In order to study the determining factors for oxygen transport the oxyhaemoglobin dissociation curve (ODC), red cell 2,3-diphosphoglycerate (2,3-DPG), and plasma inorganic phosphate were estimated in insulin-requiring juvenile and adult diabetics in various conditions of metabolic control. 2,3-DPG has been shown to vary much more in diabetics than in normals, depending upon the state of metabolic control. These fluctuations of 2,3-DPG are mediated by variations in plasma inorganic phosphate as indicated by a close correlation. While 2,3-DPG was markedly decreased in diabetic ketoacidosis, it tended to be increased in ambulatory, non-acidotic patients. Since in the non-acidotic patients the oxygen-carrying capacity, i.e. the haemoglobin concentration was simultaneously elevated, these findings suggest the presence of relative tissue hypoxia in diabetes. Both in non-acidotic and in ketoacidotic patients there was a strong correlation between the amount of 2,3-DPG and the P50 at actual pH as an experssion of the oxygen affinity of haemoglobin. In order to guarantee an optimal erythrocyte oxygen release in diabetics the content of red cell 2,3-DPG and plasma inorganic phosphate should be higher than normal.

Using the Trivelli method haemoglobin A1c (HbA1c) concentrations were determined in 7 patients with newly detected, non-insulin-dependent, diabetes mellitus before and after commencement of treatment with glibenclamide. Investigations were continued at weekly intervals over a period of 3 months. In all cases there was hardly any reduction of HbA1c values during the first 3 weeks of treatment. However, a continuous decrease of HbA1c values occurred thereafter. Nearly normal values were reached after patients had been adjusted to a considerably lower blood sugar level for more than 80 days. HbA1c concentration correlated significantly (p less than 0.001) both with the concurrently determined fasting blood sugar values as well as with fasting blood sugar values in each of the preceding 8 weeks.

In order to examine the short- and long term effects of basal/bolus insulin therapy on the metabolic regulation assessed by glycosylated haemoglobin (HbA1c) the first 201 patients in the diabetes out-patient clinic of the Section of Endocrinology, Department of Medicine, Aalborg Hospital, assigned for this treatment were prospectively studied. In all 201 patients a significant decrease in mean HbA1c value was observed after 21 months on multiple injection therapy (8.5% vs 8.1%; p < 0.001). The higher the HbA1c value on conventional therapy, the greater was the observed decrease in HbA1c following six months on basal/bolus therapy (r = 0.57, p < 0.001). According to an anonymous questionnaire completed by the first 140 patients six months after the start of multiple injection therapy, 97% of the patients preferred to continue with basal/bolus therapy with NovoPen, and 87% felt that they had achieved a better general condition and that the basal/bolus regime made their daily life easier. It is concluded that basal/bolus therapy with NovoPen may combine the attainment of improved metabolic control assessed by a decrease in mean HbA1c in many poorly regulated patients and the subjective experience of an improved quality of life.

Lipoprotein(a) [Lp(a)] is an LDL particle in which apoliporotein B-100 is attached to a large plasminogen-like protein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated, and plasma Lp(a) concentrations above 20-30 mg dl-1 are an independant risk factor for ischaemic heart disease (IHD). To investigate whether Lp(a) could be important for the high cardiovascular mortality rate in patients with insulin dependent diabetes mellitus (IDDM), we determined Lp(a) concentrations and phenotypes in a group of 108 men (median age 32 years) with IDDM without nephropathy. A group of 40-year-old men (n = 466) served as controls. The median Lp(a) concentration was 7.4 mg dl-1 [95% CI 4.9 to 11.7] in the diabetic patients and 6.3 mg dl-1 [95% CI 5.2 to 7.0] in controls. The Lp(a) concentration exceeded 30 mg dl-1 in 22% of IDDM patients and in 20% of controls (P = 0.13). Moreover, the distribution of apo(a) phenotypes did not differ between patients and control. Lp(a) levels and apo(a) phenotypes are thus apparently the same in IDDM patients without nephropathy and controls. These findings do not exclude the possibility that Lp(a) may be increased in patients with nephropathy in whom coronary artery disease frequently co-exist or that Lp(a) in a given concentration is more atherogenic in IDDM patients than in persons without IDDM.

