Nocturnal hypoglycaemia in type 1 diabetes--frequency and predictive factors.

BACKGROUND: Nocturnal hypoglycaemia (NH) remains a problem in type 1 diabetes and spontaneous asymptomatic NH may be a risk factor for sudden death ('Dead in Bed' syndrome). AIMS: To explore whether any predictive relationship exists between the average or time-specific glycaemia and the occurrence of NH. METHODS: Twenty-five healthy patients with type 1 diabetes underwent two separate overnight periods of continuous glucose monitoring (CGM) using a MMT-7002 Medtronic MiniMed System. There was a 6-week interval before the second monitoring period. CGM glucose levels recorded between 23:00 and 08:00 h defined the nocturnal period and recorded glucose monitoring levels <3.5 mmol/l for at least 10 min during this time-defined NH. A CGM recording at 23:00 h and 08:00 h were taken as the bedtime and fasting glucose levels, respectively. RESULTS: The mean +/- SD age was 37 +/- 7 years and duration of diabetes 13 +/- 7 years; 16 (64%) were on long-acting analogue insulin. Forty-nine CGM data sets were recorded. Fourteen episodes of NH occurred in 12 patients (Group 1), 13 patients (Group 2) had no NH. Group 1 (NH) had a lower mean bedtime glucose recorded compared with Group 2 (7.7 +/- 4.3 vs. 11.4 +/- 4.0 mmol/l, P = 0.0035). Fasting glucose level was also lower in Group 1 following the occurrence of NH (P = 0.014). There was no difference in the type of insulin used between the two groups. CONCLUSION: Our data show that in normal day to day settings, NH is common and that the bedtime glucose level is a significant predictive factor.

Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes--the 'dead in bed' syndrome revisited.

AIMS/HYPOTHESIS: Sudden nocturnal death in type 1 diabetes ('dead in bed' syndrome) is thought to be due to ECG QT prolongation with subsequent ventricular tachyarrhythmia in response to nocturnal hypoglycaemia. We investigated this theoretical mechanism using continuous ECG and continuous glucose monitoring in a group of patients with type 1 diabetes. METHODS: Twenty-five patients with type 1 diabetes (age 20-50 years) underwent two separate 24 h ECG and continuous glucose monitoring periods. Patients were fully ambulant and carried out normal daily activities. RESULTS: There were 13 episodes (26% of recordings) of nocturnal hypoglycaemia, eight of <2.2 mmol/l and five of 2.2-3.4 mmol/l. Corrected QT interval (QTc) was longer during nocturnal hypoglycaemia compared with normoglycaemic control periods (445 +/- 40 vs 415 +/- 23 ms; p = 0.037). Cardiac rate and rhythm disturbances (excluding sinus tachycardia) were seen in eight of the 13 nocturnal hypoglycaemia episodes (62%). These were sinus bradycardia (<40 beats/min; three episodes), ventricular ectopics (three episodes), atrial ectopics (one) and P wave abnormalities (one). CONCLUSIONS/INTERPRETATION: This study demonstrates QTc prolongation and cardiac rate/rhythm disturbances in response to episodes of nocturnal hypoglycaemia in ambulant patients with type 1 diabetes. This may support an arrhythmic basis for the 'dead in bed' syndrome.

The North West Diabetic Pregnancy Audit: a practical system for multi-centre diabetic pregnancy audit.

AIMS: Improving care for women with pre-gestational diabetic pregnancy is a core objective of the St Vincent Declaration and the Diabetes National Service Framework. The aim was to develop a practicable collaborative audit methodology for pre-gestational diabetic pregnancy. METHODS: In 1999, care professionals in the north-west of England agreed standards and a simple monthly data collection system. Annual reports are compiled to summarize compliance with the standards. Each hospital receives an individualized report comprising tables and funnel plots that allow between-hospital comparisons. RESULTS: Data on pre-gestational diabetic pregnancies are collated from 30 maternity units. Funnel plots and tables presented in the annual reports highlight any large differences between hospitals in booking and outcome measures for diabetic pregnancies. CONCLUSIONS: The annual audit reports allow the assessment of current management and outcomes for diabetic pregnancies at a regional and local level. These reports help to identify areas where diabetic pregnancy care requires further attention.

Pregnancy in women with diabetes--after the CEMACH report, what now?

