The care of students with insulin-treated diabetes mellitus living in university accommodation: scope for improvement?

Concern has been expressed about the welfare of young adults with Type 1 diabetes mellitus who leave home to attend university or college for tertiary education. This has been highlighted by the local experience in Edinburgh of two male students with Type 1 diabetes, both of whom died from metabolic complications of diabetes during their first term at universities distant from their homes. One student died following the development of cerebral oedema secondary to diabetic ketoacidosis, which was probably precipitated by prolonged coma after an episode of severe hypoglycaemia. Another student, who was found 'dead in bed', had a history of previous severe hypoglycaemia. At a Fatal Accident Inquiry in Edinburgh, held following the death of the first student, recommendations were made to improve the care and personal safety of students with diabetes living in university accommodation. Despite the report being circulated to all Scottish universities, the second student died within three years of the inquiry. Further efforts to protect the welfare of students with Type 1 diabetes who are attending centres for tertiary education away from their home environment may require the more active participation by diabetes healthcare professionals.

Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Mendenhall's syndrome.

Rabson-Mendenhall's syndrome is one of the most severe forms of insulin resistance syndrome. We analyzed an English patient described elsewhere and found novel mutations in both alleles of the insulin receptor gene. One is a substitution of G for A at the 3' splice acceptor site of intron 4, and the other is an eight-base pair deletion in exon 12. Both decrease mRNA expression in a cis-dominant manner, and are predicted to produce severely truncated proteins. Surprisingly, nearly normal insulin receptor levels were expressed in the patient's lymphocytes, although the level of expression assessed by immunoblot was approximately 10% of the control cells. Insulin binding affinity was markedly reduced, but insulin-dependent tyrosine kinase activity was present. Analyzing the insulin receptor mRNA of the patient's lymphocytes by reverse transcription PCR, we discovered aberrant splicing caused by activation of a cryptic splice site in exon 5, resulting in a four-amino acid deletion and one amino acid substitution, but restoring an open reading frame. Skipped exon 5, another aberrant splicing, was found in both the patient and the mother who had the heterozygotic mutation, whereas activation of the cryptic splice site occurred almost exclusively in the patient. Transfectional analysis in COS cells revealed that the mutant receptor produced by cryptic site activation has the same characteristics as those expressed in patient's lymphocytes. We speculate that this mutant receptor may be involved in the relatively long survival of the patient by rescuing otherwise more severe phenotypes resulting from the complete lack of functional insulin receptors.

Circulating cell adhesion molecule concentrations in diabetic women during pregnancy.

OBJECTIVE: To determine whether circulating concentrations of defined cell adhesion molecules, which are thought to reflect endothelial expression, are increased in insulin-dependent diabetic women during pregnancy. METHODS: Pregnant diabetic women demonstrating good glycemic control and without major complications before pregnancy were studied at 8-12 (n = 15), 18 (n = 15), 28 (n = 16), 32 (n = 16), and 36 (n = 16) weeks' gestation. A subgroup of ten diabetic women was sampled longitudinally through all five gestational ages. The diabetic women were compared with healthy nondiabetic women sampled cross sectionally at 12 (n = 20), 28 (n = 19), and 36 (n = 19) weeks' gestation. Nonpregnant diabetic (n = 22) and nonpregnant nondiabetic women (n = 28) also were studied. Plasma concentrations of the cell adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular endothelial cell adhesion molecule-1 (VCAM-1) were measured by enzyme-linked immunosorbent assay. RESULTS: Significantly higher median (range) concentrations of E-selectin (63.0 [20.2-107.0] ng/mL) and ICAM-1 (281.5 [171.6-778.4] ng/mL) but not VCAM-1 (459.7 [301.0-909.7] ng/mL) were found in nonpregnant diabetic women compared with nonpregnant nondiabetic women (43.5 [18.1-93.2], 243.6 [174.4-329.2], and 476.0 [253.8-929.4] ng/mL, respectively). During pregnancy these significant differences between diabetic and control groups were lost. The median (range) concentration of E-selectin (50.0 [21.2-96.3] ng/mL) was significantly lower in pregnant compared with nonpregnant diabetic women. The plasma concentrations of E-selectin and ICAM-1 did not change significantly with gestation in either diabetic or nondiabetic pregnant groups. Vascular endothelial cell adhesion molecule-1 concentration changed significantly with gestation in the diabetic pregnant group only. CONCLUSION: Circulating concentrations of defined vascular cell adhesion molecules are not increased abnormally in diabetic women with good glycemic control during otherwise uncomplicated pregnancy.

