations between HLA-B8 or BW15 and family history of diabetes, occurrence of infection before onset of diabetes, ketonuria at onset or the age at onset of diabetes. Serum C-peptide, insulin binding capacity of IgG and total serum insulin, IRI, were determined in 94 patients who had had diabetes for more than two years and who were beyond the remission period. Measurable amounts of C-peptide were found in 33 patients (34.7%). There was no evidence of a relationship between any particular HLA-antigen and the B-cell function except for an increased incidence of detectable C-peptide in patients with HLA-B18 and a tendency to a decreased incidence of detectable C-peptide in patients with the combination HLA-B8, W15. Only four patients (4.3%) were lacking insulin antibodies. HLA-BW15 positive patients had higher levels of insulin antibodies than other groups, while HLA-B7 positive patients had lower levels. The results suggest that HLA-B7 and HLA-B 18 might be associated with a different and perhaps milder form of juvenile diabetes.This work was supported by the Swedish Medical Research Council no 16X-3557 and no 19X-04 528, by the Swedish Diabetic Association and by the Medical Faculty, Linköping University, Sweden     

C-peptide prevents hippocampal apoptosis in type 1 diabetes

To explore mechanisms underlying central nervous system (CNS) complications in diabetes, we examined hippocampal neuronal apoptosis and loss, and the effect of C-peptide replacement in type 1 diabetic BB/W rats. Apoptosis was demonstrated after 8 months of diabetes, by DNA fragmentation, increased number of apoptotic cells, and an elevated ratio of Bax/Bcl-xL, accompanied by reduced neuronal density in the hippocampus. No apoptotic activity was detected and neuronal density was unchanged in 2-month diabetic hippocampus, whereas insulin-like growth factor (IGF) activities were impaired. In type 1 diabetic BB/W rats replaced with C-peptide, no TdT-mediated dUTP nick-end labeling (TUNEL)-positive cells were shown and DNA laddering was not evident in hippocampus at either 2 or 8 months. C-peptide administration prevented the preceding perturbation of IGF expression and reduced the elevated ratio of Bax/Bcl-xL. Our data suggest that type 1 diabetes causes a duration-dependent programmed cell death of the hippocampus, which is partially prevented by C-peptide.     

Diabetic microangiopathy in patients with pancreatitic diabetes mellitus

Summary Clinically evident diabetic microangiopathy (retinopathy and nephropathy) occurred in 18% of diabetic patients with acute pancreatitis and 14% of diabetic patients with chronic pancreatitis. The presence of diabetic retinopathy and nephropathy in patients with pancreatitic diabetes without a family history of diabetes mellitus suggests that these patients have primary diabetes mellitus unmasked by the pancreatitis. The occurrence of diabetic microangiopathy is significantly correlated with the duration of diabetes. The frequency of these diabetic complications seems to increase when there is a family history of diabetes in patients whose pancreatitis is simultaneous with or precedes the onset of diabetes. The majority of patients with diabetic microangiopathy were on insulin therapy, but the need for insulin treatment is an indication of the severity of the diabetes, rather than the insulin being a causative factor of the microangiopathy. The degree of steatorrhea in diabetic patients with chronic pancreatitis did not protect against the development of microangiopathy.     

Erectile dysfunction,microangiopathy and UKPDS risk in type 2 diabetes

BackgroundErectile dysfunction (ED) is a frequent comorbidity in patients with type 2 diabetes mellitus (T2DM), and is now increasingly considered a surrogate marker of endothelial dysfunction as well as a sentinel predictor of new-onset macroangiopathic events. Less attention, however, has been directed at the potential association of ED and microangiopathy in hyperglycaemic states.MethodsWe analyzed 221 consecutive male T2DM outpatients in whom ED was assessed by the International Index of Erectile Function (IIEF-5) questionnaire. ED(+) patients (IIEF-5 1–20; n = 83) were compared with an age-matched ED(−) cohort (IIEF-5 21–25; n = 51), with similar diabetes duration, in terms of cardiovascular (CV) risk factors, micro-/macroangiopathy and the United Kingdom Prospective Diabetes Study (UKPDS) risk score.ResultsMean age and diabetes duration were 58 and 10 years, respectively. IIEF-5 score (1 S.D) was 23 (1) in ED(−) vs 11 (6) in ED(+). Anamnestic impotence and erectogenic drug use were reported by 52% and 36%, respectively, of ED(+) vs 12% and 8%, respectively, of ED(−) (P < 0.0002 and P < 0.0001, respectively). The metabolic syndrome prevalence (88% vs 64%; P = 0.002) and central adiposity markers (waist, waist/height and visceral fat) were all significantly higher in ED(+). HbA_1c was similar in both groups: 7.5% (1.3%), and there were also no significant differences in smoking, blood pressure, HOMA insulin sensitivity, cholesterol and glomerular filtration rate. However, prevalences of retinopathy, polyneuropathy and elevated albuminuria, and the composite endpoint of peripheral artery disease, transient ischaemic attacks and/or stroke, were markedly increased in ED(+) (all P < 0.05). No differences were observed in coronary artery disease prevalence or in the UKPDS 10-year CV risk between the two ED groups.ConclusionIIEF-5-defined ED in men with T2DM is associated with a marked increase in the metabolic syndrome, central adiposity and microangiopathy. These data suggest that diagnosing ED in T2DM warrants detailed screening and monitoring for microangiopathy in target organs.     