To clarify whether glomerular hyperfiltration or disturbances in renal tubular function may be early markers of the later development of nephropathy a follow‐up study was performed in 34 young Type 1 diabetic patients, who had originally been investigated 12 years previously. The initial median age was 14 (range 7–18) years and median diabetes duration 7 (2–14) years. At initial examination only one of the 34 diabetic patients exhibited increased urinary albumin excretion rate. The median glomerular filtration rate was increased (136 vs 107 ml min−1 1.73 m−2; p < 0.0001) and median threshold concentration of phosphate per litre of glomerular filtrate was decreased (1.27 vs 1.76 mmol I−1; p < 0.0001) in the diabetic group as compared to that of 28 healthy children. At follow‐up 17 patients showed increased urinary albumin excretion rate and the median glomerular filtration rate in this group was significantly lower than that of 17 patients with normal urinary albumin excretion rate (108 vs 125 ml min−1 1.73 m−2; p < 0.05). However, no relationships were found between the increased urinary albumin excretion (incipient and/or overt diabetic nephropathy) at follow‐up to either the initial glomerular filtration rate (134 vs 137 ml min−1 1.73 m−2; p > 0.05) or to renal tubular function assessed from urinary excretion rate of β2‐microglobulin (0.059 vs 0.069 μg min−1; p > 0.05) and the renal threshold concentration of phosphate per litre of glomerular filtrate (1.29 vs 1.22 mmol I−1; p > 0.05).

The influence of maternal blood glucose regulation, weight gain, pre-pregnancy weight, vascular complications and smoking on the birth weight of infants was investigated in 72 type 1 (insulin-dependent) pregnant diabetic women. In patients with vascular complications (n = 23) the birth weight was significantly lower than in patients without vascular involvement (n = 49) (mean 380 g, P < 0.05). The mean RBWR (relative birth weight ratio) of infants of patients who smoked more than 10 cigarettes per day was statistically significant lower compared to the mean RBWR of infants of non-smokers (P < 0.025). A significant correlation was present between haemoglobin A1c (HbA1c) and RBWR (r = 0.28, P < 0.02) and between maternal net weight gain and RBWR (r = 0.36, P < 0.005) and this correlation became even stronger when only patients without vascular lesions were considered (n = 49) (r = 0.51, P < 0.005) and (r = 0.50, P < 0.005), respectively. In contrast no correlation was found between pre-pregnancy weight and RBWR. The study suggests that factors other than maternal hyperglycaemia stimulate fetal growth and may explain why fetal macrosomia may occur despite of strict blood glucose regulation.

The bone mineral content (BMC) in patients with insulin-dependent diabetes is reduced by 10% early in the disease, but due to a lack of long-term longitudinal studies it is unknown whether this diabetic osteopenia develops further through life. Over a time period of 11 years we examined the BMC in a group of seven adult insulin-dependent diabetics, in whom physiological and pathological factors affecting bone metabolism had been excluded; the patients were well regulated without diabetic complications. The BMC was not significantly decreased at the initial examination. The longitudinal study revealed a small but statistically significant fall in BMC, mainly in trabecular bone. The narrow (95%) confidence interval of median end value (93.3-99.0% of initial BMC) indicates that the annual decrease in BMC in such patients is of the order of 0.5%, a reduction that is probably clinically insignificant.

Insulin-dependent diabetic patients have an approximately 10% decreased bone mineral content (BMC) when they are studied a few years after clinical onset of diabetes. After that time, patients without diabetic microvascular complications have no, or only very little, further bone loss. The aim of the present study was to investigate if any substantial long-term bone loss occurs in diabetic patients with microvascular complications. We studied 19 insulin-dependent diabetic patients with neither physiologic nor pathologic conditions known to interfere with bone metabolism, other than diabetes. BMC was determined twice, with an interval of 11 years. At initial examination, no patient had diabetic microangiopathy, but at final examination 7 patients had developed diabetic microvascular complications while 12 patients had not. As compared with gender- and age-matched controls, both subgroups had significantly decreased BMC at the initial examination. During the study period, the patients with complications showed further bone loss, whereas the subgroup without complications had unchanged decreased BMC. At final examination, BMC was significantly lower in patients with microvascular complications than in patients without them. The biochemistry of bone metabolism showed a significantly increased fasting urinary excretion of calcium and hydroxyproline in patients with complications, but not in the group without complications, and there was a negative correlation between plasma BGP (osteocalcin) and hemoglobin A1C for all patients. These findings indicate that, in addition to a decreased BMC (before or shortly after clinical onset of diabetes), patients who develop microvascular complications also develop ongoing bone loss. This loss may be caused by an increased bone resorption, but decreased bone formation during periods of poor diabetic control may be involved as well.