Four mutant alleles of the insulin receptor gene associated with genetic syndromes of extreme insulin resistance.

We identified four novel mutant alleles of the insulin receptor gene in three patients with genetic syndromes associated with insulin resistance. Two mutant alleles of the insulin receptor gene were identified in a patient with the Rabson-Mendenhall syndrome who was a compound heterozygote for a mutation at the 3'-splice acceptor site of intron 4 (AG-->GG), the first mutation causing an aberrant splicing at this locus, and a deletion of eight base pairs in exon 12. The second patient with leprechaunism was also a compound heterozygote for a deletion of one base pair in exon 19 and a mutation, Thr910-->Met, which causes impaired receptor processing. Interestingly, the third patient with type A syndrome was a simple heterozygote for the identical one base pair deletion. The fact that the same one base pair deletion links to type A in a simple heterozygote and to leprechaunism in a compound heterozygote appears consistent with the hypothesis that the severity of mutations will determine the phenotype.

Attenuated neutrophil respiratory burst following acute hypoglycaemia in diabetic patients and normal subjects.

The effects of insulin-induced hypoglycaemia on the neutrophil respiratory burst were investigated in six patients with type 1 diabetes and six non-diabetic control subjects. Plasma glucose reached similar nadirs in control subjects (0.9 +/- 0.1 mmol 1(-1); mean +/- SEM) and diabetic patients (1.2 +/- 0.2 mmol 1(-1)) (NS). The resting neutrophil respiratory burst was similar in control subjects (1.26 +/- 0.15 mV) and diabetic patients (1.03 +/- 0.18 mV) (NS). The neutrophil respiratory burst fell following hypoglycaemia in control subjects and diabetic patients to 0.38 +/- 0.05 mV (P < 0.001) and 0.54 +/- 0.09 mV (P < 0.05), respectively. This fall was significantly greater in control subjects (ANOVA; P < 0.001). Resting neutrophil counts were not significantly different in control subjects (3.2 +/- 0.3 x 10(9) 1(-1)) and diabetic patients (6.1 +/- 1.5 x 10(9) 1(-1)). Following hypoglycaemia, neutrophil numbers increased in control subjects and diabetic patients to 11.5 +/- 1.4 x 10(9) 1(-1) (P < 0.01) and 9.7 +/- 1.7 x 10(9) 1(-1) (P < 0.05), respectively. This increase was significantly greater in control subjects (ANOVA; P < 0.001). These results suggest that the neutrophil respiratory burst is suppressed in response to hypoglycaemia and that this phenomenon is more pronounced in non-diabetic subjects.

Hormone replacement therapy and cardiovascular risk in post-menopausal women with NIDDM.

Female patients with NIDDM have a high prevalence of, and mortality from, coronary heart disease (CHD). Hormone replacement therapy (HRT) may favourably influence several CHD risk factors in post-menopausal NIDDM patients, including dyslipidaemia, hypertension, prothrombotic changes, and endothelial dysfunction. Insulin resistance appears to have a central role in the pathogenesis of these abnormalities and can also be modified by HRT. However, the potentially beneficial effects of HRT in women with NIDDM have been extrapolated from the results of studies in non-diabetic females, as to date there have been few studies in NIDDM patients. In view of their excessive CHD mortality, further research is needed to investigate the effects of different HRT preparations on lipid and non-lipid risk factors in this high-risk population.

Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control.

