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The effects of human proinsulin and insulin on lipid metabolism in Type 2 diabetes were examined in a randomized cross-over study in 15 patients. Blood glucose control was indistinguishable at the end of the two treatment periods, but fasting levels of triglycerides appeared somewhat lower after proinsulin (1.17(SE 0.16) vs 1.39(0.21) mmol I-1; p less than 0.07), and the maximal postprandial triglyceride response (2.19 (0.25) vs 2.87(0.28) mmol I-1, p less than 0.001) and triglyceride area under the curve (p less than 0.01) were significantly reduced. In five hyperlipidaemic patients postprandial triglyceridaemia was reduced with proinsulin (2.89(0.60) vs 3.68(0.56); p less than 0.001), but in addition fasting serum triglycerides (1.20(0.30) vs 1.96(0.30) mmol I-1, p less than 0.04) and possibly VLDL-cholesterol (0.49(0.15) vs 0.60(0.20) mmol I-1; p less than 0.10) were lower and fasting LDL-cholesterol levels higher (4.82(0.42) vs 3.92(0.57) mmol I-1, p less than 0.03) after proinsulin therapy. Proinsulin appears to preferentially suppress the production of triglyceride-rich lipoproteins in Type 2 diabetes, particularly postprandially, and may enhance their clearance and conversion to LDL, especially in hyperlipidaemic Type 2 diabetes.

The effects of bezafibrate 400 mg day-1 or placebo administered for 3 months, were compared in 36 patients with stable Type 1 diabetes and hypercholesterolaemia and/or hypertriglyceridaemia. Baseline characteristics of the 17 bezafibrate- and 19 placebo-treated patients were comparable in most respects with the exception of concentrations of fasting serum triglycerides and blood glucose which were lower (NS) and plasma fibrinogen which were higher (p less than 0.05), in those later treated with bezafibrate. Serum cholesterol concentrations decreased after 3 months bezafibrate treatment (from 7.1(0.2) (SE) to 6.3 (0.3) mmol l-1, p less than 0.05), predominantly due to a reduction in low density lipoprotein (LDL) cholesterol (from 4.8(0.3) to 4.2(0.3) mmol l-1, p less than 0.05). Over the same period bezafibrate reduced serum triglycerides from 1.78 (95% Cl 1.23-2.57) to 1.26(1.02-2.09) mmol l-1 (p less than 0.05), and plasma fibrinogen from 4.1(0.2) to 2.9(0.2) g l-1, p less than 0.001. Serum apolipoprotein B and apolipoprotein (a) showed no statistically significant changes. Overall there was no change in high density lipoprotein (HDL) cholesterol. However, in patients who were initially hypertriglyceridaemic there was significant increase in the cholesterol content of HDL and the HDL2-cholesterol subfraction (both p less than 0.05). After 3 months treatment with bezafibrate, fasting blood glucose levels were reduced from 8.5(1.1) to 6.4(0.7) mmol l-1, p less than 0.05, without any change in glycosylated haemoglobin (9.2(0.4) to 9.1(0.5)%).(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between psychosocial traits and glycaemic control and complications was examined in 130 adults (83 men, 47 women) with insulin-dependent diabetes mellitus. Abnormal depression ratings were observed in more women (19.1%) than men (12.0%), p less than 0.01, whilst obsessive symptoms were recorded more frequently in men (41.0 v 21.3%, p less than 0.01). Abnormal anxiety ratings were present in roughly 8-13% of men and women, although a notably low feeling of insecurity rating was observed more frequently in men (56.5%) than in women (38.3% of cases), p less than 0.05. Psychological scores were related to age, employment status and social class, but not to duration of diabetes or glycaemic control. The anxiety, depression and obsessive ratings correlated with one another (rs range 0.24-0.62, all p less than 0.001). Higher anxiety and depression ratings or overt psychological dysfunction was recorded in patients with neuropathic symptoms and signs, impotence, macrovascular disease or proliferative retinopathy. It is concluded that the presence of diabetic complications and adverse social circumstances are more relevant to psychological status than glycaemic control.