Insulin-dependent diabetes mellitus (IDDM) is associated with an increased risk of coronary artery disease (CAD). There is some evidence that polyunsaturated fatty acids of the marine n-3 type (n-3 PUFA's) may offer protection against CAD. We have studied the effect of short-term dietary supplementation with n-3 PUFAs on lipids, haemostasis, neutrophil and monocyte chemotaxis in 10 patients with IDDM. The patients were given 4 g daily of n-3 PUFAs (fish oil) for 6 weeks and were investigated before and after the supplement. No significant effects on platelets or haemostasis were observed. High density lipoprotein (HDL)-cholesterol significantly increased, and triglycerides and the ratio of total cholesterol to HDL-cholesterol significantly decreased. Monocyte chemotaxis was unaltered, while neutrophil chemotaxis significantly increased after fish oil. The finding of an improvement in neutrophil chemotaxis after supplementation with n-3 PUFAs to patients with IDDM needs to be confirmed in future studies.

Serum beta 2-microglobulin was measured in 38 patients with thyroid diseases. Serum levels of beta 2-microglobulin were significantly increased in patients with untreated Graves' disease (median: 200 nmol l-1; P less than 0.0002), and in patients with untreated toxic adenomas (222 nmol l-1; P less than 0.0005) compared to 60 healthy control subjects (147 nmol l-1). Following antithyroid treatment of euthyroidism, serum beta 2-microglobulin decreased significantly in both Graves' disease (162 nmol l-1) and toxic adenomas (175 nmol l-1); values which were not significantly different from that of the control group. The level of serum beta 2-microglobulin in 12 patients with hypothyroidism was not different from that of the control group. However, in untreated hypothyroidism serum beta 2-microglobulin was positively correlated with serum thyroxine (T4) (rho = 0.69; P less than 0.05) and free thyroxine index (FT4I) (rho = 0.72; P less than 0.02). It is concluded that elevated levels of serum beta 2-microglobulin may reflect the increased metabolism in patients with thyrotoxicosis. Increased levels in active Graves' disease may also partly be caused by immunological activation.

Hypertension may eventually develop in response to chronic slight retention of sodium and expansion of the extracellular fluid volume, either due to intrinsic pathology or to neurohormonal influences of the kidneys. As almost half of all juvenile diabetic patients sooner or later will develop diabetic nephropathy and hypertension, data are discussed which tend to indicate that renal sodium metabolism is altered already early during the course of diabetes. Compared to healthy subjects the absolute total tubular sodium reabsorption is increased by approximately 30-40 per cent, as is the filtered sodium load. Insulin may stimulate sodium reabsorption in man through an effect on the distal nephron segment. However, by means of combined lithium and 51Cr-labelled EDTA clearances it has been clearly demonstrated that the excess sodium reabsorption in ambulatory insulin-dependent diabetics exclusively takes place in the proximal tubules, while the distal tubular function appears normal. In these studied patients the extracellular fluid volume was also significantly increased. The increased fractional sodium reabsorption of the proximal tubules remains unaffected by increasing duration of diabetes and is also demonstrable in patients with overt diabetic nephropathy. Glucose is reabsorbed in the early portion of the proximal tubules coupled to Na+ transport, utilizing a common carrier protein. An increased load of glucose will therefore be expected to induce an increase in the proximal tubular reabsorption rate of sodium and water, at least as long as the proximal tubular reabsorption capacity for glucose is not exceeded to a degree inducing significant osmotic diuresis. This deviation from normal in proximal renal sodium and fluid handling may be relevant to the development of hypertension in long-term insulin-dependent diabetes.

We performed a follow-up study of the glomerular function in a series of 29 Type 1 (insulin-dependent) diabetic patients who had been studied 18 years previously. Initial median duration of diabetes was 2 years (range 0–9) and at follow-up 21 (17–27) years. At follow-up, 8 diabetic patients exhibited increased urinary albumin excretion rate 515 (32-3234) μg/min with glomerular filtration rates significantly lower than 21 diabetic patients with normal urinary albumin excretion (85 vs 126ml/min/1.73 m2; p<0.01). The patients with increased urinary albumin excretion rate also had higher arterial blood pressure (145/90 vs 120/80) mm Hg; p<0.02) and increased frequency of proliferative retinopathy (7 out of 8 vs 2 out of 21; p = 0.0001) as compared to the group with normal urinary albumin excretion. However, we found no association of increased urinary albumin excretion rate (incipient or overt nephropathy) to early glomerular hyperfiltration as median initial glomerular filtration rate was 142 ml/min/1.73 m2 in the diabetic patients with increased urinary albumin excretion and 147 ml/min/1.73 m2 in the patients with normal excretion rate (p>0.05)

