Biomedical subjects
Publications and source records attributed to E Standl.
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The use of insulin analogues is rapidly expanding. At present, there are two short-acting analogues available for practical use, insulin aspart and insulin lispro, and one long-acting analogue, insulin glargine. Another long-acting analogue, insulin detemir, is still under development. The time action profile of short-acting analogues is both much more rapid and shorter than that of human insulin; the prominent feature of the long-acting analogues is their peakfree and fairly constant action. Insulin analogues offer alternative options for the whole spectrum of insulin therapy in type 1 and type 2 diabetes patients. The perception by many patients is strikingly positive, in particular regarding the overall quality of life. In objective efficacy terms, however, the potential to improve the degree of metabolic control appears to be only minor, yet demonstrable, provided the analogues are used according to their specific time action profile. This ensured, analogues are instrumental in minimizing the side effects of insulin therapy, i.e. the risk of (nocturnal) hypoglycaemia or problems with body weight control. Although there are no indications of safety concerns with insulin analogues, the availability of long-term outcome data based upon observations in human patients would be very valuable.
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OBJECTIVE: The study compared the long-term efficacy and safety of miglitol to placebo in Type 2 diabetic outpatients inadequately controlled on combination therapy of diet, glibenclamide and metformin. METHODS: Type 2 diabetic patients (n = 154) receiving glibenclamide 7-20 mg/day and at least one 500-850 mg tablet metformin per day were randomized to receive additional miglitol or placebo for 24 weeks, titrated up stepwise from 25 to 100 mg trice daily. RESULTS: Addition of miglitol to sulphonylureas and metformin (per protocol analysis) produced a statistically, significantly greater reduction in HbA1c (-0.55%, P = 0.04) and postprandial glucose (-2.6 mmol/l, P = 0.0009) from baseline to endpoint than placebo (-0.2% and -0.6 mol/l, respectively). Reduction in fasting blood glucose was greater with miglitol than placebo, and there was a possible difference in favor of miglitol for fasting and postprandial triglyceride levels, but these did not reach statistical significance. Flatulence and diarrhea were reported by statistically, significantly more patients receiving miglitol than placebo, but adverse events overall were reported by only 10% more patients in the miglitol group. No cases of hypoglycaemia were reported. CONCLUSIONS: Miglitol can safely and effectively be added to long-term combination therapy in people with Type 2 diabetes inadequately controlled with glibenclamide plus metformin.
AIMS: To examine the relationship between increased urinary albumin excretion rate and fasting plasma lipids among male and female respondents to the EURODIAB IDDM Complications Study, and attempt to explain inconsistencies in previous reports. METHODS: A cross-sectional study of 3250 randomly selected Type 1 diabetic patients from 31 diabetes clinics in 16 European countries was carried out between 1989 and 1990. Plasma lipids and urinary albumin were measured centrally. The present analysis was confined to the subgroup of 2205 patients attending after a 10-12 h overnight fast. Mean age was 33 years (SD 10) and mean duration of Type 1 diabetes mellitus was 15 years (SD 9). RESULTS: The prevalence of microalbuminuria (24-h urinary albumin excretion rate 20-200 microg/min) was 21.7% (95% confidence interval 19.9-23.5) and macroalbuminuria (24-h urinary albumin excretion rate > 200 microg/min) 7.8% (6.6-9.0). In comparison to patients with normal urinary albumin excretion rate (< 20 microg/min), and after controlling for age, sex, glycaemic control, duration of diabetes and current smoking, macroalbuminuria was associated with significantly (P<0.01) increased fasting plasma triglycerides, cholesterol, LDL-cholesterol, cholesterol:HDL-cholesterol ratio and, in women, reduced HDL-cholesterol. In men and women with microalbuminuria, the only significant association was with increased plasma triglycerides. CONCLUSIONS: These data confirm that there is an association between fasting plasma lipids and increasing urinary albumin excretion rate in European Type 1 diabetic patients. In microalbuminuric patients, however, the association was weaker than previously reported and partly explained by confounding factors.