Mitogen-induced lymphocyte transformation was examined in 23 elderly patients with poorly controlled Type II diabetes before and after achieving improved glycaemic control with sulphonylureas and compared with 11 healthy controls of similar age. No difference between groups was seen after incubation of lymphocytes with phytohaemagglutinin (PHA). Lymphocyte transformation after 10 micrograms/ml concanavalin A (con A) was significantly greater in diabetic patients after improved control and when compared to healthy controls (p less than 0.025). The response to 5 micrograms/ml and 10 micrograms/ml pokeweed mitogen (PWM) was greatest in diabetic patients after effective metabolic control.

The effect of residual C-peptide secretion in longer standing IDDM on glycaemic control and the prevalence and evolution of complications over 2 years was evaluated. Thirty-one subjects with IDDM of 15.4 (1.5) years duration (mean SEM)) and residual C-peptide secretion, were matched for age, duration of diabetes and body mass index with 31 subjects without detectable C-peptide secretion. At trial entry and over 2 years, levels of HbA1, fructosamine and mean blood glucose were essentially similar in both groups. Levels of glycated albumin (GSA) were significantly higher in the C-peptide negative group after 3 and 9 months (P less than 0.05). An increased prevalence of proliferative retinopathy in the C-peptide negative group and of peripheral vascular disease in the C-peptide secretor group was apparent at entry to the study (both P less than 0.05), although no significant differences were observed after 1 or 2 years. There was no difference in the prevalence of peripheral or autonomic neuropathy, hypertension, nephropathy or ischaemic heart disease. Subjects with C-peptide concentrations greater than 0.100 pmol/ml at entry to this study had lower daily insulin requirements after 1 and 2 years, but behaved like the larger group with any detectable C-peptide secretion in all other respects. Residual C-peptide secretion was lost after 1 year in 7 patients, in whom glycaemic control during the year had been particularly poor. Insulin antibody titres were no different in the 2 groups at any time point. This study suggests that residual C-peptide secretion in longer standing IDDM confers the potential for limited improvements in glycaemic control. This effect appears to be insufficient to prevent the evolution of microvascular complications over a 2-year period. Residual C-peptide secretion and relative hyperinsulinaemia may be associated with an excess of peripheral vascular disease.

Nineteen obese patients with Type 2 diabetes mellitus were treated for periods of 3 months with placebo, guar gum (5 g three times daily) and metformin (500 mg three times daily) in a randomized double-blind, double-placebo, cross-over study. Both active agents decreased fasting blood glucose from 11.4 +/- 3.7 mmol l-1 (mean +/- SD) to 8.6 +/- 2.8 mmol l-1 on metformin (p less than 0.001) and to 9.5 +/- 3.9 mmol l-1 on guar gum (p less than 0.01). Metformin significantly reduced the very low density lipoprotein (VLDL) cholesterol concentration from 0.62 (+0.73, -0.34) mmol l-1 (geometric mean (+SD, -SD)) to 0.43 (+0.58, -0.25) mmol l-1, (p less than 0.02), but unless hyperlipidaemia was present there were no changes in other serum lipid or lipoprotein levels. In patients with serum cholesterol greater than 6.5 mmol l-1 decreases in serum triglycerides from 3.29 (+3.27, -1.64) to 2.46 (+2.55, -1.25) mmol l-1 (p less than 0.02) occurred with metformin. In these patients guar gum produced a reduction in serum cholesterol (from 7.70 +/- 0.90 to 6.41 +/- 1.11 mmol l-1, p less than 0.01) due to an effect on low density lipoproteins. These differential effects may be important in planning therapy when hyperlipidaemia accompanies Type 2 diabetes.

