The Microalbuminuria Education Medication and Optimisation (MEMO) study: 4 years follow-up of multifactorial intervention in high-risk individuals with type 2 diabetes.

AIMS: The Microalbuminuria Education Medication and Optimisation (MEMO) study, revealed improved cardiovascular risk and glycaemic control with 18 months of intensive multifactorial intervention in high-risk people with type 2 diabetes, without any increase in severe hypoglycaemia. Our aim was to assess longer-term outcomes at 4-year follow-up in these participants. METHODS: Some 189 individuals with type 2 diabetes and microalbuminuria were recruited from a multi-ethnic population in Leicestershire, UK. The intervention group (n = 95) received multifactorial intervention with self-management education, and the control group (n = 94) received usual care. The primary outcome was change in HbA1c , and secondary outcomes were blood pressure (BP), cholesterol, microalbuminuria, estimated GFR, cardiovascular risk scores and major adverse cardiovascular events. RESULTS: Some 130 participants (68.7%), mean (sd) age 60.8 (10.4) years, duration of diabetes 11.5 (9.7) years, completed 4 years of follow-up. Mean change [95% confidence intervals (CI)] in HbA1c over 4 years was greater with intensive intervention compared with control (-3 mmol/mol, 95% CI -4.95,-1.11; -0.4%, 95% CI -0.67,-0.15; P = 0.002). Significant improvements over the 4 years were also seen in systolic BP (-7.3 mmHg, 95% CI -11.1, -3.5; P < 0.001), diastolic BP (-2.9 mmHg, 95% CI -5.4, -0.3; P = 0.026), cholesterol (-0.3 mmol/l, 95% CI -0.52,-0.12; P = 0.002), and 10-year coronary heart disease (-5.3, 95% CI -8.2,-2.3; P < 0.001) and stroke risk (-4.4, 95% CI -7.5, -1.3; P < 0.001). CONCLUSION: Multifactorial intervention with structured diabetes self-management education compared with usual diabetes care has benefits for cardio-metabolic risk factor profile. There was no increase in severe hypoglycaemia and cardiovascular mortality despite intensive glycaemic control, although the study was not powered to assess these outcomes.

Association of cardiac and non-cardiac chronic disease comorbidity on glycaemic control in a multi-ethnic population with type 1 and type 2 diabetes.

AIMS: To determine the prevalence of chronic disease comorbidity in south Asians (SAs) and white Europeans (WEs) with diabetes and to quantify the relationship of cardiac disease comorbidity (CDCM) and non-cardiac disease comorbidity (NCCM) to glycaemic control in SAs and WEs with type 1 and type 2 diabetes mellitus. METHODS: A cross-sectional study using a database of patients of SA (25.5%) and WE (74.5%) origin attending a specialist diabetes clinic in the UK between 2003 and 2005 (n=5664). RESULTS: The prevalence of SAs and WEs with type 1 diabetes was 12% and 88%, respectively; for those with type 2 diabetes the prevalence was 30% and 70%, respectively. Overall, the prevalence of comorbidity in people with type 1 diabetes was 25.5% and with type 2 diabetes was 47%. NCCM was more prevalent in WEs than SAs (17.6% vs 12.8%, p<0.001). In type 2 diabetes, the prevalence of suboptimal glycaemic control was significantly greater in SAs compared to WEs with NCCM and CDCM (79% vs 62%, p<0.001; 78% vs 65%, p<0.001, respectively). SAs with type 2 diabetes and comorbidity had excess odds of suboptimal glycaemic control compared to WEs: OR 2.27 (95% CI 1.50 to 3.43) for those with NCCM and OR 1.91 (95% CI 1.49 to 2.44) for those with CDCM. CONCLUSIONS: The prevalence of CDCM is higher in SAs compared to WEs with type 2 diabetes, whereas the prevalence of NCCM is higher in WEs compared to SAs. Taking into account comorbidities, SAs (compared to WEs) with type 2 diabetes had an excess risk of having HbA1c ≥7% ranging from 1.86- to 2.27-fold. Further research is needed to identify the reasons for unfavourable metabolic conditions in SAs and also develop and evaluate interventions.

Insulin U-500 in severe insulin resistance in type 2 diabetes mellitus.

Some patients with type 2 diabetes mellitus (T2DM) are profoundly insulin resistant and require large insulin doses to achieve optimal glycaemic control. However, large volumes of subcutaneous conventional U-100 insulin can cause discomfort at the injection site, resulting in poor concordance with insulin therapy. One therapeutic option is the use of U-500 insulin, thus reducing the insulin volume by 80%. This review will address the practical issues associated with the use of U-500, clinical efficacy and safety aspects of this concentrated insulin, which has an important role in a subgroup of patients with T2DM.

