Paul G. McNally

Using Continuous Glucose Monitoring to Measure the Frequency of Low Glucose Values When Using Biphasic Insulin Aspart 30 Compared With Biphasic Human Insulin 30 A double-blind crossover study in individuals with type 2 diabetes

OBJECTIVE—Rapid-acting insulin analogs in basal-bolus regimens can reduce nocturnal hypoglycemia, so it is conceivable that twice-daily biphasic insulin analogs might reduce hypoglycemia in patients with insulin-treated type 2 diabetes. We used a continuous glucose monitoring system (CGMS) and self-reported episodes to investigate differences in the frequency of low glucose values in patients with type 2 diabetes, using either biphasic insulin aspart 30 (BIAsp 30) or biphasic human insulin 30 (BHI 30). RESEARCH DESIGN AND METHODS—This was a double-blind, two-period, crossover trial involving 160 subjects. After 8 weeks’ run-in, subjects were randomized to the first of two 16-week treatment periods. RESULTS—No differences in overall incidence of low interstitial glucose (IG) were found. Twenty-four–hour plots of CGMS showed low IG was more frequent at night than during the day and was unrecognized by patients. At night, subjects spent significantly less time (percentage of total CGMS recorded) with IG <3.5 and <2.5 mmol/l during BIAsp 30 than during BHI 30 treatment, respectively (<3.5 mmol/l: 6.36 vs. 7.93% [mean], 0.67 vs. 2.43% [median], P = 0.018; <2.5 mmol/l: 2.35 vs. 2.86% [mean], 0 vs. 0% [median], P = 0.0467). No treatment difference in A1C was observed. CONCLUSIONS—Overall rates of low glucose over 24 h were not different but were twice as frequent at night than during the day in individuals with type 2 diabetes. Compared with BHI 30, BIAsp 30 was associated with similar low IG readings over 24 h but with fewer nocturnal episodes and less self-reported nocturnal hypoglycemia.

Comparative incidence of Type I diabetes in children aged under 15 years from South Asian and White or Other ethnic backgrounds in Leicestershire, UK, 1989 to 1998.

Abstract.Aims/hypothesis: Estimates of incidence of Type I (insulin-dependent) diabetes mellitus in childhood populations vary around the world. This study aimed to estimate and compare the incidence of Type I diabetes in Leicestershire of children of South Asian and White or Other ethnic backgrounds. Methods: All new cases of childhood-onset Type I diabetes diagnosed before 15 years of age in Leicestershire during the period 1989–98 were studied. Population data for Leicestershire from the 1991 census was used. Ethnicity was assigned to all children in the study according to their surnames. Incidence rates (95 %-Confidence limits) for the South Asian and white or other ethnic group were estimated and compared. Results: Over the 10-year period, 46 South Asian children and 263 children who were white or from another ethnic group fulfilled the criteria for inclusion in the study. Crude incidence rates per 100 000 person-years were 19.2 (12.0, 29.1) girls and 20.3 (13.0, 30.3) boys for South Asians and 17.7 (14.8, 21.1) girls and 17.7 (14.8, 20.9) boys for whites/others. Age and sex-specific rates were higher for South Asians over 5 years of age but differences were not statistically significant. Conclusion/interpretation: Type I diabetes incidence rates for South Asian children in Leicestershire were very similar to those for children who were in the white/other ethnic group, in contrast to very low rates reported from Asia. The convergence of rates for South Asians with other ethnic groups in Leicestershire suggests that environmental factors are more important than genetic predisposition in causing Type I diabetes in people of South Asian ethnic background. [Diabetologia (2001) 44 [Suppl 3]: B 32–B 36]

Lipohypertrophy and lipoatrophy complicating treatment with highly purified bovine and porcine insulins.

Lipoatrophy and lipohypertrophy were the most frequently reported local complications of conventional insulin therapy. Early reports following the introduction of highly purified insulins suggested a reduction in the frequency of lipohypertrophy and lipoatrophy. Since highly purified insulins have been in common usage for 10 years, the present frequency of these complications was assessed in a study of 281 insulin treated diabetics. Lipohypertrophy was recorded in 76 (27.1%) patients including 3 with associated lipoatrophy. Lipoatrophy was found in 7 (2.5%) cases (3 porcine and 4 bovine insulin treated), 4 of which had only ever used highly purified insulins. Despite the introduction of highly purified insulins, lipohypertrophy and lipoatrophy remain prevalent in insulin treated patients. This common complication may be limited by routinely inspecting injection sites.

