Long-term intensified insulin treatment, as compared with standard treatment, retards the development of microvascular complications in patients with insulin-dependent diabetes mellitus.

No abstract

Ninety-six patients with insulin-dependent diabetes mellitus (IDDM) and non-proliferative retinopathy were randomized to intensified conventional treatment (ICT) (n = 44) or regular treatment (RT) (n = 52), and followed up for 5 years. HbA1c decreased from 9.5 +/- 0.2% (mean value +/- SEM) to 7.2 +/- 0.1% in the ICT group, and from 9.4 +/- 0.2% to 8.7 +/- 0.1% in the RT group (difference between the groups, P less than 0.001). Retinopathy increased in both groups (P less than 0.001), but after 5 years it was worse in the RT group (P less than 0.05). The urinary albumin excretion rate was higher in the RT group than in the ICT group after 5 years (239.9 +/- 129.7 micrograms min-1 vs. 46.0 +/- 26.1 micrograms min-1, P less than 0.05). Eight RT patients developed manifest nephropathy, compared with none in the ICT group (P less than 0.01). After 5 years the conduction velocities of the sural (P less than 0.05), peroneal (P less than 0.01) and tibial (P less than 0.001) nerves were lower in the RT group. The respiratory sinus arrhythmia was 12.1 +/- 1.2 beats min-1 in the RT group and 16.7 +/- 1.4 beats min-1 in the ICT group at the end of the study (P less than 0.01). The increases in retinopathy (P less than 0.01), nephropathy (P less than 0.01) and neuropathy (P less than 0.001) were all related to the mean HbA1c value during the study. Smoking habits only influenced the progression of retinopathy (P less than 0.05). Serious hypoglycaemia occurred in 34 ICT patients and 29 RT patients (242 and 98 episodes, respectively) (P less than 0.05). Whereas weight was stable in the RT group, the body mass index increased by 5.8% in the ICT group (P less than 0.01). In conclusion, microvascular complications of diabetes were retarded by intensified conventional insulin treatment. However, such treatment increased the frequency of serious hypoglycaemia, and led to an increase in body weight.

Blood glucose values close to normal reduce the microvascular complications of insulin-dependent diabetes mellitus. The Stockholm study of this effect continued after the initial 7.5-year period in order to see what happened when intensively treated patients were left to control their own treatment while treatment was intensified in the control group. Forty-three patients with insulin-dependent diabetes randomised to intensified conventional treatment (ICT) and 48 patients randomised to standard treatment (ST) were followed-up for 10 years. Vascular complications, treatment side-effects and well-being were studied. Risk factors for complications were sought. HbA1c (normal range 3.9-5.7%) was reduced from 9.5 +/- 1.4% (mean +/- SD) in the ICT group and 9.4 +/- 1.2% in the ST group to a mean (during 10 years) of 7.2 +/- 0.6% and 8.3 +/- 1.0%, respectively (p < 0.001). Serious retinopathy (63 vs 33%, p = 0.003), nephropathy (26 vs 7%, p = 0.012) and symptoms of neuropathy (32 vs 14%, p = 0.041) were more common in the ST group after 10 years. HbA1c and age were the only risk factors for complications. Self-reported well-being increased to a greater degree and severe hypoglycaemia was more common in the ICT group. Cognitive function after 10 years was similar in both treatment groups, and was not related to the number of severe hypoglycaemic episodes. Intensified insulin treatment leads to reduced long-term complications and increased well-being without causing undue side-effects.

