[Long-term effect of combination glibenclamide-insulin treatment in the secondary failure of sulfonylurea therapy--results of a one-year double blind study]. / Langzeiteffekt der Glibenclamid-Insulin-Kombinationsbehandlung beim Sekundärversagen der Sulfonylharnstofftherapie--Ergebnisse einer einjährigen Doppelblindstudie.

The long-term efficacy of combined insulin-glibenclamide treatment was investigated in 79 secondary drug failure patients by means of a double-blind, randomized placebo-controlled study. During a one-year follow-up period the patients on insulin plus glibenclamide required significantly lower exogenous insulin doses. Coincidentally, C-peptide concentrations were significantly raised in the verum versus the placebo group. Additionally, the administration of glibenclamide resulted in a decreased level of hyperglycaemia during the first six months of the observation period. Glibenclamide withdrawal after six and again after twelve months of the combined therapy provoked a deterioration of glycaemic control, as well as a lowering of the C-peptide concentrations. The findings demonstrate a prolonged beneficial effect of the combined treatment, in contrast to the solely short-term effects predicted by numerous studies. The metabolic improvement must be ascribed in part to the beta-cytotropic effect of glibenclamide. Extrapancreatic pathways via receptor/postreceptor mechanisms cannot be excluded.

[Studies on mortality in diabetics in a circumscribed region: age and death, length of diabetes and causes of death]. / Untersuchungen über Sterbealter, erlebte Diabetesdauer und Todesursachen unter den Verstorbenen einer geschlossenen Diabetespopulation

Studies were carried out in regard to the age at death, duration of diabetes mellitus at the time of death and cause of death in an unselected evaluation of the findings in all 1694 diabetics who died in Erfurt and environs over an 11-year period. The The mean age of the patients at the time of death was 70.6 years, with virtually no difference between the sexes. Only six patients died prior to the age of 40. In accordance with the age structure of diabetics in a circumscribed area, the average survival time was 6.5 years. The interval between the first manifestation of the disease and death was 0 to 4 years in 45% of the patients; only every fifth patient survided for 10 or more years. These results are interpreted as being a reflexion of the frequent incidence of preceding or simultaneously-occuring atherosclerosis in these diabetics. Cardiovascular incidents affecting, above all, the coronary and cerebral vessels, account for about 60% of the deaths. Differences between these results and other statistical analyses can be explained on the basis of the unselective nature of the case material in the present study which was, moreover, collected in a defined region over a definite period of time.

Epidemiologic data on excess mortality and life expectancy in insulin-dependent diabetes mellitus--critical review.

Generalizations of prognosis with regard to insulin-dependent diabetes (IDDM) in epidemiological statistics are impaired not only by great intraindividual variations, but also due to methodical difficulties. Due to recent prognostic studies IDDM, particular in young age, must be considered as a rather serious disease with a 5 to 10 fold higher excess mortality in comparison with the general population. There are only few exact data about the extent of life shortening. Age of onset represents the most significant factor in life shortening. The younger the patient is at the age of onset the shorter he lives. From about 70 years onward diabetes has little or no effect on longevity. Whether the prognosis of IDDM has improved within the last decades remains uncertain. Long-term studies clearly indicate that IDDM is compatible also with a long life in a good health. Why many diabetics develop life shortening complications and why some patients do not cannot be answered with conclusive evidence.

[Circadian behavior of hemostaseologic parameters in diabetic patients and metabolically healthy individuals]. / Untersuchungen über das zirkadiane Verhalten hämostaseologischer Parameter bei Diabetikern und Stoffwechselgesunden.

In three groups of test persons [10 persons each with healthy metabolism under fasting (A) and intake of food (B); 10 insulin-dependent diabetics (C)] the determinations of the thromboplastin time, the partial thromboplastin time, the bleeding time, the spontaneous fibrinolytic activity, the number of thrombocytes and the aggregation of platelets were carried out on the day (A) and round the clock (B abd C), respectively. The values of the fasting persons with healthy metabolism distributed themselves on the day constantly in the area of width of errors. Under food intake persons with healthy metabolism showed circadian variations of the several tests. In diabetics the parameters of haemostasis revealed in the course of day a clear increase of the unstable behaviour compared with the control group B. There were no relations to the actual blood sugar value. In a tendency to more coagulation-active values in the late afternoon interindividually a general biorhythmical behaviour pattern could not be recognized. The proved increased circadian labilisation of the haemostasis potential in diabetics deserves more attention with regard to the connection between thrombophilia and atherogenesis.