U‐500 insulin: why, when and how to use in clinical practice

Some patients with type 2 diabetes mellitus (T2DM) have severe insulin resistance. Their insulin requirements are significantly greater. These patients need to take 2–3 injections at the same time to take the correct insulin dose or to redial the insulin pen. When daily insulin requirements are in excess of 300 units/day, the volume of the injected insulin becomes an issue. Large‐volume injection can cause discomfort and lead to poor concordance with treatment. Using high‐strength insulin e.g. U‐500 insulin can reduce the volume of the injected insulin. Despite publications of small case reports or case series, no universal guidelines exist on the use of U‐500 insulin. We discuss common sense approaches when considering the use of U‐500 insulin in clinical practice. Copyright

Trends in Mortality of Childhood-onset Insulin-dependent Diabetes Mellitus in Leicestershire: 1940–1991

The relative risk of death by calendar date of diagnosis was investigated in a population‐based incident cohort of 845 (463 males:382 females) IDDM diagnosed in Leicestershire before the age of 17 years between 1940 and 1989. The mortality status of 844 (99.9 %) patients was determined as of the 31 December 1991, representing 14 346 person‐years of risk. Trends in relative risk of death were investigated using Cox proportional hazards modelling for within cohort comparisons and age/sex and calendar time adjusted standardized mortality ratios (SMR) using generalized linear modelling for external comparisons. Median age at diagnosis was 10 years (range 3 months to 16 years); median duration of diabetes 15 years (range 1–51 years). Forty‐four patients had died (5.2 %; median age at death 31 years, range 11–51 years). A further four patients died at presentation (within 24 h) from ketoacidosis and are excluded from all analyses. Calendar date of diagnosis was found to be an important predictor of mortality. Adjusting for attained age there was evidence of a decline in relative risk of death with calendar date of diagnosis of 3.4 % (95 % CI, 0.005–6.9 %) per annum, equivalent to a 32 % fall per decade (95 % CI, 5–51 %), or 84 % (95 % CI, 21–97) from 1940 to 1989. The data are consistent with a large fall in mortality between the 1940s and 1950s representing over 50 % of the total reduction in mortality between 1940 and 1991. Neither sex nor age at diagnosis were significant predictors of mortality. Over the study period 1940–89 the SMR (male and female combined) fell from 981 (541–1556) to 238 (60–953) relative to the general population. This population‐based study shows that the prognosis for Type 1 (insulin‐dependent) diabetes mellitus has improved markedly over the period 1940–1991.

Preliminary observations using endocrine markers of pituitary venous dilution during bilateral simultaneous inferior petrosal sinus catheterization in Cushing's syndrome: is combined CRF and TRH stimulation of value?

OBJECTIVE We determined whether the measurement of hormones in pituitary blood permits correction for dilution by non‐pituitary blood during bilateral simultaneous inferior petrosal sinus blood sampling in Cushings syndrome. DESIGN Bilateral simultaneous inferior petrosal sinus blood sampling was performed after combined hCRF and TRH stimulation. Peak ACTH concentrations were corrected for the TSH and PRL inter‐sinus ratio, assuming uniform secretion of both hormones into each inferior petrosal sinus.

Sudden death in type 1 diabetes

Sudden and unexpected death in young patients with type 1 diabetes is a devastating complication, albeit rare. Nonetheless, most physicians dealing with patients affected by diabetes will be familiar with this scenario. The cause of unexpected and sudden death is ill-de®ned but evidence is beginning to accrue to implicate both cardiac autonomic dysfunction and concomitant hypoglycaemia. This review will focus on the role both cardiac autonomic dysfunction and hypoglycaemia play and offer persuasive evidence that malignant cardiac dysrhythmias might be a common ®nal pathway.

Is impaired baroreflex sensitivity a predictor or cause of sudden death in insulin-dependent diabetes mellitus?

