I. G. Lawrence

Impaired endothelium-dependent relaxation in isolated resistance arteries of spontaneously diabetic rats

1 Previous studies have shown that endothelium‐dependent relaxation in the aorta of spontaneously diabetic bio bred rats (BB) is impaired. 2 We have investigated noradrenaline (NA) contractility, endothelium‐dependent acetylcholine (ACh) and bradykinin (BK) relaxation, and endothelium‐independent sodium nitroprusside (SNP) relaxation in mesenteric resistance arteries of recent onset BB rats and established insulin treated BB rats, compared to their age‐matched non diabetic controls. 3 There was no significant difference in the maximum contractile response or sensitivity to noradrenaline in either of the diabetic groups compared to their age‐matched controls. 4 Incubation with the nitric oxide synthetase inhibitor NG‐nitro‐L‐arginine (L‐NOARG) resulted in a significant increase in maximum contractile response to noradrenaline in the recent onset age‐matched control group (P<0.05). Analysis of the whole dose‐response curve (using ANOVA for repeated measures with paired t test) showed a significant left‐ward shift following the addition of l‐NOARG (P<0.001). A similar but less marked shift (P<0.01) was evident in vessels from recent onset diabetics. An overall shift in both sensitivity and maximum response was also evident in the age‐matched non diabetic controls of the insulin‐treated group (P<0.05). However, by contrast, there was no significant change in sensitivity in the insulin‐treated diabetic rats. 5 ACh‐induced endothelium‐dependent relaxation was significantly impaired in the recent onset diabetic rats compared to their age‐matched controls (47 ± 11% versus 92 ± 2%, P<0.05, n = 6), and in the insulin treated diabetic rats (34 ± 5% versus 75 ± 6%, P<0.05, n = 6). The relaxation responses to BK also were significantly impaired in the diabetic rats compared to their age‐matched controls (recent onset: 20 ± 3% versus 72 ± 7%, P<0.05, n = 6; insulin treated: 12 ± 9% versus 68 ± 7%, P<0.05, n = 7). 6 Incubation with either the nitric oxide synthetase substrate, L‐arginine, or the free radical scavenging enzyme superoxide dismutase (150 μml−1) failed to improve the attenuated response of acetylcholine‐induced relaxation in the diabetic vessels. 7 Endothelium‐dependent relaxation mediated by ACh and BK was significantly attenuated in both the diabetic and control vessels after incubation with L‐NOARG. 8 Pretreatment with a cyclo‐oxygenase inhibitor, indomethacin, significantly enhanced the relaxation to ACh in both the recent onset and insulin treated diabetic rats (42 ± 10%, n = 7 versus 64 ± 7%, n = 7, P<0.05, and 40 ± 5%, n = 7 versus 65 ± 9%, n = 6, P<0.05). 9 Following endothelium removal, there was a marked impairment in endothelium‐dependent relaxation responses to ACh and BK in both the diabetic and control vessels. 10 Incubation with the thromboxane A2 receptor antagonist SQ29548, did not significantly improve the ACh endothelium‐dependent relaxation response in the diabetic vessels. 11 Endothelium‐independent relaxation to sodium nitroprusside was significantly impaired in the first group of diabetic vessels studied; however, subsequent studies showed no impairment of the sodium nitroprusside response in the diabetic vessels. 12 In conclusion, the ability of the endothelium to regulate vascular contractility is reduced in recent onset diabetic vessels, and significantly impaired in established insulin treated diabetics. Relaxation to the endothelium‐dependent vasodilators ACh and BK was impaired in both the recent onset and the established insulin treated diabetics, and the ACh response was significantly improved following pretreatment with indomethacin, suggesting a role for a cyclo‐oxygenase‐derived vasoconstrictor. Preliminary studies with a thromboxane A2 receptor antagonist, SQ29548 did not significantly improve the impaired relaxation to ACh, indicating that the vasoconstrictor prostanoid is not thromboxane A2.