Neutrophil bactericidal activity was assessed in patients with type 1 (n = 45) and Type 2 diabetes mellitus (n = 68) and non-diabetic control subjects (n = 40) by measurement of whole blood chemiluminescence. Though chemiluminescence values tended to be highest in the non-diabetic subjects these differences were not statistically significant (mean +/- SD) (2.73 +/- 1.65 mV (controls), 2.33 +/- 1.41 mV (Type 1 diabetes) and 2.38 +/- 1.12 mv (Type 2 diabetes), F = 1.12, p = 0.33). Significant negative correlations were evident, however, in patients with both Type 1 and Type 2 diabetes between chemiluminescence and glycated haemoglobin (rs = -0.35, p = 0.005 (Type 1), rs = -0.45, p = 0.002 (Type 2), fructosamine (rs = -0.36, p = 0.003 (Type 1), r = -0.42, p = 0.004 (Type 2)), and random blood glucose (rs 0 -0.25, p = 0.04 (Type 1), rs = -0.48, p = 0.001 (Type 2)). Changes in whole blood chemiluminescence in a further group of 10 patients with Type 2 diabetes mellitus commenced on insulin therapy were followed for 21 days. Serum fructosamine concentrations fell significantly over this time (524 +/- 58 mumol l-1 to 405 +/- 47 mumol l-1, p < 0.001), however, although chemiluminescence values tended to rise these changes were not statistically significant (1.01 +/- 0.38 mV to 1.60 +/- 0.91 mV, S = 4.24, df = 5, p = 0.52). These results suggested that impaired neutrophil bactericidal function is associated with poor blood glucose control. While it is likely that neutrophil bactericidal function will improve as blood glucose control improves, further studies are required both to confirm this and to demonstrate a reduction in the incidence of clinical bacterial infection.

Quantitative determination of functional thiol groups on intact cell surfaces by resonance Raman spectroscopy.

The sensitivity and selectivity of resonance Raman spectroscopy, combined with electronic spectroscopy, has been used to develop a method to quantify the membrane thiol population in situ in viable erythrocytes. This technique is based on the thiol-disulfide reaction of Ellman's reagent (5,5'-dithio-bis-2-nitrobenzoic acid). It has the advantage that continuous monitoring of lysis is simple and a correction can be made for any interference resulting from lysis. In addition, the extent of reaction can be expressed as a ratio of the reagent signal, providing an internal calibrant.

Screening and treatment for hyperlipidaemia in non-insulin-dependent diabetes: a prospective assessment of 350 patients.

This report presents experiences in screening 350 non-insulin-dependent diabetics for hypercholesterolaemia and results of 1 year's treatment. Mean serum total cholesterol was 6.4 mmol/l at screening; 46 patients whose initial total serum cholesterol was above 7.0 mmol/l attended for detailed assessment and treatment. Mean total cholesterol concentrations fell between screening and review (7.8 vs 7.1 mmol/l, P < 0.01). Levels fell below 7.0 mmol/l in 13 patients with diet alone. After excluding patients with secondary dyslipidaemia (including poor diabetic control), 10 patients received lipid-lowering drug treatment. Total cholesterol and triglyceride concentrations fell significantly and the HDL/non- HDL cholesterol ratio improved on treatment. Screening diabetic patients identifies a small group of hyperlipidaemic patients, whose lipoprotein profiles improve with drug treatment. Many of those screened, however, do not ultimately require drug treatment using a cut-off of 7.0 mmol/l.

Blood rheology and albumin excretion in diabetic pregnancy.

Blood rheology is altered in diabetes and also in non-diabetic pregnant women. The cumulative effect of hyperfiltration, abnormal rheology of pregnancy, and diabetes could be one mechanism contributing to increased intraglomerular pressure and albuminuria in diabetic pregnancy. We conducted a prospective study of 22 Type 1 (insulin-dependent) diabetic patients and 22 non-diabetic women to determine if there was an association of altered blood rheology on glomerular function in diabetic pregnancy. Albumin excretion showed no increment with increasing gestation and was similar in diabetic and non-diabetic women throughout pregnancy (first trimester: 5.0 (3.0-14.0) vs 5.8 (3.7-10.7) mg l-1, p = 0.89; second trimester: 6.0 (5.0-12.0) vs 5.1 (3.6-10.4) mg l-1, p = 0.25; third trimester: 7.5 (3.5-16.0) vs 4.9 (2.9-7.3) mg l-1, p = 0.18). Red cell aggregation index increased in both groups between the first and third trimesters (diabetic patients: mean difference 2.0; Cl: 1.0-2.9, p = 0.003, and control patients: mean difference 2.3, Cl: 1.0-3.5, p = 0.002). Fibrinogen levels were significantly higher between the third and first trimesters in diabetic patients (mean difference 0.7, Cl: 0.2-1.3 g l-1, p = 0.006). Pregnancy, therefore, was associated with increased red cell aggregation, related in part to increased fibrinogen levels but the extent of change was similar in diabetic and nondiabetic women and appeared to have no adverse effect on glomerular function in pregnant insulin-dependent diabetic women.