Sudden death at night is known to occur in young patients with insulin‐dependent (Type 1) diabetes mellitus (IDDM) but the aetiology is uncertain. A cardiac arrhythmia has been postulated, but there has been little evidence to support this. We present the case of a 31‐year‐old man with IDDM of 17 years duration, who died suddenly while asleep. Over preceding months, he had had strict glycaemic control (HbA1 8.9 %), normal 24 h blood pressure (mean 131 ± 2.1/76 ± 2.2 mmHg), no evidence of microangiopathy or endothelial dysfunction and normal standard clinical tests of autonomic function. An electrocardiogram was similarly unremarkable, with a QTc interval of 0.414 s, and an echocardiogram had demonstrated normal left ventricular mass index (96.4 g m−2). However, there was no nocturnal dip in heart rate (daytime 74 ± 2.7, and nocturnal 68 ± 1.6 beats min−1), and he had grossly impaired baroreflex sensitivity during Phase 4 of the Valsalva manoeuvre (0.5 ms mmHg−1), with power spectral analysis studies suggesting an abnormality of parasympathetic function. The coroner’s autopsy demonstrated no structural abnormalities. We hypothesize that abnormal baroreflex sensitivity could either predict a risk of or account for some of the unexplained deaths in IDDM, in that relative overactivity of the sympathetic nervous system could cause ventricular arrhythmias.

The effect of insulin on the vascular reactivity of isolated resistance arteries taken from healthy volunteers.

SummaryImpaired reactivity of the resistance vasculature may contribute to the development of diabetic microangiopathy by altering microvascular haemodynamics. This study investigates the acute effects of insulin on the contractility and relaxation properties of isolated human resistance arteries (<300 Μm internal diameter) taken from gluteal subcutaneous fat of 33 (18 male: 15 female) normotensive healthy volunteers (supine blood pressure 115.6±1.6/ 70.0±1.5 mm Hg [mean±SEM], with no family history of hypertension or diabetes mellitus. Resistance arteries were mounted in a small vessel myograph to measure isometric tension. Contractile responses to noradrenaline were reduced after incubation in 1 mU/ml of insulin for 20 min (p<0.01; Group 1). Increasing concentrations of insulin were found to reduce the contractile response to noradrenaline in a dose-dependent manner (Group 2; 0.1 mU/ml by 8% [p<0.01], 1 mU/ml by 17% [p<0.02] and 10 mU/ml by 22% [p< 0.01]). Sensitivity to insulin (ED50) only decreased at the highest concentration of insulin. However, acetycholine-induced relaxation was not altered by insulin (Group 2). Time control studies (Group 3) showed that contractile and relaxation responses over the 4-h study period were unchanged. Furthermore, the length of time the vessels were exposed to insulin did not progressively impair responses (Group 4). These findings suggest that insulin may induce abnormalities in vascular smooth muscle contractility, a factor that may contribute to or exacerbate the abnormal haemodynamics observed in the capillary microcirculation of numerous vascular beds in diabetes.

Inequalities in access to diabetes care: evidence from a historical cohort study

Objective—To establish which factors predict attendance at a hospital diabetes clinic and for diabetes review in general practice. Design—A historical cohort study of individuals with diabetes identified from general practice records. Information on service contacts and other clinical, social, and demographic variables was collected from general practice records and postal questionnaires. Setting—Seven Leicestershire general practices. Subjects—Individuals registered with study practices who had a diagnosis of diabetes made before 1990. Main outcome measurements—Attendance at a hospital diabetes clinic or for a documented diabetes review in general practice at least once between 1990 and 1995. Results—124 (20%) had at least one recorded diabetes review in general practice and 332 (54%) attended a hospital diabetes clinic at least once. The main predictors of attending a hospital clinic were younger age, longer duration of diabetes, and treatment with insulin. Access to a car (OR 1.34, 95% CI 1.06 to 1.71), home ownership (OR 1.48, 95% CI 1.14 to 1.58) and a non-manual occupation (OR 1.56, 95% CI 1.09 to 2.24) were all associated with an increased likelihood of attending, although living in a less deprived area was not. The main predictors of attending for review in general practice were older age, less co-morbidity, and being white. Living in a more deprived area was related to a reduced chance of review in general practice (OR 0.81, 95% CI 0.76 to 0.86) while individual socioeconomic indicators were not. Conclusions—Whilst an indicator of area deprivation predicts reduced likelihood of review in general practice, individual indicators predict reduced likelihood of attending outpatients. This suggests a need for different approaches to tackling inequalities in access to care in primary and secondary care settings. (Quality in Health Care 2000;9:85–89)