The capacity of prostacyclin production determined as plasma 6-keto-PGF1α was investigated in 12 Type 1 (insulin-dependent) diabetic patients with a median duration of diabetes of 14 years during ordinary metabolic control. Using high pressure liquid chromatography preceding radioimmunoassay, the plasma concentration of 6-keto-PGF1α, the stable metabolite of prostacyclin, was determined at rest and after a standardised bicycle exercise test. The plasma 6-keto-PGF1α in diabetic patients at rest did not differ from that of 25 healthy volunteers; 2.9 pg/ml (range<0.2–15.3) versus 1.7 pg/ml (range<0.2–16.6). During the exercise test plasma 6-keto-PGF1α increased significantly in the diabetic patients as well as in the control group (p< 0.05). The increment of 6-keto-PGF1α in the diabetic patients was neither related to the metabolic regulation, duration of diabetes nor to changes in platelet volume, platelet number or the production of thromboxane B2 and prostaglandin E2. Our results do not support the hypothesis that Type 1 diabetic patients have a decreased capacity of prostanoid production, as suggested from in vitro studies.

Tissue hypoxia is thought to be one of the possible factors involved in the etiology of diabetic retinopathy. Buflomedil has been reported to improve microvascular perfusion with a secondary increase in tissue oxygen pressure and may therefore be of interest in the study of diabetic retinopathy. We investigated 10 males with insulin-dependent diabetes and non-proliferative retinopathy, aged 24-46 with a duration of diabetes of 5-31 years. Buflomedil, 600 mg daily, or placebo was given for 4 weeks in a randomized, double-blind cross-over design, with a one-week washout in between. Patients were studied initially and at the end of each of the three periods. Ocular fluorophotometry was performed at each visit and a penetration index (PI) calculated by dividing the ocular measurements with the preceding average free fluorescein concentration. There was a slight, but significant decrease in the PI of the posterior vitreous while on buflomedil, from 10.6 +/- 13.4 (mean +/- SD) to 8.8 +/- 9.6 10(-4), p less than 0.05. No measurable changes were found in metabolic control as estimated by HbA1, and no side effects were observed. That the drug may act by increasing blood flow, was illustrated by measurements on capillary blood, where pH increased (7.43 +/- 0.01 to 7.45 +/- 0.01, p less than 0.05) and pCO2 decreased (5.48 +/- 0.4 to 5.15 +/- 0.24 kPa, p less than 0.05). Buflomedil may reduce the permeability of the posterior ocular barriers in diabetic retinopathy.

The contribution of the exocrine pancreas to hyperamylasemia in diabetic ketoacidosis was investigated by measuring total amylase, salivary and pancreatic isoamylases, cathodic trypsin-like immunoreactivity, and pancreatic lipase in 12 consecutive patients recovering from diabetic ketoacidosis. Hyperamylasemia was present in six of the patients [50%; expected incidence: 21.1-78.9% (95% confidence limits)]--in five with simultaneously increased activities of all three specific pancreatic enzymes, and in one with only increased salivary isoamylase. The serum concentration of hypoxanthine--an indicator of the cellular energy state--was above normal in all patients at admission. We found no differences in concentrations of hypoxanthine in serum of patients with or without hyperamylasemia or in patients with or without increases in the specific pancreatic enzymes. In none of the patients was the clinical course or the time--concentration curves of the pancreatic enzymes consistent with acute pancreatitis. The pathogenic mechanism leading to hyperamylasemia in diabetic ketoacidosis remains uncertain.

To evaluate the glomerulo-tubular balance of sodium and water in the proximal tubules of diabetic patients with elevated glomerular filtration rate, the renal plasma clearance of lithium and the glomerular filtration rate (51Cr-EDTA plasma clearance) were determined simultaneously in 11 ambulatory Type 1 (insulin-dependent) diabetic patients (aged 25–35 years) with no evidence of diabetic nephropathy and in 10 age-matched healthy subjects. The renal plasma clearance of lithium, which is a measure of flow from the proximal tubule into the thin descending limb of the loop of Henle, did not differ between diabetic and control subjects (28.9±4.0 versus 28.3±5.1 ml/min per 1.73m2 surface area, mean±SD), whereas the glomerular filtration rate in the diabetic patients was significantly higher than in the control sub jects (136±10.2 versus 108±13.6 ml/min per 1.73m2, p< 0.001). The same held true for the fractional reabsorption rate in the proximal tubules (78.7±3.2 versus 73.6±4.9%, p< 0.02). The results indicate that the elevation of the glomerular filtration rate in diabetic patients is associated with a parallel increase in the proximal reabsorption rate. This type of glomeralo-tubular balance implies that the flow of water and flux of sodium to the segments distal to the proximal tubule are kept constant during variations in the glomerular filtration rate.