Search

Two and a half years after manifestation of treatment-refractory lipoatrophic diabetes a 16-year-old girl had blood-sugar levels of about 500 mg/dl and hypertriglyceridaemia with fasting levels of about 3000 mg/dl, while there was no increase in ketone bodies. All the clinical, histological and radiological findings were those of generalized fatty tissue atrophy. In addition, she had marked axillary and periorbital acanthosis nigricans. Main symptoms were fatigue, weakness and excessive appetite. Intravenous insulin of at first 1200 IU daily reduced blood-sugar levels to normal. A good metabolic state was maintained by intensive insulin treatment with four intramuscular injections daily. On a dosage of 600-700 IU daily the HbA1 value dropped from 16.7% to 7.8%, triglyceride concentration to 300-400 mg/dl. The symptoms also regressed with normalization of the metabolic state.

OBJECTIVE To evaluate the efficacy and safety of oral treatment with the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic neuropathy (CAN), assessed by heart rate variability (HRV). RESEARCH DESIGN AND METHODS In a randomized, double-blind placebo-controlled multicenter trial (Deutsche Kardiale Autonome Neuropathie [DEKAN] Study), NIDDM patients with reduced HRV were randomly assigned to treatment with daily oral dose of 800 mg ALA (n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at rest included the coefficient of variation (CV), root mean square successive difference (RMSSD), and spectral power in the low-frequency (LF; 0.05–0.15 Hz) and high-frequency (HF; 0.15–0.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed. RESULTS Seventeen patients dropped out of the study (ALA n = 10; placebo n = 7). Mean blood pressure and HbA1 levels did not differ between the groups at baseline and during the study, but heart rate at baseline was higher in the group treated with ALA (P < 0.05). RMSSD increased from baseline to 4 months by 1.5 ms (−37.6 to 77.1) [median (minimum-maximum)] in the group given ALA and decreased by −0.1 ms (−19.2 to 32.8) in the placebo group (P < 0.05 for ALA vs. placebo). Power spectrum in the LF band increased by 0.06 bpm2 (−0.09 to 0.62) in ALA, whereas it declined by −0.01 bpm2 (−0.48 to 1.86) in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a trend toward a favorable effect of ALA versus placebo for the CV and HF band power spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo). The changes in cardiovascular autonomic symptoms did not differ significantly between the groups during the period studied. No differences between the groups were noted regarding the rates of adverse events. CONCLUSIONS These findings suggest that treatment with ALA using a well-tolerated oral dose of 800 mg/day for 4 months may slightly improve CAN in NIDDM patients.

Background Percutaneous transluminal coronary angio-plasty (PTCA) with its various manipulations could create a dangerous, sudden haemostatic response. This study was performed to investigate PTCA-induced periprocedural changes in platelet activation and its consequences. Methods Twenty-five consecutive patients admitted for elective PTCA were preclassified as having or not having circulating activated platelets. Blood samples were taken for platelet activation marker analysis before, six times during and 2 h after PTCA. Intravascular platelet activation was analysed by flow cytometry to measure activation-dependent surface markers thrombospondin, P-selectin (CD62) and lysosomal GP53 (CD63). Results PTCA was associated with a significant reduction of peripheral platelet count. The initiation of the PTCA procedure led to a significant loss of more than 50% of the degranulated, activated platelets. After PTCA, the number of degranulated, activated platelets uniformly increased. Conclusions We conclude that PTCA can induce consumption, particularly of preactivated platelets, and lead to sustained platelet activation after the procedure. This might explain why preactivated patients are at increased risk of suffering periprocedural ischaemic events and why increased thrombogenicity favours acute flow disruption and the progression of coronary stenosis at the lesion site.