[The course of asymptomatic diabetes under varying preventive therapy--concluding report of a 5-year prospective study]. / Verlauf des asymptomatischen Diabetes bei untershiedlicher Präventivbehandlung - Abshlussbericht einer 5jährigen prospektiven Studie.

During a prospective study the course of asymptomatic diabetes in different preventive treatment (diet, additionally tolbutamide, carbutamide or buformin) was observed concerning the frequency of manifestation and the behaviour of the oral glucose tolerance. Among the 100 protodiabetics after 5 years 38 clinical manifestations could be established, which finally nearly equally were distributed to all 4 groups of treatment. Only under the influence of buformin an effect preventing manifestation limited to 2 years appeared. Patients with persisting full or partial remissions continuously and more decreased in weight than cases of manifestation. Furthermore, the course was determined by the initially existing degree of hyperglycaemia as well as by the improvement of the glucose tolerance achieved in the first year. On account of the results of the examinations and the existing literature a preventive use of oral antidiabetics cannot be recommended.

[The influence of insulin, glucose and other monosaccharides on the platelet functions (author's transl)]. / Einfluss von Insulin, Glukose und anderen Monosacchariden auf Plättchenfunktionen

In vitro investigations were carried out on the action of insulin, glucose, xylose, galactose, fructose and sorbitol on the platelet aggregation test according to Breddin, on the ADP- and collagen-inducced aggregation and the release of platelet factor 4 as well as on the retraction. When incubating platelet-rich plasma with insulin and glucose simultaneously, a marked inhibition of the ADP- or collagen-induced platelet aggregation and release reaction results. Insulin as well as glucose impaired the platelet function only at high concentrations, this inhibition however did not reach that of a combination of both. Fructose, xylose and sorbitol exerted no significant inhibitory effects. In contrast to the prevented aggregation, the retraction was enhanced. As the causal mechanism for the inhibition of the platelet function the Crabtree effect is discussed.

Long-term diabetes--associated factors in survivorship and mortality.

Patients with long standing diabetes mellitus were analysed in order to identify associated factors in survivorship and mortality. Two population-based investigations were performed. In the Erfurt district all 20 years' survivors (208 patients, survival time up to 42 years) were studied longitudinally. Within the total diabetic population of the GDR all 40 years' survivors (159 patients, survival time up to 59 years) were investigated cross-sectionally in a multicentre study. During a 12-year follow-up a 2,6 fold excess mortality was registered. Although most patients in both studies were insulin-treated type-1 diabetics, death due to renal failure was observed only in 7%. In general the appearance of macroangiopathy was considerably postponed. Coronary heart disease represented the main cause of death (41.9%). Taking together both studies, to successfully overcome several decades of diabetes appears to be associated with age, age of onset, body weight, blood pressure, daily insulin dose, serum triglycerides, dietetic adherence and degree of compliance. In long-term diabetics, duration of illness exerts no prognostic influence. Some patients have survived for even half a century of diabetes despite additional atherogenic risk factors and bad compliance. Obviously, long-term diabetes is a multifactorial event including protective mechanisms yet unknown. Most long-term studies in diabetes so for have been based on case material from specialized centres (Oakley et al. 1974, Paz-Guevara et al. 1975, Dekkert et al. 1975) or have been performed without an epidemiologic background (Chazan et al. 1970, Ryan et al. 1970, Cochran et al. 1979). Due to unavoidable selection factors those studies do not provide representative samples of the diabetic population.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chlorpropamide-alcohol flush test in non-insulin-dependent diabetes mellitus in young age (MODY type)]. / Der Chlorpropamid-Alkohol-Flush-Test beim nicht insulinabhängigen Diabetes mellitus im jungen Lebensalter (MODY-Typ).

The chlorpropamide alcohol flush test (CPAF) has been described as a dominantly inherited feature in NIDDM, particularly of young people (MODY-type). Validity and usefulness of the CPAF were analyzed in 40 MODY-patients recruiting from a population study (criteria acc. to Tattersall and Fajans, 1975), 59 first degree relatives (24 diabetics, 35 non-diabetics), 40 NIDDM of maturity onset, 40 IDDM, and 40 healthy controls. The CPAF (single challenge test, placebo control, subjective evaluation by questionnaire acc. to Köbberling, 1980) proved to be positive in only 8 MODY-patients and 5 of diabetic first-degree relatives. In comparison to NIDDM of maturity onset (40/8), IDDM (40/6) and healthy controls (40/2) the frequency of positive CPAF showed no significant differences. Between flushers and non-flushers within the MODY-group no relationship to vascular findings, metabolic and genetic data (including HLA-typing) could be found. It is concluded that the CPAF is a real but rather nonspecific phenomenon unsuitable as a genetic marker.