The excess of glucose appears to play an important and specific role in the genesis of macroangiopathy in diabetics. Activation of protein kinase-C, the sorbitol pathway, and AGE formation are thought to be the major pathways linking the degree of glycaemic compensation with the pathogenetic process of macrovascular disease. HSPG is likely to be a key element in this process since it is a regulator of endothelial permeability, vascular antithrombotic capacity, insulin sensitivity (with respect to lipoprotein lipase availability), and vascular extracellular matrix content and smooth-muscle-cell activation. Loss of HSPG is suggested clinically by the presence of microalbuminuria, to the development of which diabetic control also contributes significantly. However, genetic factors also seem to be involved. Much more insight into the precise mechanismus is necessary to unravel the cellular and molecular chains of events for the premature and accelerated atherosclerosis in diabetic patients.
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UNLABELLED: This review discusses some of the mechanisms inherent in diabetes that predispose patients to increased cardiac morbidity and mortality. Single photon emission computerized tomography or photon emission tomography with radioactive labeled analogues of norepinephrine have shown that cardiac sympathetic dysfunction and incompetence are early and also late abnormalities in patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus. Furthermore, myocardial blood flow assessment with photon emission tomography has shown that in patients without myocardial perfusion deficits, endothelial-dependent vasodilatation is severely reduced in relation to cardiac sympathetic dysfunction. In addition, signs of endothelial activation have also been found early in patients with Type I and Type II diabetes in whom vascular disease has not been clinically detected. This activation in conjunction with glycaemic control is important in determining macrovascular mortality. Cardiac sympathetic dysfunction is partially restored to normal with near normalisation of glycaemia. INTERPRETATIONS: Recently unrecognized "subtle" changes predispose the heart to failure, after ischaemia-induced remodelling, and arteriosclerotic plaques to instability and rupture. These changes act in conjunction with effects, driven by hyperglycaemia and diabetes, on the endothelium of large blood vessels, e.g. on nitric oxide release or on protein kinase-C beta activation. Meticulous glucose control early on and rapid recompensation of hyperglycaemia in patients with acute coronary syndrome are part of a successful intensive multifactorial approach to prevent the heart in diabetes converting from ailing to failing.
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A central finding of the UKPDS was that in type 2 diabetic patients, tight glycemic control with HbA1c targets as close to the normal range as possible must be achieved to further reduce diabetes related-complications, -mortality, and -cardiovascular disease, highlighting the need for new, optimized treatment strategies. With a focus on clinical efficacy, this paper discusses the results from the 20 major therapeutical trials published in the years 1997-1999, that evaluated the new insulinsensitizing thiazolidinediones Rosiglitazone and Pioglitazone and the new insulin-releasing potassium channel blockers Repaglinide and Nateglinide. While for Nateglinide, promising, but only preliminary data is available at current, Rosiglitazone, Pioglitazone, and Repaglinide have been shown appropriate for both mono- and combination therapy with current standard drug treatment of type 2 diabetes. Similar to the known, older antidiabetic drugs, the new agents discussed have comparable blood glucose lowering potentials with a dose-related capacity of 0.5 to 1.5% HbA1c reduction. These beneficial effects were both seen in drug-naive patients previously treated with diet only and in combination therapies where patients had previous antidiabetic standard drug treatment suggesting effectiveness of glitazones and glinides also in more advanced stages of the disease. Problems with adverse effects appeared minor although long-range implications of weight gain, edema, lowering of hemoglobin, increase of total cholesterol for the glitazones, and hypoglycemia for glinides warrant further consideration. What becomes clear from the variety of most recent mono- and combination treatment studies with as much as five different classes of antidiabetic drugs is that individually tailored therapies that recognize quality of life parameters and target the predominant features of metabolic pathology (such as early postprandial versus fasting hyperglycemia, degree of insulin resistance, progressive loss of 1-cell function) may become a feasible goal in the future.