Objective To determine whether a lack of symptoms in diabetic patients with gastrointestinal motility disorders is associated with visceral afferent neuropathy. Research Design and Methods We investigated cerebral evoked potentials (EPs) after esophageal stimulation in 10 patients with motor dysfunction of the gastrointestinal tract and in 10 healthy control subjects. All patients had insulin-dependent diabetes mellitus (5 men, 5 women, age range 31–60 yr, diabetes duration 8–36 yr, 10 of 10 with polyneuropathy, 6 of 10 with cardiac autonomic neuropathy). Their esophageal and gastric motor disorders had been diagnosed by scintigraphy, and gastrointestinal stenosis had been excluded by gastroscopy. Only 2 patients had severe symptoms, whereas 6 patients complained of minor discomfort (distension, bloating), and 2 patients were symptom free. Results EPs were recorded after electrical stimulation of the esophagus (32 cm from the incisors) at intensity just above the perception threshold. All control subjects exhibited regular EPs at 0.1 ms/30 mA stimulation intensity. In 6 diabetic patients, no EPs were detected at 0.1 and 0.3 ms/30 mA, and the perception thresholds were significantly elevated. In 4 patients with normal perception threshold, EPs of regular shape but decreased amplitude were recorded. These patients had mild or severe gastroparetic complaints. Conclusions These data show for the first time an association between a lack of symptoms in diabetic gastrointestinal motility disorders and visceral afferent neuropathy.

The interrelationships between fibrinogen, von Willebrand factor, a marker of vascular endothelial cell damage, and serum lipids were explored in well-characterised subjects with insulin-dependent diabetes mellitus. The 2091 subjects were enrolled into a cross-sectional, clinic-based study of complications, from 16 European countries: the EURODIAB IDDM Complications study. The anticipated significant relationships between both plasma fibrinogen and plasma von Willebrand factor concentrations and age and glycaemic control, and between fibrinogen and body mass index, were noted. Fibrinogen, adjusted for age and glycated haemoglobin concentration, was also related to smoking habits and was higher in the quartiles with highest systolic and diastolic blood pressures. There was a clustering of vascular risk factors, with a positive relationship between plasma fibrinogen and serum triglyceride concentrations in both genders and between fibrinogen and total cholesterol in males. An inverse relationship between fibrinogen and high density lipoprotein cholesterol was also apparent in males. A prominent feature was a positive relationship between both fibrinogen and von Willebrand factor and albumin excretion rate (p < 0.001 and p < 0.003 respectively) in those with retinopathy but not in these without this complication. In view of previous observations on blood pressure and albuminuria in these subjects the findings are consistent with the hypothesis that microalbuminuria and increased plasma von Willebrand factor are due to endothelial cell perturbation in response to mildly raised blood pressure in subjects with retinopathy. Fibrinogen may also contribute to microvascular disease and its relationships to lipid vascular risk factors suggest a possible pathogenic role in arterial disease in diabetes.

The EURODIAB IDDM Complications Study, a cross-sectional, clinic-based study, was designed to measure the prevalence of diabetic complications in stratified samples of European insulin-dependent diabetic (IDDM) patients. As diet may be related to diabetic complications, nutritional intake was analysed in the study population. The aims of this first nutritional paper are to describe the nutrient intake in 2868 IDDM patients from 30 centres in 16 countries throughout Europe, to investigate the degree of regional differences in nutrient intake and to compare current intakes with recommended levels. Nutritional intake from 1458 male and 1410 female IDDM patients was assessed by a validated 3-day record (two weekdays, Sunday) and centrally analysed. Mean energy intake for all patients was 2390 +/- 707 kcal/day. Mean protein intake was 1.5 +/- 0.5 g/kg body weight. Carbohydrate intake was 43% and fibre intake 18 g/day. Alcohol intake for the total cohort was 2% of energy. Total fat contributed 38% of energy, with 14% from saturated fat. The Italian centres reported lower total and saturated fat intakes compared with other centres. Recommendations from the Diabetes and Nutrition Study Group of the EASD for total fat, saturated fatty acids and carbohydrate were only achieved by 14%, 14% and 15% of patients, respectively. The data of the present study clearly indicate current problems in the nutritional intake of European IDDM patients. These findings contribute to the definition of future targets in the nutritional management of IDDM patients, to be achieved as part of the initiatives taken by the St. Vincent Declaration action programme.