Insulin-like growth factor binding protein 1 response to acute insulin induced hypoglycaemia in type 1 diabetes.

OBJECTIVES: Insulin is believed to be the prime regulator of insulin-like growth factor binding protein 1 (IGFBP-1) secretion, and in normal subjects acute insulin induced hypoglycaemia exerts a rapid effect on concentrations of IGFBP-1, and may also influence insulin-like growth factor I (IGF-I) concentrations. The rise in IGFBP-1 concentrations in normal subjects following hypoglycaemia has been suggested to be due to suppression of endogenous insulin secretion. We have examined this further by studying diabetics with no endogenous insulin secretion. DESIGN: We have compared the IGFBP-1 response to acute insulin induced hypoglycaemia in normal subjects and patients with Type 1 (insulin dependent) diabetes mellitus. METHODS: Insulin tolerance tests were performed using a bolus of insulin (0.15 U/kg), in six control subjects and six patients with Type 1 diabetes. MEASUREMENTS: Serum levels of IGFBP-1, insulin, glucose, and IGF-I were measured at regular intervals during the insulin tolerance test. RESULTS: Blood glucose fell to a nadir which coincided with the onset of the acute autonomic reaction 'R' in both groups. The basal concentration of IGF-I was significantly lower in the diabetic group at 0.4 +/- 0.1 kU/l, compared to 0.9 +/- 0.1 kU/l in the control group, but there was no significant change in IGF-I concentrations in response to hypoglycaemia in either group. Hypoglycaemia provoked a fall in IGFBP-1 in patients with Type 1 diabetes, from 38 +/- 9 micrograms/l basally to 17 +/- 3 micrograms/l at R + 120 minutes, with a return to basal values of 45 +/- 11 micrograms/l at R + 180 minutes. In the control subjects there was no fall in IGFBP-1, but a significant increase to 71 +/- 14 micrograms/l at R + 180 minutes. CONCLUSION: This difference in the IGFBP-1 response in the presence of a similar glucose response suggests that in Type 1 diabetes there may be different sensitivities to the actions of exogenous insulin on IGFBP-1 regulation.

The role of general practitioners in diabetic eye care in Lanarkshire.

This study reports data from 50 practices (3550 patients) in Lanarkshire taking part in an audit of diabetes care. Data were obtained by review of general practitioner records and the correspondence from consultants and opticians contained in them. The principal study measures examine the process of care. Overall levels of performance were low: only 35.5% of patients had visual acuity and 54.5% fundoscopy recorded in the previous year. Significantly better results were observed for both examinations in those few practices which performed these examinations in more than 10% of their patients (51.4% vs 32.0% (mean difference 19.4, 95% CI 16.1-23.7) for visual acuity and 65.7% vs 53.3% (mean difference 12.4, 95% CI 3.0-21.8) for fundoscopy. Less than half of diabetic patients in Lanarkshire currently receive adequate screening for the ocular complications of diabetes. Most practices rely on hospital diabetic and ophthalmology services. Where practices undertake ocular examination of patients, this is currently in addition to those services provided elsewhere.

The effect of recombinant insulin-like growth factor I on ketone body, lipid and apolipoprotein concentrations and its use to treat ketoacidosis in severe insulin resistance.

The effect of recombinant insulin-like growth factor I (rhIGF-I) on ketone body concentrations was studied in a patient with the Mendenhall syndrome, a rare insulin-resistant state. Treatment with intravenous rhlGF-I for an episode of ketoacidosis led to a clinical and biochemical improvement. One month later, the effect of 20 mg rhlGF-I infused daily for 4 days on ketone body concentrations was studied. From peak concentrations 24 h prior to the study to a nadir 72 h after the infusion commenced, acetoacetate fell from 4.17 mmol l-1 to 0.86 mmol l-1, beta-hydroxybutyrate from 9.91 mmol l-1 to 2.03 mmol l-1, and acetone from 2 mmol l-1 to 0.4 mmol l-1. Further studies of rhlGF-1 use caused a fall in concentrations of cholesterol, triglyceride, VLDL, LDL, and apolipoprotein B. Infusion of rhlGF-1 reduces ketone body concentrations and may be life-saving in the treatment of ketoacidosis developing in a patient with a severe insulin-resistant state.