There is evidence that autoimmune factors contribute to the pathogenesis of cardiac autonomic dysfunction in Type 1 Diabetes mellitus (DM). To evaluate the presence of autoantibodies against autonomic nervous tissues in Type 2 DM, 127 patients were studied for complement-fixing sympathetic and parasympathetic ganglia (CF-SG and CF-PSG) autoantibodies with an indirect immunofluorescence technique. Five cardiac reflex tests were performed to investigate cardiac autonomic neuropathy. QTc interval was assessed in all patients. As a control group, 60 healthy non-diabetic subjects were also tested for CF-SG and CF-PSG autoantibodies. CF-SG autoantibodies were detected in 11 (9%) and CF-PSG autoantibodies were observed in 7 (6%) Type 2 DM patients, whereas in control subjects, the frequency was 1 (2%) and 0 (0%) respectively (ns vs. Type 2 DM patients). In Type 2 DM patients with cardiac autonomic neuropathy (n=31, 24%), CF-SG autoantibodies and CF-PSG autoantibodies were detected in 3 (10%) patients, respectively, compared to 8 (8%) and 4 (4%) in Type 2 DM patients without cardiac autonomic neuropathy (n=96, 76%, ns v. Type 2 DM with cardiac autonomic neuropathy). Both CF-SG autoantibodies and CF-PSG autoantibodies were observed in 2 (7%) Type 2 DM patients with cardiac autonomic neuropathy and 3 (3%) Type 2 DM patients without cardiac autonomic neuropathy. Type 2 DM patients with cardiac autonomic neuropathy demonstrated a longer QTc-interval (446+/-42 ms) than Type 2 DM patients without cardiac autonomic neuropathy (413+/-45 ms, p=0.0001). In Type 2 DM patients with a prolonged QTc-interval (>440 ms: n=29, 23%), 2 (7%) patients presented with CF-SG and 3 (10%) had CF-PSG autoantibodies. In Type 2 DM, CF-SG and CF-PSG autoantibodies are not frequently observed. The results do not give evidence, that immunological factors--like in Type 1 DM--play a role in the pathogenesis of cardiac autonomic dysfunction in Type 2 DM.
BACKGROUND: Patients with insulin dependent diabetes require frequent advice if their metabolic control is suboptimal. A telemedical system for transmission of self monitoring blood glucose values from the patients' home to the diabetes center with a combined modem-interface is described. Data are processed by PC and advice is given by telephone. The study focuses on metabolic outcome, fiscal and administrative aspects. METHODS: A prospective, randomized trial with 46 patients with intensified insulin therapy was conducted, 30 patients used telecare and 16 conventional care. RESULTS: HbA1c, as a parameter of metabolic control, dropped from 8.3% to 7.3% in the telecare group and from 8.0% to 6.8% in the conventional group after 8 months of observation. There was no significant difference between the two groups. Time expenditure for telemanagement, compared to conventional advice, was moderately higher, but there was a substantial amount of time on the patients side that could be saved mainly by reduction of to travel time and work stoppage. Setting up an optimal telemanagement scenario a cost analysis was done. This yields a cost saving of about 650 EURO per year. CONCLUSION: Telemanagement of insulin-requiring diabetic patients is a cost and time saving procedure for the patients and results in metabolic control comparable to conventional outpatient management.
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AIM: The present study investigated the effect of acarbose on insulin requirements and glycaemic control in patients with type 2 diabetes receiving exogenous insulin due to secondary failure of maximum dose sulphonylurea therapy. METHODS: A single-centre, double-blind, randomized, placebo-controlled study was performed in 48 type 2 diabetic patients with late-term failure following at least 3 years of sulphonylurea therapy requiring additional insulin therapy to determine the impact of acarbose on glycaemic control and insulin requirements. The primary end points were glycaemic response rate (responders being predefined as patients who achieve a decrease in HbA1c to less than 8% or a reduction by at least 15% as compared to the baseline values) and the daily insulin dose at 6 months. Secondary parameters assessed included postprandial changes in blood glucose, serum insulin and C-peptide during the treatment period. RESULTS: There were significantly more responders in the acarbose-treated group compared with the placebo group (20/24 patients vs. 10/19 patients; p < 0.05). The mean daily insulin dose after 24 weeks of treatment was 16.4 +/- 10.1 IU in the acarbose group and 22.4 +/- 12.2 IU in the placebo group (mean +/- s.d.; p < 0.07). Postprandial increases in blood glucose, insulin and C-peptide were consistently lower in the acarbose-treated group than in the placebo group. For example, the mean increase in 2-h postprandial serum insulin remained almost unchanged in the acarbose group at the end of 24 weeks of treatment compared to an increase to 43 +/- 29 microU/ml (mean +/- s.d.) at the end of the study period for the placebo group. CONCLUSIONS: The findings of this study suggest that the addition of acarbose to sulphonylurea/insulin combination therapy can improve glycaemic control in type 2 diabetic patients. Acarbose may also reduce insulin resistance and hyperinsulinaemia.