The second of three studies being undertaken by the Confidential Enquiry into Maternal and Child Health (CEMACH) has recently reported its findings and recommendations. The standards of diabetes and maternal care and the outcomes of 3808 pregnancies in England, Wales and Northern Ireland are described. Pre-pregnancy planning and care before conception is poor. Stillbirth rate (26.8 per thousand) and perinatal mortality (41.8 per thousand) were 4-5 times higher than the background population, and congenital anomaly (41.8 per thousand) double the background rate. Type 2 diabetes now represents 27.3% of pre-gestational diabetes and more often of ethnic minority and deprived background than Type 1 diabetes. The ideals of the Diabetes National Service Framework and the target of the Saint Vincent declaration are far from being achieved. Much can be done to improve the outcomes of pregnancy within existing resources with better systems and organization of care. However, if significant progress is to be made, it is incumbent upon health-care professionals and health-care commissioners to direct resources specifically at improving pre-pregnancy and maternity services. Research is needed firstly to analyse in greater detail the wealth of data collected in the CEMACH survey and consider the implications of health-care costs. Further research to discover ways of reducing the adverse outcomes is urgently required. The need to educate, motivate and bring about improved pre-pregnancy care in women with diabetes is a priority.

Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors.

AIMS: To determine the prevalence of overweight and obesity among patients with type 1 and type 2 diabetes mellitus attending a secondary care diabetes clinic in the United Kingdom, and to assess the impact of overweight and obesity on glycaemic control and cardiovascular risk factors in patients with type 2 diabetes. METHODS: 3637 patients with diabetes were identified from the hospital electronic diabetes register, 916 with type 1 diabetes (mean (SD) age 40.4 (15.1) years, 496 male) and 2721 with type 2 diabetes (mean (SD) age 62.5 (11.8) years, 1436 male). Data on body mass index (BMI), glycaemic control, lipid profiles, and blood pressure were extracted. RESULTS: Of patients with type 1 diabetes, 55.3% were overweight (BMI >or=25 kg/m(2)), 16.6% were obese (BMI >or=30 kg/m(2)), and 0.4% had morbid obesity (BMI >or=40 kg/m(2)). In contrast, 86% of patients with type 2 diabetes were overweight or obese, 52% were obese, and 8.1% had morbid obesity. Obese patients with type 2 diabetes were younger, had poorer glycaemic control, higher blood pressures, worse lipid profiles, and were more likely to be receiving antihypertensive and lipid lowering drugs compared with patients with BMI <30 kg/m(2). CONCLUSIONS: Obesity is the rule among patients attending this hospital diabetes clinic, with 86% of those with type 2 diabetes overweight or obese. Obesity is associated with significantly worse cardiovascular risk factors in this patient group, suggesting that more active interventions to control weight gain would be appropriate.

St Vincent's Declaration 10 years on: outcomes of diabetic pregnancies.

AIMS: To monitor pregnancies in women with pregestational Type 1 diabetes for pregnancy loss, congenital malformations and fetal growth parameters, in a geographically defined area in the north west of England. METHODS: Population cohort study of 547 pregnancies in women with Type 1 diabetes from maternity clinics in 10 centres over a 5-year period (1995-1999 inclusive). Main outcome measures were numbers and rates of miscarriages, stillbirths, neonatal and post-neonatal deaths; prevalence of congenital malformations; birth weight in relation to gestational age. RESULTS: Among 547 pregnancies, there were six (1.1%) pairs of liveborn twins, 439 (80.3%) liveborn singletons; 72 (13.2%) spontaneous abortions, 14 (2.6%) stillbirths and 16 (2.9%) terminations. Four of the terminations were performed because of congenital malformations. Both the stillbirth rate (30.1/1000 total births (95% confidence interval (CI) 16.6-50.0)), and prevalence of congenital malformations (84.3/1000 live births (95% CI 60.3-113.8)) were significantly higher than the local population (P < 0.001). When corrected for gestational age, mean birth weight in the sample was 1.3 sd greater than that of infants of non-diabetic mothers (P = 0.12). Infants with congenital malformations weighed less than those without. CONCLUSION: In an unselected population, the infants of women with pregestational Type 1 diabetes mellitus have 6.4 times the reported risk of a congenital malformation and 5.1 times the reported risk of perinatal mortality than infants in the general population. Further improvements in the management of diabetes and pregnancy in these women are needed if the St Vincent's Declaration target is to be met.

Glycated haemoglobin assays. Approaches to standardization of results.