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]

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

Type 2 diabetes in younger adults: the emerging UK epidemic

There is an emerging epidemic of type 2 diabetes (T2DM) in younger adults. They represent an extreme phenotype: likely to be obese, lead a sedentary lifestyle, have a strong family history of T2DM, be of black or minority ethnic origin, and come from less affluent socioeconomic groups. An accurate diagnosis of T2DM in younger adults, while essential to guide management, can be challenging even for the experienced diabetologist. Comorbidities such as hypertension, nephropathy and hyperlipidaemia are prevalent in this group, and, despite the lack of longitudinal data, they represent a very high risk group, with a need for aggressive management. This focused review of the epidemiology, aetiology, clinical outcomes, comorbidities and management of younger adults with T2DM will provide the non-specialist with up-to-date insight into the UKs emerging epidemic.

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.

Characteristics, complications and management of a large multiethnic cohort of younger adults with type 2 diabetes

AIMS To describe the characteristics and management of a cohort with type 2 diabetes (T2DM) <40 years. METHODS Cross-sectional study of the last visit of 648 adults attending 2 specialist centres in the UK. Differences between the lowest (≤22) vs. highest quintile (≥33) of age of diagnosis were analysed. RESULTS 57.9% were female; 45.5% Black or Minority Ethnic origin (91.9% of South Asian origin); median age at diagnosis was 28 years (24-31); diabetes duration of 4.0 years (1.9-7.0); BMI of 33.0 kg/m(2) (28.3-38.7). HbA1c of 8.2% (6.8-9.9) with HbA1c >7% in 70%. 71.8% had cholesterol >4 mmol/l, 54.9% triglycerides >1.7 mmol/l, 45% had hypertension, 19.8% retinopathy, 16.9% microalbuminuria. Insulin was used in 43.3%. 27.7% received antihypertensives and 31.5% a statin. Compared to the highest quintile of age of diagnosis, the lowest quintile had more often retinopathy (22.1% vs. 16.9%, p=0.021), was less on insulin (45.6% vs. 46.4%, p=0.039) and often managed with diet only (9.6% vs. 6.2%, p=0.005). CONCLUSIONS These younger adults with T2DM often have inadequately treated risk factors. In particular, patients from the lowest quintile of age of diagnosis were less aggressively treated. There is a need for tailored strategies to manage this high-risk group.

Type 2 diabetes in younger adults: Clinical characteristics, diabetes-related complications and management of risk factors

AIM To describe the clinical characteristics and risk factors of adults <35 years with type 2 diabetes (T2DM). METHODS Observational study of 185 younger adults attending a specialist diabetes clinic. RESULTS In this cohort 65% were female, 51% Caucasian, 43% South Asian. Characteristics at presentation: age 24 ± 5.5 years, BMI 33 ± 7.6 kg/m(2) and HbA1c 9.0% ± 2.3. Follow up of 3.2 ± 2.8 years with a diabetes duration of 4.5 ± 3.6 years. HbA1c had improved compared with diagnosis (8.3 ± 2.2% vs. 9.0% ± 2.3%, p<0.0001), but 63% still had an HbA1c>7%. Oral anti-diabetic drugs were used in 72%, insulin alone in 19% and both in 26%. 41% had a BP ≥ 140/80 mmHg, 78% total cholesterol >4 mmol/l, 63% LDL >2 mmol/l, 56% triglycerides >1.7 mmol/l. From diagnosis only the cholesterol and LDL improved significantly, with a modest increase in primary prevention therapy (statin 12-26%, p<0.0001, anti-hypertensives 16-29%, p<0.0001, aspirin 8-12%, p=0.18). 13% had retinopathy, 21% microalbuminuria. 46% had not been reviewed within the past year. CONCLUSIONS This group represents an extreme phenotype with a high prevalence of insufficiently treated metabolic risk factors. There is need for tailored management strategies to engage and aggressively manage this high-risk group.

Searching for the right outcome? A systematic review and meta-analysis of controlled trials using carotid intima-media thickness or pulse wave velocity to infer antiatherogenic properties of thiazolidinediones.

Introduction: Recent meta‐analyses cast doubt over purported beneficial effects of Peroxisome Proliferator Activated Receptor‐Gamma (PPAR‐γ) receptor agonists. Thiazolidinedione (TZD) trials using surrogate outcomes to postulate an antiatherogenic paradigm have been criticised as misinformative. We conducted an independent systematic review and meta‐analysis of controlled TZD studies incorporating carotid intima‐media thickness (CIMT) or pulse wave velocity (PWV) as primary outcome measures. The aim was to provide an evidence‐based overview of TZD intervention studies using markers prospectively linked to vascular outcome in type 2 diabetes.