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Diabetic neuropathy is thought to comprise a reversible metabolic and an irreversible structural component of neuronal abnormality. To study whether cardiac sympathetic dysinnervation in poorly controlled longer-term Type 1 Diabetes Mellitus (DM) without myocardial perfusion abnormalities is partially reversible with improved metabolic control, 123-I-metaiodobenzylguanidine (123-I-MIBG) scintigraphy (myocardial uptake score 1-6) was performed in 11 Type 1 DM patients (HbA1c 12.0 +/- 1.8%, duration of diabetes 10 +/- 4 yrs) one year after initial assessment. During follow-up, all patients had been treated with intensive insulin therapy and at one year, HbAlc had fallen to 8.4 +/- 1.4% (p < 0.01). The global myocardial 123-I-MIBG uptake score had improved in 5 patients at one year, remained unchanged in 5 patients, and deteriorated in 1 patient. Cardiac sympathetic dysinnervation (123-I-MIBG myocardial uptake (MU) score >2), initially observed in 10 patients, was detectable in 8 patients at follow-up. Myocardial uptake scores of the anterior, lateral, posterior, septal and apical region had improved in 6, 6, 6, 7 and 6 patients, but the mean changes of these scores did not reach significance. In patients with substantial improvement of metabolic control (HbAlc 7.3 +/- 0.6% at one year, mean HbA1c of months 2-12: 7.8%, n = 6), global myocardial uptake had improved from 4.3 +/- 1.0 to 3.2 +/- 1.0 (p < 0.05). Respectively, myocardial uptake score of the anterior, posterior and septal region had ameliorated: 3.8 +/- 1.3 vs 2.3 +/- 0.8 (p < 0.05), 4.0 +/- 1.7 vs 2.5 +/- 1.0 (p < 0.05), 4.3 +/- 1.2 vs 3.2 +/- 1.5 (p < 0.05). In conclusion, cardiac sympathetic dysinnervation in poorly controlled longer-term Type 1 DM patients is dominated by irreversible neuronal abnormalities. Substantial metabolic improvement, however, partially restores cardiac sympathetic dysinnervation, indicating the presence of a reversible component of cardiac sympathetic dysfunction in longer-term Type 1 DM.
There is growing evidence for the involvement of immunological factors in the pathogenesis of cardiac autonomic dysfunction in Type 1 diabetes mellitus (DM). To evaluate the presence of autoantibodies against autonomic nervous tissues and their relationship with tests of autonomic function, 64 newly diagnosed and 142 long duration Type 1 DM patients were investigated for sympathetic and parasympathetic ganglia (CF-SG and CF-PSG) autoantibodies with a complement-fixing indirect immunofluorescence technique. Five cardiac reflex tests were performed to assess autonomic function. Fifty-seven patients with neurological diseases other than diabetic neuropathy and 131 healthy control subjects were also tested for CF-SG and CF-PSG autoantibodies. CF-SG autoantibodies were observed in 47 (23%) and CF-PSG autoantibodies in 21 (10%) of 206 Type 1 DM patients (p < 0.001). In contrast, these autoantibodies were detected in 3 (5%) and 1 (2%) of patients with non-diabetic neurological diseases and 3 (2%) and 4 (3%) of control subjects (p < 0.01, p < 0.05, p < 0.0001, p < 0.05 vs Type 1 DM patients). All except two Type 1 DM patients with CF-PSG autoantibodies also presented with CF-SG autoantibodies. In diabetic patients with long duration, CF-SG autoantibodies were more frequent in patients with ECG-based cardiac autonomic neuropathy (CAN; > or =2 of 5 cardiac reflex tests abnormal) compared to patients without CAN although this did not reach statistical significance (29% vs 17%, p = 0.06). However, 4 (80%) of 5 newly diagnosed and 23 (32%) of 73 established Type 1 DM patients with abnormalities in heart rate variation during deep breathing and/or standing from lying presented with CF-SG autoantibodies compared to 12 (25%) of 58 newly diagnosed (p < 0.05) and 7 (11%) of 63 established Type 1 DM patients (p < 0.01), in whom both tests were normal. The results suggest that autoimmune factors contribute to the pathogenesis of cardiac autonomic dysfunction in Type 1 DM and that autoantibodies against sympathetic and parasympathetic nervous tissues are relatively specific for Type 1 DM.
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