OBJECTIVE To study the prevalence of cardiovascular disease (CVD), its risk factors, and their associations in IDDM patients in different European countries. RESEARCH DESIGN AND METHODS The prevalence of CVD (a past history or electrocardiogram abnormalities) and its risk factors were examined in a cross-sectional study in 3,250 IDDM patients from 16 European countries (EURODIAB IDDM Complications Study). The patients were examined in 31 centers and were stratified between centers for age, sex, and duration of diabetes. The mean ± SD duration of diabetes was 14.7 ± 9.3 years. RESULTS The prevalence of CVD was 9% in men and 10% in women. The prevalence increased with age (from 6% in patients 15–29 years old to 25% in patients 45–59 years old) and with duration of diabetes. The between-center variation for the whole population was from 3 to 19%. In both sexes, fasting triglyceride concentration was higher and HDL cholesterol lower in those patients with CVD than in those without. In men, duration of diabetes was longer, waist-to-hip ratio greater, and hypertension more common in patients with CVD. In women, a greater BMI was associated with increased prevalence of CVD. There was no association between insulin dose, HbA1c level, age-adjusted rate of albumin excretion, or smoking status and CVD. Waist-to-hip ratio, particularly in men, was positively associated with age, age-adjusted HbA1c, prevalence of smoking, daily insulin dose, albumin excretion rate, and fasting triglyceride concentrations. CONCLUSIONS The overall prevalence of CVD in these IDDM patients was ∼ 10%, increasing with age and duration of diabetes and with a sixfold variation between different European centers. CVD prevalence was most strongly associated with elevated triglyceride and decreased HDL cholesterol concentrations. CVD was also associated with albuminuria, but when adjusted by age, this association vanished. Increasing waist-to-hip ratio was associated with a number of adverse characteristics, particularly in IDDM men, reflecting the metabolic syndrome previously described in other populations.

Several studies have shown an association between blood pressure and nephropathy, but few have been large enough to examine whether, or how, this relation is influenced by retinopathy. We have therefore examined the independent relations of blood pressure to urinary albumin excretion and retinopathy in a cross-sectional observational study of over 3000 insulin-dependent diabetic patients (the EURODIAB IDDM Complications Study). The relation of blood pressure to urinary albumin excretion differed strikingly between patients with (46%) and without (54%) retinopathy. In those with retinopathy, mean urinary albumin excretion rate was normal (20 micrograms/min) below median diastolic pressure (75 mmHg) and increased steeply (p0.001) with blood pressure above this level. However, in patients without retinopathy, mean albumin excretion rate was normal across the range of diastolic pressure. This finding could not be explained by differences in glycaemic control or duration of diabetes between patients with and without retinopathy. These data identify a subgroup of patients whose high risk of nephropathy may reflect abnormal renal vulnerability to mildly raised blood pressure. Retinopathy is a close correlate of this vulnerability. Detection of even mild retinopathy, together with raised blood pressure, may be important in assessing nephropathy risk.

OBJECTIVE To examine the relationship between smoking and both glycemic control and microvascular complications in patients with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS This was a prevalence survey of 3,250 men and women aged 15–60 years with IDDM from 31 diabetes centers in 16 European countries. Participants completed a questionnaire, had retinal photographs taken, and performed a 24-h urine collection. HbA1c, frequency of hypoglycemic and ketoacidotic episodes, urinary albumin excretion rates, and retinopathy were compared by smoking category. RESULTS The prevalence of smoking was 35% in men and 29% in women. Current smokers had poorer glycemic control and, among men, were more likely to have had a ketoacidotic episode than were those who never smoked. Ex-smokers had equivalent glycemic control and marginally more hypoglycemic episodes did than those who never smoked. Current smokers had a higher prevalence of microalbuminuria and total retinopathy than did those who never smoked. Ex-smokers had a higher prevalence of macroalbuminuria and proliferative retinopathy than did those who never smoked, but both had a similar prevalence of microalbuminuria. Adjustment for either current or long-term glycemic control could not fully account for these differences. CONCLUSIONS Smoking is associated with poorer glycemic control and an increased prevalence of microvascular complications compared with not smoking. Ex-smokers can achieve glycemic control equivalent to and have a prevalence of early complications similar to that of those who never smoked. We suggest that poorer glycemic control can account for some of the increased risk of complications in smokers, and that quitting smoking would be effective in reducing the incidence of complications. Urgent action is required to reduce the high smoking rates in people with IDDM.