糖尿病并发微血管病变患者心电图分析

目的 分析2型糖尿病(T2DM)并发微血管病变患者异常心电图(ECG)检出率和ECG异常类型,探讨ECG对T2DM患者并发微血管病变时心脏损害的临床诊断价值.方法 选择T2DM未并发微血管病变(对照组)患者和T2DM并发微血管病变(观察组)患者各110例.对每例患者ECG表现进行比较分析.结果 对照组患者ECG异常39例,异常检出率35.45％;观察组患者ECG异常98例,异常检出率89.09％;两组ECG异常检出率比较,差异有统计学意义(P＜0.05);两组ECG异常类型均以ST-T改变最为常见,其次为心律失常,差异均有统计学意义(P＜0.05).结论 T2DM并发微血管病变患者ECG异常检出率高于未并发微血管病变患者.临床应定期对T2DM进行ECG检查,并动态观察分析,及时发现T2DM并发微血管病变时心脏损害,对预防和早期治疗糖尿病并发冠心病和糖尿病心肌病(DCM)有重要意义.     

C-peptide levels as a criterion in treatment of maturity-onset diabetes

C-Peptide levels, both basal and glucose-stimulated, were contrasted in diet-controllable vs. nondiet-controllable maturity-onset diabetic patients. Fasting and glucose-stimulated plasma C-peptide values in diet-controlled diabetics were similar to those in normal subjects. Diabetic patients who were not solely diet controllable could be differentiated into two subgroups. One diet failure subgroup was truly insulin dependent, in that insulin treatment could not be stopped for even a brief period. In these patients, fasting C-peptide levels were very low, in the same range as in the majority of juvenile-onset diabetic patients. In the second diet failure subgroup, it was possible to manage patients without insulin therapy for varying periods of time, although most patients eventually needed insulin. Fasting C-peptide levels in this second subgroup were also in the same range as those in normal subjects. However, their C-peptide responses to glucose were significantly blunted. Measurement of C-peptide may furnish a useful criterion for the categorization of maturity-onset diabetic patients. Furthermore, C-peptide levels help considerably in the selection of treatment modalities for these patients. Low C-peptide levels identify those patients who require insulin treatment, whereas high C-peptide levels in insulin-treated patients suggest the possibility of discontinuing insulin.     

C-peptide, Na+,K(+)-ATPase, and diabetes

Na+,K(+)-ATPase is an ubiquitous membrane enzyme that allows the extrusion of three sodium ions from the cell and two potassium ions from the extracellular fluid. Its activity is decreased in many tissues of streptozotocin-induced diabetic animals. This impairment could be at least partly responsible for the development of diabetic complications. Na+,K(+)-ATPase activity is decreased in the red blood cell membranes of type 1 diabetic individuals, irrespective of the degree of diabetic control. It is less impaired or even normal in those of type 2 diabetic patients. The authors have shown that in the red blood cells of type 2 diabetic patients, Na+,K(+)-ATPase activity was strongly related to blood C-peptide levels in non-insulin-treated patients (in whom C-peptide concentration reflects that of insulin) as well as in insulin-treated patients. Furthermore, a gene-environment relationship has been observed. The alpha-1 isoform of the enzyme predominant in red blood cells and nerve tissue is encoded by the ATP1A1 gene. A polymorphism in the intron 1 of this gene is associated with lower enzyme activity in patients with C-peptide deficiency either with type 1 or type 2 diabetes, but not in normal individuals. There are several lines of evidence for a low C-peptide level being responsible for low Na+,K(+)-ATPase activity in the red blood cells. Short-term C-peptide infusion to type 1 diabetic patients restores normal Na+,K(+)-ATPase activity. Islet transplantation, which restores endogenous C-peptide secretion, enhances Na+,K(+)-ATPase activity proportionally to the rise in C-peptide. This C-peptide effect is not indirect. In fact, incubation of diabetic red blood cells with C-peptide at physiological concentration leads to an increase of Na+,K(+)-ATPase activity. In isolated proximal tubules of rats or in the medullary thick ascending limb of the kidney, C-peptide stimulates in a dose-dependent manner Na+,K(+)-ATPase activity. This impairment in Na+,K(+)-ATPase activity, mainly secondary to the lack of C-peptide, plays probably a role in the development of diabetic complications. Arguments have been developed showing that the diabetes-induced decrease in Na+,K(+)-ATPase activity compromises microvascular blood flow by two mechanisms: by affecting microvascular regulation and by decreasing red blood cell deformability, which leads to an increase in blood viscosity. C-peptide infusion restores red blood cell deformability and microvascular blood flow concomitantly with Na+,K(+)-ATPase activity. The defect in ATPase is strongly related to diabetic neuropathy. Patients with neuropathy have lower ATPase activity than those without. The diabetes-induced impairment in Na+,K(+)-ATPase activity is identical in red blood cells and neural tissue. Red blood cell ATPase activity is related to nerve conduction velocity in the peroneal and the tibial nerve of diabetic patients. C-peptide infusion to diabetic rats increases endoneural ATPase activity in rat. Because the defect in Na+,K(+)-ATPase activity is also probably involved in the development of diabetic nephropathy and cardiomyopathy, physiological C-peptide infusion could be beneficial for the prevention of diabetic complications.