[Prognosis of diabetes mellitus after an early diagnosis by means of glucosuria screening. Results of a 10 year course control]. / Prognose des Diabetes mellitus nach Frühdiagnose durch Glucosurie-Screening. Ergebnisse einer 10jährigen Verlaufskontrolle.

The 10-year course of diabetes in 250 patients detected by glucosuria screening in 1963 was evaluated in an inter-individual pair comparison with patients from the same territory admitted during the same calendar year. Pairs were grouped according to age, sex, and weight. Judged by mortality, survival time, causes of death, and vascular complications, the medium-term prognosis was not improved by screening, although in the screening group a strict diet could be maintained to a greater extent. Problems of evaluation and effectiveness of mass examination in chronic diseases are discussed. Glucosuria and hyperglycemia do not suffice as screening criteria for the early recognition of the complex risk of arteriosclerosis in maturity onset diabetes. Multi-screening in groups with especially high diabetes risk is expected to yield higher effectiveness than the mass screening hitherto performed.

[Results of a population study of non-insulin dependent diabetes mellitus in childhood and adolescence]. / Ergebnisse einer Populationsstudie über den nicht-insulinabhängigen Diabetes mellitus im Kindes- und Jugendalter.

Among 40 927 diabetics centrally registered in the Erfurt district, 61 non-insulin-dependent diabetics (0.15%) in early life have been recorded. The age of onset of 58 examined patients (36 males, 22 females) was 10 to 24 years. The insulin secretion after a 50 g oral glucose load varied markedly and corresponded to a control group of 62 adult NIDDM patients. 76.4% of the patients had a diabetic parent. In 17 patients (30%) diabetes had been transmitted through at least three generations. Sporadic occurrence was found in 19% of the case material. Families of MASON type with a marked diabetes accumulation were observed in only 3 cases. In the HLA system (A, B and C locus) there were characteristic differences from insulin-dependent diabetics but no significant (Pcorr) differences in comparison to the normal population. Variations of heredity, as well as differences in body weight, insulin secretion and varying susceptibility to vascular complication suggest that NIDDM in early life is a heterogeneous disorder. Besides the early age of onset, the balanced sex ratio and the partly marked inheritance, most patients of this population study present the typical features of type 2 diabetes.

[Clinical and functional studies of diabetic cardiopathy]. / Klinische und funktionsanalytische Untersuchungen zur diabetischen Kardiopathie.

In 30 diabetics and 30 patients with healthy metabolism who anamnestically, clinically and electrocardiographically did not show any references to a coronary heart disease the systolic time intervals and contractility indices of the carotid pulse curve were determined in lying position as well as under passive and active orthostasis load. Diabetics with a microangiopathy already under conditions of rest showed a tendency to pathological values. Unequivocal deviations were to be registered under conditions of the tilting table, particularly when the values obtained under orthostasis are related to the measuring data in rest. The restricted cardiac regulation breadth of diabetics with microangiopathy is particularly expressed in a compared with the control groups clearly reduced reaction of the presphygmic phase, the time of pressure increase as well as the quotients PEP/LVET, LVET/ICT and PEPstanding/PEPlying.

[Prospective analysis of the natural course of non-insulin dependent diabetes mellitus in early adulthood]. / Prospektive Analyse zum natürlichen Verlauf des nichtinsulinabhängigen Diabetes mellitus im Jugendalter (NIDDY).

Non-insulin-dependent diabetics with early manifestation of the disease (NIDDM) who were registered by an epidemiological cross-sectional study 1979 in the Erfurt district were pursued prospectively and 47 of the 58 patients underwent a re-examination five years later. The changes of therapy performed (7 new administrations of insulin, 9 change from diet to normal food) as well as the metabolic development of the patients under epidemiological aspect prove the heterogeneity of NIDDM and the doubtfulness of hitherto existing MODY-criteria. The oGTT performed in 37 patients 9 times resulted in a full remission and in 4 cases in an IGT. Including the 10 insulinized patients 34 diabetics (72.3%) had remained manifest. In contrast to the initially different degree of post-load hyperglycaemia in patients with and without remission the behaviour of the insulin secretion did not show any significant differences in the course and between the groups of patients. Young non-insulin-dependent diabetics are mainly among a representative target population type-II-diabetics with early onset. In contrast to this type-I-diabetics with a long insulin-free initial phase go into the background. In our population real MODY-cases are apparently extraordinarily rare.