Abnormal glucose tolerance was found in 30 of 100 patients with endogenous hypertriglyceridaemia (74 males, 26 females, age 45.9 +/- 11.4 years, Broca index 116 +/- 25%; 44 type II b, 7 type III and 49 type IV hyperlipoproteinaemia). In 19 cases the abnormal glucose tolerance was discovered during treatment with diet and, if necessary, lipid-lowering substances for an average of 5.8 +/- 2.8 years. Compared with the normal population there was in these patients an 8- to 10-fold increase in the incidence of abnormal glucose tolerance. Therapy-induced lowering of the serum triglyceride concentration was followed by an improvement of the abnormal glucose tolerance. The "antidiabetic" effect of hyperlipidaemia treatment was only slightly improved by concurrent weight reduction. These results indicate that the treatment of hyperlipidaemia in patients with endogenous hypertriglyceridaemia is of importance in the prevention of diabetes.

In a study extending over five years 35 of 70 excessively overweight patients with subclinical diabetes mellitus who had not significantly changed their weight, demonstrated a further deterioration in glucose tolerance, and manifest diabetes occurred in ten. In the remaining 35 patients who had achieved 20% weight reduction from the initial level glucose tolerance had become normal. The two groups were similar as to age, initial weight, and original degree of glucose intolerance. There was a significant correlation between loss of weight and increased glucose tolerance. No such correlation occurred with subgroups of patients whose initial overweight was more than +100 relative percentage and who had been over 50 years old at the start of the study.

It was demonstrated that hemolysed blood and/or crystalline hemoglobin inactivated insulin either by irreversible destruction due to the presence of SH compounds or by reversible binding to hemoglobin. The increased pancreatic insulin content and pancreatic islet cell hyperplasia observed in infants with erythroblastosis fetalis may represent a compensatory response to inactivation of circulating insulin.

Am subcutanen menschlichen Fettgewebe wurde der Einflus von Glucose auf die Lipolyse in vitro untersucht. Durch steigende Glucosekonzentrationen im Inkubationsmedium wird die Freisetzung von FFS zunehmend gebremst. Die Glycerinfreisetzung wird bei Glucosekonzentrationen uber 2,5 mg/ml gleichfalls gehemmt, dagegen bei niedrigeren Glucosekonzentrationen stimuliert. Es ist anzunehmen, das Glucose in physiologischen Konzentrationen nicht nur die intracellulare Eigenhemmung der Lipolyse uber die Ruckveresterung von FFS beeinflust, sondern auf noch nicht bekannte Weise die Lipolyse direkt stimuliert.

The aim of this study was to examine whether therapeutical doses of nitrendipine influence platelet function. In eight healthy subjects, the platelet aggregation response to collagen in whole blood and platelet-rich plasma (PRP) was monitored over 12 h after single administration of 40 mg nitrendipine given orally and was strongly inhibited between 60-83% (0.3 microgram/ml collagen) versus baseline at the third and fourth hour. Stimulated thromboxane formation from exogeneous arachidonic acid decreased almost continuously, with lowest levels at the 12th hour. Basal thromboxane remained below 25 pg/ml, but platelet factor 4 increased to more than twice the baseline level in the fourth hour, presumably reflecting adrenergic counterregulation of hypotensive effects. These preliminary data show that therapeutic drug concentrations of nitrendipine inhibit platelet function. Therefore, calcium channel blockers may be of therapeutical value in the treatment of prethrombotic states with primary platelet hyperactivity as present, for example, in diabetes mellitus.