Leukocyte dysfunction may contribute to infection in the elderly diabetic. Leukocyte oxidative metabolism assessed by chemiluminescence, correlates with microbicidal activity, and may be impaired with hyperglycaemia and ageing. The leukocyte chemiluminescence response to zymosan +/- luminol was assessed in 12 healthy controls (3M, 9F), aged 69 +/- 5 (mean +/- SD) years and in 23 non-insulin dependent diabetics, aged 68 +/- 5 years, before and after improving glycaemic control with sulphonylureas, when the glycosylated haemoglobin fell from 11.2 +/- 2.3 to 7.9 +/- 1.4% (p less than 0.001). The onset of maximal chemiluminescence with zymosan was similar in controls and diabetics, although the actual counts after improved glycaemic control were less in diabetic patients at all time points than initially (p range less than 0.025-less than 0.001) or when compared to the controls (p range less than 0.05-less than 0.005). Following luminal enhancement the onset and magnitude of maximum chemiluminescence was similar in all groups although an increase early response was observed in diabetics initially. We suggest that sulphonylureas may modify chemiluminescence by suppressing superoxide radical generation. Hyperglycaemic elderly non-insulin dependent diabetics may have subtle disturbances of the leukocyte oxidative burst but in general behave in a similar fashion to healthy elderly controls.

The measurement of blood glucose using discs punched from dried spots on filter paper has been examined as a method to monitor patients' home blood glucose results. We confirm that the method is precise, reproducible, and accurate, but show that impregnation of the filter paper with boric acid leads to an initial false elevation in measured glucose levels and does not improve stability of the sample more than does refrigeration. Degradation of blood glucose is insignificant over 28 days if samples are stored at -20 degrees C, and samples kept at 4 degrees C show minimal falls provided they are analysed within 7 days. The greatest breakdown of glucose was shown to occur during the first 48 hours after application. The filter paper glucose measurements correlated closely with parallel measurements using a Yellow Springs Glucose Analyser.

We have studied associations between various direct measures of glycaemia and glycated blood proteins in 113 subjects with insulin-dependent diabetes mellitus (IDDM), and examined whether or not the 'fructosamine' assay results were affected by differing patient serum concentrations of lipids, albumin or C peptide. Serum fructosamine correlated less closely with HbA1 (r = 0.44) than did HbA1 with glycated serum albumin (GSA) (r = 0.68). Serum fructosamine and GSA also were poorly correlated (r = 0.48). Although fructosamine, HbA1 and GSA correlated to a similar degree with fasting blood glucose (r range 0.34 to 0.37), GSA was most closely related to mean blood glucose (r = 0.39 vs. 0.30-0.35) and the M value (a marker of diurnal glycaemic instability) (r = 0.42 vs. 0.33-0.35). The serum concentration of fructosamine was not significantly affected by a variation in serum cholesterol, but tended to be lower in subjects with moderate hypertriglyceridaemia (p = 0.05). The fructosamine assay may be altered by moderately lipaemic serum but is not affected by serum albumin concentration in normoalbuminaemic patients with IDDM. Our study indicates, however, that GSA is a more reliable marker of short-term glycaemic control in IDDM than fructosamine.

There is evidence to suggest that renal function may alter in the presence of autonomic neuropathy. Albumin excretion rate (AER) and sodium excretion rate (NaER) in timed daytime (erect) and night-time (supine) urine collections were assessed in 20 insulin-treated diabetics with and in 20 without established autonomic neuropathy, matched for age, sex, duration of diabetes, diabetic control, and systolic blood pressure. All patients were free of proteinuria on albustix testing and had normal serum levels of urea and creatinine. AER based on daytime and pooled 24-hour collections was higher, but not significantly so, in the group with autonomic neuropathy. The nocturnal AER on the other hand was significantly elevated in the group with autonomic neuropathy (p less than 0.02) as was the nocturnal urine volume (p less than 0.01) and sodium excretion rate (p less than 0.05). The corrected nocturnal albumin/creatinine ratio was likewise greater in this group (p less than 0.02). These findings suggest that autonomic neuropathy can independently affect renal function and that nocturnal renal haemodynamics and glomerulotubular balance may be deranged in insulin-treated diabetics with autonomic neuropathy.