[Studies on prognosis of diabetes mellitus]. / Untersuchungen zur Prognose des Diabetes mellitus.

On the epidemiologically defined number of all diabetics who were detected in the district of Erfurt in 1966 the prognosis with medium time limit was investigated retrospectively. The 2,500 patients (1,650 females, 910 males) correspond above all to type 2 of diabetes. According to the observation time of 10 years altogether died 1,054 patients (44.3%), 63.4% of cardiovascular causes of death (autopsy rate 20.9%). In all age groups with a sufficient number of subjects the mortality of the males was above the mortality of the females; according to that their median survival time was shorter. In comparison to the total population of the district of Erfurt the diabetics examined showed an aged-depending excess mortality between 1.1 and 1.9. By means of several methods an over-mortality could be proved already for the first year after the manifestation. The worse prognosis of the diabetics type 2 is interpreted as a consequence of an increased cardiovascular comorbidity, the causes of which have to be found in the complex action of atherogenic risk factors in the time before the manifestation of diabetes.

Prognosis of diabetes mellitus in a geographically defined population.

The centralised registration and care of all diabetics in a geographically defined population has provided an epidemiological basis for a longitudinal investigation of the prognosis of this disease. Records of all newly diagnosed diabetics who had been registered in the Erfurt district (population 1.25 million) in 1966 were studied in relation to the time period 1966-1976. Of the known 2,560 diabetics (910 men, 1,650 women; 93.7% greater than 40 years of age), 1,054 had died during the 10-year follow-up period. Cardiovascular causes accounted for the majority of deaths (63%). In almost all age classes proportionally more men than women had died at follow-up; there was a significant difference in the 60-69 year group (men 61.6%, women 46.2%). In comparison with the general population, excess mortality ranged from 2.1 to 1.0, decreasing with age at onset without significant differences between men and women. Excess mortality was present in most age classes and was evident within the first year after diagnosis. Current life-table analysis confirmed the shortened life expectancy of the diabetics. The lower life expectancy of noninsulin-dependent diabetics may not be due to hyperglycaemia alone but probably also involves a variety of atherongenic risk factors.

[Longitudinal studies on the prognostic significance of plasma fibrinogen in diabetes mellitus]. / Längsschnittuntersuchungen zur prognostischen Bedeutung des Plasmafibrinogens beim Diabetes mellitus.

In 243 diabetics of different duration of the disease the prognostic value of an initial estimation of plasma fibrinogen for life expectancy and development of macroangiopathy was controlled over a period of ten years. Diabetics with a cardiovascular cause of death showed at the beginning with 3.68 in contrast to 3.24 g/l weakly significantly higher fibrinogen values than the surviving patients. In analogy to this in the surviving patients the diabetics with a meanwhile appearing myocardial infarction, chronic ischaemic heart disease or manifest disturbances of the peripheral blood supply differed by higher fibrinogen concentrations from test persons without manifest macroangiopathy. There was a close correlation between plasma fibrinogen level and development of hypertension. The increase of plasma fibrinogen is apparently associated with the atherogenesis without rendering a secure prognosis in the individual case on account of a critical limiting value.

[Development of angiopathies in type 2 diabetes mellitus--results of a prospective 10 year study]. / Angiopathieentwicklung beim Typ 2-Diabetes mellitus--Ergebnisse einer prospektiven 10-Jahres-Studie.

In 150 newly detected type 2 diabetics the formation of macro- and microangiopathic complications during a 10-year control period was prospectively analysed, in order to demarcate possible factors of influence for the vascular prognosis under preventive points of view. Already at the time of manifestation there was with 34.3% an above average high prevalence of the coronary heart disease, particularly in the female sex. The prevalence of the coronary heart disease further increased to 49.7% in the course of diabetes and showed a correlation to the initial age, to the existence of overweight, hypertension, hyperlipoproteinaemia and nicotine consumption. The PMA was found comparatively more infrequent in the manifestation of diabetes (9.7%), but in the course of the disease highly significantly and independently of sex increased to 61.9%. The development of PMA was correlated with the age, the existence of hypertension and overweight. The frequency of retinopathy increased from initially 3.7% to 18.7%, the prevalence of nephropathy from 4.0% to 22.2%, without having found prognostic influence factors at the date of the diagnosis of diabetes.