Das klinische Bild der Spontanhypoglykamie ist vielfaltig und erfordert eine sorgfaltige differentialdiagnostische Abklarung. Hypoglykamische Symptome nach Nahrungskarenz treten bei einer Vielzahl von Neoplasien auf [2]. Die tumorbedingten Hypoglykamien konnen durch Insulinome oder extrapankreatische Tumoren bedingt sein. Zur Abklarung von Spontanhypoglykamien liegt ein festes Untersuchungsprogramm vor [1]. Nach diesem Schema haben wir drei Patientinnen mit Spontanhypoglykamie durch extrapankreatische Tumoren untersucht.

Clofibrat wird seit einigen Jahren vorwiegend zur Behandlung von Hypertriglyceridamien eingesetzt. Sein Wirkungsmechanismus beruht u. a. auf einer Hemmung der hepatischen VLDL-Produktion [1] bzw. Triglyceridsynthese [2]. Nach Untersuchungen von Reaven et al. [3] und Gruneklee et al. [4] besteht zwischen Triglyceridkonzentration und Insulinsekretion eine positive Korrelation. Eine Hemmung der Insulinsekretion z. B. durch Diazoxid fuhrt sowohl zu einer Verminderung der VLDL-Synthese als auch der Triglyceridproduktion [5]. Somit kommt dem Insulin eine wesentliche Rolle bei der Regulation der hepatischen Triglyceridsynthese zu.

Bei der menschlichen Fettsucht sind unter Basalbedingungen und unter Belastungen verschiedene Besonderheiten des Kohlenhydrat- und Fettstoffwechsels gefunden worden [1, 3, 4, 7, 8, 9, 10, 11, 18, 20]. Da die zirkulierenden Metabolite, auf deren Studium sich die bisherigen Untersuchungen im wesentlichen beschrankten, Stoffwechselvorgange des Gewebes reflektieren, ist zu erwarten, das mogliche Fettstoffwechselstorungen bei Adipositas am ehesten durch direkte Messung von Stoffwechselvorgangen des Fettgewebes selbst aufgedeckt werden. Bisherige Untersuchungen dazu sind widerspruchlich [2, 5,13,16, 21]. Fur die Pathogenese der Fettsucht waren Regulationsstorungen der Lipogenese oder der Lipidmobilisation von Bedeutung. Im folgenden soll uber Studien zur Fettmobilisation berichtet werden: An subcutanem Fettgewebe von 17 mannlichen Personen mit unterschiedlichen relativen Korpergewichten wurde die basale und die durch Noradrenalin stimulierte Lipolyse in vitro untersucht.

Patienten mit essentieller Hyperlipamie (HL) weisen in rund drei Viertel aller Falle Storungen des Kohlenhydratstoffwechsels auf. Die Grunde dafur sind nicht bekannt. Dies veranlaste uns, unter Glucosebelastung das Verhalten der freien Fettsauren und des Insulins im Serum bei essentiellen Hyperlipamien sowie bei der Alkohol-induzierten Hyperlipamie zu untersuchen.