Renal function, blood pressure and glycaemic control were assessed during gestation in 23 non-azotaemic insulin-dependent diabetic women. Pre-eclamptic toxaemia (PET) developed in nine cases, and was predicted by higher levels of albuminuria excretion, mean blood pressure and serum urate early in pregnancy, as well as by the primigravid state. Mean blood pressure, serum creatinine and urate remained stable in the first trimester and rose thereafter in women who developed PET. Levels of mean blood pressure were significantly higher in the second (p less than 0.005) and third (p less than 0.0001) trimesters, serum urate was higher in the first, second (p less than 0.04) and third (p less than 0.0001) trimesters, as was AER (p range less than 0.02-0.0001), and serum creatinine levels were higher in the third trimester (p less than 0.02) in comparison to those women who did not develop PET. Glycaemic control was similar in both groups. In addition, physiological alterations in creatinine clearance, and in serum levels of creatinine and urate were attenuated in cases uncomplicated by PET. Insulin-dependent diabetic pregnancies are characterized by disturbances of renal function early in pregnancy which may be predictive of PET, particularly in primigravidae and/or when accompanied by increases in mean blood pressure.

A precise and easy method for measuring glycated serum albumin using affinity chromatography and immunoturbidimetry on a centrifugal analyser, ensuring complete recovery of serum albumin is described.

Despite the increased risk of atherosclerosis in diabetes mellitus, levels of serum cholesterol, triglycerides, low-density-lipoprotein (LDL) cholesterol, and high-density-lipoprotein (HDL) cholesterol were similar in 57 men with insulin-dependent diabetes mellitus (IDDM) and 81 non-diabetic controls. However, substantially lower serum levels of apolipoprotein B, the principal apolipoprotein of LDL, and a concomitant increase in the cholesterol-loading of apolipoprotein B were found in IDDM. The likely changes in LDL density and particle size resulting from this compositional abnormality might lead to accelerated atherogenesis analogous to that seen in type III hyperlipoproteinaemia. In addition, there was an increase in the concentration of cholesterol in the smaller, denser, HDL3 subfraction of serum HDL in IDDM.

The prevalence of hyperlipidaemia and related clinical features was examined in 205 individuals with insulin-dependent diabetes mellitus. Overall, 40 per cent (82) of the individuals had hyperlipidaemia. Whilst the prevalence of hypertriglyceridaemia and combined hyperlipidaemia was greater in patients with insulin-dependent diabetes mellitus than non-diabetics, this was not the case for hypercholesterolaemia. Hyperlipidaemia was present in older patients, and the daily insulin dose and levels of HbA1 were highest in those with combined hyperlipidaemia. In addition normolipidaemic subjects had the lowest levels of serum creatinine. Triglyceride levels were predicted (in order of importance) by insulin dose, age at diagnosis, HbA1 and body mass index, whilst cholesterol levels were predicted by the age at the time of study, body mass index, urinary protein excretion, and levels of fasting blood glucose and HbA1. Hyperlipidaemia is common in insulin-dependent diabetes mellitus, and may be particularly apparent in older patients and/or those with early renal dysfunction or poor glycaemic control.