AIMS: To compare different approaches to DCCT standardization of glycated haemoglobin (HbA(1c)) results. METHODS: In the first part of the study seven laboratories in the Mersey area participated, using a variety of methods of measurement. The approaches used were the Standardization Initiative for Glycated Haemoglobin Scheme (SIGH) using fresh blood samples and the Wales External Quality Assurance Scheme (WEQAS) using both fresh and lyophilized blood samples. Additional studies performed in the Royal Liverpool University Hospital (RLUH) laboratory involved: (i) re-calibration of the HPLC analyser using lyophilized blood samples supplied by the manufacturer and (ii) the use of fresh blood samples from the UK National External Quality Assurance Scheme (UKNEQAS). RESULTS: Inter-laboratory analytical coefficients of variation following DCCT alignment showed little change. The effect on percentage bias was more marked and was independent of the level of HbA(1c). Comparing DCCT-aligned HbA(1c) results from 3902 diabetic patients attending the RLUH, indicated that there was a statistically significant difference (P < 0.0001) between the corrected results produced by the five schemes. The effect of DCCT alignment on reported HbA(1c) values using the different approaches was variable resulting in an apparent increase in the number of diabetic patients with poor glycaemic control (HbA(1c) values > 7.0%) in all cases. CONCLUSION: The method of HbA1c standardization used determines the degree of correction required and a consensus approach is recommended. Implementation will assist extrapolation from research-based evidence to local practice. Associated changes to patient management must come under the jurisdiction of the physicians responsible for the diabetic service.

Outcomes of pregnancy in insulin dependent diabetic women: results of a five year population cohort study.

OBJECTIVE: To monitor pregnancies in women with pre-existent insulin dependent diabetes for pregnancy loss, congenital malformations, and fetal growth in a geographically defined area of north west England. DESIGN: Population cohort study. SETTING: 10 maternity units in Cheshire, Lancashire, and Merseyside which had no regional guidelines for the management of pregnancy in diabetic women. SUBJECTS: 462 pregnancies in 355 women with insulin dependent diabetes from the 10 centres over five years (1990-4 inclusive). MAIN OUTCOME MEASURES: Numbers and rates of miscarriages, stillbirths, and neonatal and postneonatal deaths; prevalence of congenital malformations; birth weight in relation to gestational age. RESULTS: Among 462 pregnancies, 351 (76%) resulted in a liveborn infant, 78 (17%) aborted spontaneously, nine (2%) resulted in stillbirth, and 24 (5%) were terminated. Of the terminations, nine were for congenital malformation. The stillbirth rate was 25.0/1000 total births (95% confidence interval 8.9 to 41.1) compared with a population rate of 5.0/1000, and infant mortality was 19.9/1000 live births (5.3 to 34.6) compared with 6.8/1000. The prevalence of congenital malformations was 94.0/1000 live births (63.5 to 124.5) compared with 9.7/1000 in the general population. When corrected for gestational age, mean birth weight in the sample was 1.3 standard deviations greater than that of infants of non-diabetic mothers. Infants with congenital malformations weighed less than those without. CONCLUSION: In an unselected population the infants of women with pre-existent insulin dependent diabetes mellitus have a 10-fold greater risk of a congenital malformation and a fivefold greater risk of being stillborn than infants in the general population. Further improvements in the management of pregnancy in diabetic women are needed if target of the St Vincent declaration of 1989 is to be met.

Henoch-Schonlein purpura associated with ranitidine.

Ranitidine is one of the widely prescribed H2 receptor antagonists in the treatment of peptic ulcer. It is well tolerated and has few side-effects. Vasculitic rash occurring in association with ranitidine has been described. We report a case of a 39-year-old man who developed a purpuric rash, polyarthritis, abdominal pain, melaena and impaired renal function characteristic of Henoch-Schonlein purpura, following treatment with ranitidine.

Glycation of brain actin in experimental diabetes.

Actin is a neuronal protein involved in axonal transport and nerve regeneration, both of which are known to be impaired in experimental diabetes. To determine if actin is subject to glycation, we rendered rats diabetic by injection of streptozotocin. Two or 6 weeks later brains were removed and a preparation of cytoskeletal proteins was analyzed by two-dimensional polyacrylamide gel electrophoresis. Brains from diabetic animals contained an extra polypeptide that migrated close to actin and reacted with monoclonal antibody C4 against actin. It was also found in a preparation of soluble synaptic proteins from diabetic rat brain, indicating that it was at least partly neuronal in origin. This polypeptide could be produced by incubation of cytoskeletal proteins from brains of nondiabetic rats with glucose-6-phosphate in vitro. The appearance of this glycated actin in diabetic animals was prevented by administration of insulin for a period of 6 weeks. We could not detect any effect of glycation in vitro on the ability of muscle G-actin to form F-actin filaments and its significance for the function of actin remains to be determined. The finding that glycation of platelet-derived actin from diabetic patients was significantly increased implies that the abnormality may also occur in clinical diabetes.