[Prospective follow-up studies in long-term diabetes. Results of the Erfurt study]. / Prospektive Verlaufsbeobachtungen beim Langzeitdiabetes. Ergebnisse der Erfurt-Studie.

In 1970, in cooperation with the 14 district diabetic consultation centers of the Erfurt region (German Democratic Republic), all 208 known diabetics of the region with a known history of diabetes of at least 20 years (maximally 42 years) were registered and underwent multidisciplinary investigations. They were followed prospectively for at least 15 years. At the end of this period of observation, in 1985, 135 patients had died, 59 were still alive, the course of 14 is unknown. Of the 59 patients who were still alive in 1985, 49 (44 type I) were re-examined. There was a 2.1 times excess mortality rate compared with metabolically normal, interindividually paired (by age, sex and weight) controls. Cause of death in 89 patients (69.9%) was arteriosclerosis, predominantly of the coronaries, renal failure in only 9 (6.7%). Nearly all those patients who already in 1970 had evidence of advanced microangiopathies (proliferating retinopathy; persistent proteinuria) and/or macroangiopathy (authors' scoring system for coronary, cerebral and peripheral vascular disease) died during the observation period. Ophthalmoscopically normal or only mildly abnormal fundi revealed little tendency towards progression, despite the 35-55 years' duration of diabetes. Similar observations were made in the survivors as regards initially normal ECGs. The prognosis of long-term diabetes was decisively influenced by age and the severity of any arteriosclerotic disease, but not by the duration of diabetes.

Association of coronary heart disease with serum lipid and apolipoprotein concentrations in long-term diabetes. Results of the Erfurt study.

The Erfurt study is concerned with the follow-up of all the 208 long-term diabetics out of the closed area of the Erfurt district with an at least 20 years' diabetes survival in 1970. In 1980 risk factors for coronary heart disease (CHD) were assessed in 71 (85% type I diabetes) out of 76 patients still alive. Progression of CHD within the subsequent five years (death due to CHD in 8 cases and progression of the ECG findings according to the Minnesota code in 3 cases) was associated with older age, lower body mass index, higher triglycerides, and a higher total cholesterol/HDL cholesterol ratio in comparison with the surviving patients without progression (n = 41). No significant differences could be found with regard to sex distribution, age at diabetes onset, duration of diabetes, percentage of type I diabetes, systolic and diastolic blood pressure, smoking behavior, prevalence of nephropathy, glycemic control, and serum levels of total cholesterol, LDL cholesterol, and HDL cholesterol. The subsequent reinvestigation in 1985 also included the determination of apolipoproteins. Since type II diabetes was not equally distributed, only type I diabetics were considered for the comparison of patients with ECG findings suggestive of CHD (n = 5) with the remaining subjects (n = 35). In addition to the above mentioned differences, CHD in long-term type I diabetes was also accompanied by lower HDL cholesterol, lower apolipoprotein A-I, and a higher apolipoprotein B/apolipoprotein A-I ratio. Substantially similar differences could be observed when type II diabetics were not excluded (10 patients with and 37 patients without CHD). It is concluded that the lipoprotein pattern is important for the survival in long-term diabetes.

[Studies of nephropathies in 168 diabetic patients with over 20-year onset of the disease]. / Beobachtungen zur Nephropathie bei 168 Diabetiken mit über 20jähriger Krankheitsdauer

Within a clinical epidemiological investigation 168 diabetics were examined multidisciplinarily who survived the beginning of their disease by at least 20 years. The qualitative proof of protein in the urine was regarded as criterion for the presence of a diabetic nephropathy. 29% of the long-term diabetics showed a proteinuria. In a control group of probands with healthy metabolism, however, only 2.5% proteinurias were found. Statistically ascertained correlations were the results in cases of proteinuria and retinopathy (microangio-pathy). Particularly close were the relations of proteinuria to arteriolosclerosis (macroangiopathy). There were no relations between the proof of a proteinuria and the quality of the control of the carbohydrate metabolism which was pursued during decades.