Glucagon entfaltet am Fettgewebe der Ratte starke lipolytische Wirksamkeit. Sie ist bereits bei 4 μg Hormon/ml nachweisbar (Weinges, 1961), d. h. bei Konzentrationen, die im menschlichen Blutserum mit biologischen (Makman u. Mitarb., 1958) und immunologischen Methoden (Lawrence, 1966; Samols u. Mitarb., 1965) nachgewiesen worden sind. Der Blutspiegel des Glucagon steigt bei langer dauernder Nahrungskarenz an (Unger u. Mitarb., 1963; Lawrence, 1966). Der Konzentrationsanstieg fallt zeitlich mit dem Anstieg des Serumglycerins als Ausdruck einer gesteigerten Lipolyse zusammen (Gries u. Mitarb., 1963). Dieses Verhalten des Hormons und seine Wirkung auf die Glykogenolyse und Gluconeogenese legten nahe, das Glucagon als Hormon der Hungerphase anzusehen und ihm wesentliche Bedeutung fur die Stoffwechselregulation zuzuschreiben. Neuere Untersuchungen haben jedoch diese Vorstellung in Frage gestellt. Es zeigte sich, das die gluconeogenetische und die lipolytische Wirksamkeit ausgepragte species-abhangige Unterschiede aufweisen. Ob Glucagon am Fettgewebe des Menschen lipolytische Wirksamkeit entfaltet, ist auf Grund widerspruchlicher in vivo-Beobachtungen umstritten. In vitro konnte eine Lipolysesteigerung bisher nicht nachgewiesen werden (Mosinger u. Mitarb., 1965). Wir haben deshalb die Wirkung von Glucagon auf die Freisetzung von freien Fettsauren (FFS) und Glycerin aus menschlichen Fettgewebsschnitten in vitro gepruft.

Viele Untersuchungen befassen sich mit der Frage der Aufdeckung von Stoffwechselstorungen bei Adipositas. In letzter Zeit galt das besondere Interesse dem Fettgewebe selbst, dessen morphologische Struktur und Stoffwechselaktivitat Gegenstand zahlreicher Untersuchungen war. Diese Untersuchungen fuhrten zu einigen interessanten Ergebnissen. Mehrere Autoren konnten nachweisen, das die Vermehrung des Fettgewebes bei Gewichtszunahme parallel geht mit einer Vergroserung der Fettzellen (Bjurulf [1], Hausberger u. Hausberger [4]). Preiss u. Mitarb. [5] aus unserem Arbeitskreis zeigten an isolierten menschlichen Fettzellen enge Korrelationen zwischen Fettzellgrose und Korpergewicht. Salans, Knittle u. Hirsch [7] konnten nachweisen, das die Insulinempfindlichkeit der Fettzelle mit zunehmender Grose geringer wird. Diese Befunde veranlasten uns, folgende Problemstellung aufzugreifen: Geht die Grosenzunahme der Fettzelle bei der Entwicklung einer Fettsucht mit wesentlichen Anderungen der Struktur oder chemischen Zusammensetzung parallel? Handelt es sich um eine mit Lipiden gefullte Zelle mit uberwiegenden Speicherfunktionen? In diesem Fall ware es vorstellbar, das der plasmatische Anteil der Zelle mit seinen Enzymen und Co-Enzy-men so eingeschrankt wird, das seine Stoffwechselkapazitat unter die Norm absinkt.

For people with insulin-dependent diabetes mellitus (IDDM) renal disease represents a life-threatening and costly complication. The EURODIAB IDDM Complications Study, a cross-sectional, clinic-based study, was designed to determine the prevalence of renal complications and putative risk factors in stratified samples of European individuals with IDDM. The present study examined the relationship between dietary protein intake and urinary albumin excretion rate (AER). Food intake was assessed centrally by a standardized 3-day dietary record. Urinary AER was determined in a central laboratory from a timed 24-h urine collection. Complete data were available from 2696 persons with IDDM from 30 centres in 16 European countries. In individuals who reported protein consumption less than 20 % of total food energy intake, mean AER was below 20 μg/min. In those in whom protein intake constituted more than 20 %, mean AER increased, a trend particularly pronounced in individuals with hypertension and/or poor metabolic control. Trends reached statistical significance for intakes of total protein (% of energy, p = 0.01) and animal protein (% of energy, p = 0.02), while no association was seen for vegetable protein (p = 0.83). These findings support the current recommendation for people with diabetes not to exceed a protein intake of 20 % of total energy. Monitoring and adjustment of dietary protein appears particularly desirable for individuals with AER exceeding 20 μg/min (approximately 30 mg/24 h), especially when arterial pressure is raised and/or diabetic control is poor. [Diabetologia (1997) 40: 1219–1226]