The clinical value of prospective measurement of several direct and indirect measures of blood glucose control in the management of Type 1 diabetes has been investigated. Ninety-eight Type 1 diabetic patients were followed over a period of 1 year after a 6-week period of intensification of management, with monthly measurements of blood glucose profiles and 3-monthly HbA1, glycosylated serum albumin, and fructosamine measurements. All measures improved markedly after the initial 6-week period (p less than 0.001), and all except glycosylated serum albumin and fructosamine then remained relatively stable. Of fourteen serial comparisons, glycosylated blood proteins were significantly correlated more often with levels of mean blood glucose and M value (on 4-7 occasions, rs 0.30-0.58) than with fasting blood glucose levels (on only 2-3 occasions, rs 0.34-0.44). Serum fructosamine levels correlated significantly with mean blood glucose on four occasion (rs 0.30-0.50), whilst glycosylated serum albumin and HbA1 correlated with mean blood glucose on six occasions (rs 0.36-0.54). Glycosylated serum albumin correlated with HbA1 and fructosamine levels throughout the year (rs 0.47-0.68 and 0.48-0.76, respectively), but HbA1 and fructosamine were less clearly correlated with each other (rs 0.38-0.44), with no significant association immediately after the period of intensive management or 3 months later.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein E (apo E), a component of VLDL, HDL and chylomicron remnants, is inherited at a single genetic locus with 3 common alleles (epsilon 2, epsilon 3 and epsilon 4). epsilon 2 homozygosity is found in 0-2% of healthy populations, but in 75-100% of subjects with type III hyperlipoproteinaemia, in whom an increased prevalence of glucose intolerance has previously been reported. The lipoprotein abnormality associated with diabetes mellitus has features in common with type III hyperlipoproteinaemia and both conditions lead to accelerated atherogenesis with a similar anatomical distribution. We have therefore examined the frequency of apo E genotypes in 120 subjects with insulin-treated diabetes mellitus (ITDM) and 107 healthy controls, and examined the effect of apo E polymorphism on lipoproteins in the diabetic group. As in the general population, the apo E phenotype in ITDM was a significant determinant of the total serum and LDL cholesterol concentrations which were lowest in patients possessing the epsilon 2 allele, intermediate in those homozygous for epsilon 3 and highest in those with an epsilon 4 allele. The observed gene frequencies of epsilon 2 (0.091), epsilon 3 (0.780) and epsilon 4 (0.130) were similar to those of the healthy control group and those in the general population. However, there was an unexpected increase (P less than 0.0002) in epsilon 2 homozygosity of 6.7% compared to a prevalence of 0.8% predicted both from the Hardy-Weinberg equilibrium and the 0.9% prevalence observed in the healthy control group. This suggests either that epsilon 2 homozygosity increases susceptibility to the development of ITDM or that the two conditions are genetically linked.(ABSTRACT TRUNCATED AT 250 WORDS)

Hand skin blood flow in 32 insulin-dependent (IDDM) diabetics was compared with 13 healthy controls at room temperature and after immersion of the hands in warm and cold water. Subjects were examined for limited joint mobility (LJM) to analyse the association between this and blood flow. Digital arteries remained patent in IDDM compared to controls after cold challenge (p = 0.0001), and the difference persisted to a lesser degree 15 min (p = 0.009) and 30 min (p = 0.03) after recovery. Capillary blood flow was reduced in IDDM at room temperature at the finger nailbeds (p less than 0.02) and the palms (p = 0.004) and remained so after warm water immersion in the palms (p = 0.002), where further vasoconstriction was observed immediately after cold water immersion (p less than 0.001) and 15 and 30 min into recovery (p = 0.07 and p = 0.009 respectively). Thermographic analysis confirmed a pattern of predominantly distal rewarming after cold challenge in IDDM with a greater mean index finger temperature than the controls. Together, these features suggested enhanced arteriovenous anastomotic blood flow. All IDDM and IDDM males with LJM had reduced palm capillary flow immediately after cold challenge (p less than 0.05). After warm water (p less than 0.03) and 30 min after cold challenge (p less than 0.05) IDDM males with LJM had reduced palm capillary flow compared to those IDDM without. A microvascular aetiology for LJM is proposed by virtue of reduced nutritional blood flow and evidence of enhanced arteriovenous shunting in the hands of insulin-dependent diabetics.

The Friedewald formula has been widely used in the estimation of the serum LDL cholesterol concentration in diabetic patients. In patients with insulin-dependent diabetes we have compared the serum LDL cholesterol concentrations obtained when VLDL was isolated in the preparative ultracentrifuge and its cholesterol content directly determined with those when the 'Friedewald Formula' assumption that there is a fixed ratio between total serum triglycerides and VLDL cholesterol was used in the calculation of the LDL cholesterol value. Both methods gave similar results which were closely correlated (r = 0.98) with a slope of 0.98 on linear regression analysis for patients with serum triglycerides of less than 2.5 mmol/l. The inclusion of a small number of hypertriglyceridaemic patients (14%) had virtually no impact on these findings.