Posttranslational modifications of nerve cytoskeletal proteins in experimental diabetes.

Axonal transport is known to be impaired in peripheral nerve of experimentally diabetic rats. As axonal transport is dependent on the integrity of the neuronal cytoskeleton, we have studied the way in which rat brain and nerve cytoskeletal proteins are altered in experimental diabetes. Rats were made diabetic by injection of streptozotocin (STZ). Up to six weeks later, sciatic nerves, spinal cords, and brains were removed and used to prepare neurofilaments, microtubules, and a crude preparation of cytoskeletal proteins. The extent of nonenzymatic glycation of brain microtubule proteins and peripheral nerve tubulin was assessed by incubation with 3H-sodium borohydride followed by separation on two-dimensional polyacrylamide gels and affinity chromatography of the separated proteins. There was no difference in the nonenzymatic glycation of brain microtubule proteins from two-week diabetic and nondiabetic rats. Nor was the assembly of microtubule proteins into microtubules affected by the diabetic state. On the other hand, there was a significant increase in nonenzymatic glycation of sciatic nerve tubulin after 2 weeks of diabetes. We also identified an altered electrophoretic mobility of brain actin from a cytoskeletal protein preparation from brain of 2 week and 6 week diabetic rats. An additional novel polypeptide was demonstrated with a slightly more acidic isoelectric point than actin that could be immunostained with anti-actin antibodies. The same polypeptide could be produced by incubation of purified actin with glucose in vitro, thus identifying it as a product of nonenzymatic glycation. These results are discussed in relation to data from a clinical study of diabetic patients in which we identified increased glycation of platelet actin. STZ-diabetes also led to an increase in the phosphorylation of spinal cord neurofilament proteins in vivo during 6 weeks of diabetes. This hyperphosphorylation along with a reduced activity of a neurofilament-associated protein kinase led to a reduced incorporation of 32P into purified neurofilament proteins when they were incubated with 32P-ATP in vitro. Our combined data show a number of posttranslation modifications of neuronal cytoskeletal proteins that may contribute to the altered axonal transport and subsequent nerve dysfunction in experimental diabetes.

Antibodies to tubulin and microtubule-associated proteins. A study in diabetes mellitus, systemic lupus erythematosus, and rheumatoid arthritis.

We report the results of a study of serum antibodies to proteins of the nerve cytoskeleton in patients with Type I and Type II diabetes mellitus, both with and without clinical signs of diabetic neuropathy. In contrast to previous reports, elevated levels of antibody to tubulin or glycated tubulin were not associated with either diabetes or diabetes with related neuropathy. Similarly, clinical evidence of neuropathy in patients with diabetes did not relate to increased levels of antibody to native or glycated microtubule-associated proteins (MAPs). The levels of antibody to MAPs and glycated MAPs were higher in control subjects over the age of 45 years compared with younger control subjects. Increased levels of antibody to tubulin and glycated tubulin were found in the sera of patients with systemic lupus erythematosus, but not rheumatoid arthritis.

Thyrotoxicosis in a patient with Addison's disease.

We report the case of a patient who suffered recurrent episodes of hypoadrenal crisis, despite conventional replacement therapy for Addison's disease. She was found to have hyperthyroidism and after this was treated, she had no further relapse. Thyrotoxicosis should be considered when patients taking replacement therapy for Addison's disease present in hypoadrenal crisis.

Identical twins discordant for Kallmann's syndrome.

A 20 year old male patient presented with lack of sexual development. On examination he was eunuchoidal and hypogonadal, and olfactory function testing showed he was anosmic. Biochemical investigations proved he was hypogonadotrophic. Kallmann's syndrome was therefore diagnosed. His appearance was very different from his alleged identical twin who had undergone a normal puberty and had normal plasma testosterone and gonadotrophin levels. However, the twin was hyposmic. Genetic fingerprinting confirmed the twins were identical. Why Kallman's syndrome was incompletely expressed in one of them is unexplained. The parents and a normally menstruating sister had normal olfactory function.