Response of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) and IGFBP-3 to IGF-I treatment in severe insulin resistance.

It has been suggested that recombinant human IGF-I (rhIGF-I) is a potential therapeutic agent in diabetes mellitus. It is known to have glucose-lowering effects in normal individuals, in patients with non-insulin-dependent diabetes (NIDDM) and in extreme insulin-resistant states. IGF-binding proteins (IGFBPs) have the potential to affect the biological activity of rhIGF-I. We have studied the effect of infused rhIGF-I on IGFBP-1 and IGFBP-3 in a patient with Mendenhall's syndrome, a rare insulin-resistant state. During an infusion of 20 mg rhIGF-I, glucose concentrations fell from 44.1 +/- 7.2 to 31.5 +/- 7.2 (S.E.M.) mmol/l (P = 0.001), and insulin and C-peptide levels fell from 920 +/- 62 to 542 +/- 45 mU/l (P = 0.008) and 5466 +/- 633 to 3071 +/- 297 pmol/l (P = 0.02) respectively. Significant lowering of phosphate, magnesium and alkaline phosphatase concentrations was also noted. IGF-I levels rose from 48 +/- 10.2 to 410 +/- 50.1 micrograms/l (P = 0.001), and those of IGF-II fell from 279.8 +/- 8.3 to 104.3 +/- 7.9 micrograms/l (P = 0.001). IGFBP-1 concentrations did not significantly change during the infusion but those of IGFBP-3 increased from 1655 +/- 127 to 2197 +/- 334 micrograms/l (P = 0.002), despite a significant fall in GH concentrations from 10.7 +/- 2.6 to 4.1 +/- 1.1 mU/l (P = 0.007), suggesting that IGFBP-3 regulation is also IGF-I-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of different methods of assessing free radical activity in type 2 diabetes and peripheral vascular disease.

Increased free radical activity in diabetes mellitus may contribute to the higher prevalence and mortality from macrovascular disease in diabetic patients. To investigate this, levels of plasma antioxidants (superoxide dismutase, caeruloplasmin, plasma, and lysate thiol), diene conjugates, lipid peroxides, and chemiluminescence were measured in diabetic and non-diabetic patients with peripheral vascular disease compared with healthy control subjects. Caeruloplasmin, diene conjugate ratio, and lipid peroxides were significantly increased in patients with vascular disease but there was no difference between diabetic and non-diabetic patients. Conjugated diene ratio correlated with caeruloplasmin (r = 0.40, p < 0.02) and inversely with superoxide dismutase level (r = 0.36, p < 0.05) but there was no significant correlation between other antioxidants and diene conjugates, lipid peroxides or chemiluminescence. The relationship between different indirect measurements of free radical activity is variable but there appears to be no additive effect of diabetes on the increased free radical activity associated with vascular disease.

An evaluation of bone density and turnover in premenopausal women with type 1 diabetes mellitus.

Measurement of bone density and turnover was assessed in 20 premenopausal females with Type 1 diabetes mellitus and 27 age-sex-matched controls. Measurement was made of spinal (L2-4) and neck of femur bone density by dual-energy X-ray absorptiometry. L2-4 density was significantly higher in the diabetic patients compared with controls (1.224 +/- 0.021 g cm-2 vs. 1.161 +/- 0.020 g cm-2: p = 0.016). No significant difference was noted between the groups in neck of femur density. Measurement of bone formation was assessed by serum alkaline phosphatase and bone resorption by fasting urinary hydroxyproline/creatinine ratio. Alkaline phosphatase was significantly higher in the diabetic patients (185 +/- 16 Ul-1 vs 135 +/- 10 Ul-1: p < 0.01) as was hydroxyproline/creatinine ratio (0.028 +/- 0.003 vs 0.017 +/- 0.002: p = 0.002). No significant correlation was found between L2-4 density and glycated haemoglobin, duration of diabetes or daily dose of insulin taken. These data suggest that osteopenia is not associated with Type 1 diabetes mellitus; however these patients do have evidence of increased bone turnover and may therefore be at risk of osteoporosis in later life, particularly after the menopause.