Altogether, 102 patients were randomized to intensified conventional treatment (ICT) (n = 48) or standard treatment (ST) (n = 54). After 7.5 years, 89 patients remained, and it was shown that microangiopathy was retarded by the lower blood glucose concentrations seen in the patients in the ICT group. HbA1c was reduced from (means +/- SE) 9.5 +/- 0.2% to 7.1 +/- 0.1% in the ICT group and from 9.4 +/- 0.2% to 8.5 +/- 0.1% in the ST group (P < 0.001). Of the patients, 4 in the ICT group and 3 in the ST group died. Mortality was predicted by albuminuria, the amplitude of the sural nerve action potential, and the test of arm blood flow during contraction of the contralateral hand (sympathetic nerve function) at baseline (P < 0.05). Weight increased by 4.4 +/- 1.1 kg in the ICT group and 1.8 +/- 0.7 kg in the ST group (P = 0.05). Atherosclerosis, measured with digital pulse plethysmography, was approximately the same in the groups at baseline and after five years. In each group, 3 patients had myocardial infarctions, and 2 from each group had ketoacidosis once. There was a mean of 1.1 episodes per patient and per year of serious hypoglycemia in the ICT group and 0.4 episodes per patient and per year in the ST group. No adverse incidents or accidents were observed in either group, and there were no differences between the groups with regard to cognitive function measured with a battery of tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Microangiopathy is retarded by improved blood glucose control in patients with IDDM. Whether or not this is true for macroangiopathy (atherosclerosis) has remained unclear. A total of 59 patients (44 +/- 1.5 years, previous HbA1C 9.4 +/- 0.2%, mean +/- SE) with IDDM were investigated. Of the 59 patients, 31 had been randomized to long-term intensified conventional insulin treatment (ICT), and the remaining 28 had received standard insulin treatment (ST). Blood glucose control was significantly better in the ICT patients with an HbAlc value (mean of 29 values during 10 years) of 7.1 +/- 0.1% compared with the ST patients' 8.2 +/- 0.2% (P < 0.0001). With high-frequency ultrasound, endothelial function was measured as flow-mediated dilation of the right brachial artery. The carotid arteries were scanned for plaques, intima-media thickness was measured, and arterial wall stiffness was calculated in the right common carotid artery. These measurements correlate with manifest and/or risk factors for coronary atherosclerosis. The patients in the ST group had stiffer arteries (P = 0.011) and thicker intima-media in the left common carotid artery (P = 0.009) than those in the ICT group. Patients with lower HbA1c generally had better endothelial function (P = 0.028) and less stiff arteries (P = 0.009). Better blood glucose control in patients with IDDM is related not only to less microangiopathy but also to a slower development of atherosclerosis.

Abstract. Jensen-Urstad K, Reichard P, Jensen-Urstad M (Karolinska Hospital and Södersjukhuset, Stockholm, Sweden). Decreased heart rate variability in patients with type 1 diabetes mellitus is related to arterial wall stiffness. J Intern Med 1999; 245: 57-61.Objective. Low heart rate variability (HRV) is, in several patient groups, related to poor prognosis. The underlying mechanisms are still unclear. The aim was to study if there is a relationship between HRV, which is a measure of baroreceptor function, and atherosclerosis. Design. The relationship between heart rate variability and carotid arterial wall stiffness was studied in subjects with type 1 diabetes mellitus in which autonomic dysfunction and early atherosclerosis are common. HRV was assessed from power spectral analysis of 24-h Holter recordings and arterial wall stiffness was assessed from an ultrasound study of the right common carotid artery. Setting. A university hospital.Subjects. Fifty-nine patients (41 Ϯ 8 years) from the Stockholm Diabetes Intervention Study (SDIS) were investigated. These patients were randomized to intensified conventional treatment or standard treatment approximately 12 years before this study. Results. Patients with stiffer arteries had lower HRV in all spectral bands (r ϭ Ϫ0.32 to Ϫ0.40, P ϭ 0.06-0.001). This relation remained on correcting for age. All spectral parameters of HRV correlated with the mean HbA1c from 10 years of study (r ϭ Ϫ0.37 to Ϫ0.40, P ϭ 0.004-0.001). Conclusions. In patients with type 1 diabetes mellitus, heart rate variability and arterial wall stiffness are related to each other. The results suggests that the autonomic nervous system could be a link between diabetes and vascular disease.

We compared regional cerebral blood flow (rCBF) and arteriojugular vein differences of glucose, ketones, glycerol, lactate, pyruvate, and O2 in eight subjects with well-controlled insulin-dependent diabetes mellitus (IDDM) and in six healthy volunteers. Duration of diabetes was 19.4 +/- 2.1 yr. Measurements were performed before and after 120 min of insulin infusion and concomitant Biostator-controlled normoglycemia. Net uptake of ketones was seen in IDDM subjects before but not after insulin. Net uptake of glucose did not differ significantly between groups. During normoglycemia the molar ratio of O2 to glucose uptake was lower in IDDM than in nondiabetic subjects (4.68 vs. 5.50; P less than 0.05; Wilcoxon test). Small but significant release of lactate and pyruvate was seen in IDDM but not in nondiabetic subjects. The rCBF was measured by 11CH3F and position emission tomography. Global mean CBF was higher in IDDM subjects (64.9 +/- 5.9 vs. 49.3 +/- 2.7 ml.100 g-1.min-1, means +/- SE in nondiabetic subjects, P less than 0.05). rCBF was enhanced in many cortical and subcortical areas, whereas it was decreased in the head of the caudate nucleus. Neuropsychological testing did not reveal obvious cognitive dysfunction. The results imply that a larger fraction of glucose is nonoxidatively metabolized in the IDDM subjects and furthermore indicate an abnormal rCBF pattern in these subjects.