Glargine versus NPH insulin: efficacy in comparison with insulin aspart in a basal bolus regimen in type 1 diabetes--the glargine and aspart study (GLASS) a randomised cross-over study.

The aim of the study was to compare the efficacy of insulin glargine and aspart with NPH insulin and aspart in a basal bolus regimen in type 1 diabetes. In this 36-week randomised open-label two-period cross-over trial, subjects received 16 weeks' treatment with either once-daily insulin glargine or twice-daily NPH insulin after 4-week run-in. Primary outcome was HbA1c and secondary outcomes were fasting plasma glucose (FPG), weight change, incidence of hypoglycaemia, effect on lipid profile and patient satisfaction. Sixty patients with type 1 diabetes were recruited (33 male, mean age 42.7 years, mean HbA1c 8.53%) with 53 completing the study. At completion, HbA1c was lower with glargine and aspart than with NPH and aspart (8.07% versus 8.26%, difference -0.19 [95% CI 0.37-0.01]%, p=0.04). FPG was significantly different between glargine and NPH (p=0.002), with mean FPG on glargine 3mmol/L lower than on NPH at the end of the study. There were no differences in hypoglycaemia rate (p=0.63), weight (p=0.45) or lipid profile (p=0.18). Patient satisfaction was greater with glargine (DTSQ, p=0.001). Three patients discontinued as they wished to remain on glargine. We suggest that glargine combined with aspart is an effective basal bolus regimen in type 1 diabetes.

Investigation of Cushing's syndrome by inferior petrosal sinus sampling.

Bilateral simultaneous inferior petrosal sinus sampling, in combination with CRH stimulation, is now able to confirm the diagnosis of pituitary-dependent Cushing's disease with near certainty. In expert hands, the procedure is straightforward and safe. As well as confirming the differential diagnosis, the test may aid surgical success, especially if no adenoma is apparent at transsphenoidal exploration. In this article, we review the technique and its interpretation and consider which patients should undergo the procedure.

Amylin stimulates plasma renin concentration in humans.

Although insulin resistance and hypertension are commonly associated, the underlying cause for this association remains unknown. Plasma concentrations of the recently described hormone amylin, which is cosecreted with insulin by the pancreatic beta cell, are reported to be elevated in various states of insulin resistance, including hypertension and obesity. Preliminary studies by our group have suggested that there are amylin binding sites in the kidney. In nine healthy humans an infusion of human amylin that resulted in steady state plasma amylin levels in the subnanomolar range led to significant increases in plasma renin and aldosterone concentrations. These changes occurred in the absence of significant changes in plasma electrolytes, catecholamines, vasopressin, total renin, or osmolality. Diastolic pressure at 30 minutes and plasma glucose at 60 minutes rose modestly. Since amylin has both metabolic and renal actions, this peptide may be an important link between hypertension, insulin resistance, and the renin-angiotensin system.

An assessment of intrarenal hydrostatic pressure measurements in the diagnosis of acute renal allograft rejection.

Postoperative intrarenal pressure measurements may be an aid to the diagnosis of acute renal transplant rejection, especially in patients treated with cyclosporine. Serial measurements of intrarenal pressure were made in 38 recipients using a fine-needle technique. Thirty-two intraoperative and 207 postoperative measurements were made, and 39 clinical rejection episodes (23 confirmed by biopsy) monitored. Intraoperative pressures in grafts with immediate function (37.4 +/- 4.0 mmHg, mean +/- SEM) were not significantly different from those with delayed function (30.9 +/- 4.8 mmHg), whereas postoperative pressures were greater (P less than 0.01) in kidneys with acute tubular necrosis (29.4 +/- 1.9 mmHg) than in functioning grafts (20.4 +/- 0.9 mmHg). Pressures recorded during clinical rejection episodes (44.3 +/- 2.3 mmHg) exceeded (P less than 0.001) those during quiescent periods (23.6 +/- 1.0 mmHg). During rejection episodes, higher pressures (P less than 0.01) were recorded from tender or palpably enlarged grafts (52.5 +/- 3.0 mmHg) than in the absence of these signs (36.3 +/- 3.1 mmHg), and patients whose transplants biopsies showed cellular rejection tended to have greater pressures (50.1 +/- 4.1 mmHg) than those with concomitant vasculopathy (36.4 +/- 3.9 mmHg), but the latter did not reach statistical significance. In 7 cases of cyclosporine toxicity the intrarenal pressure was 17.8 +/- 4.2 mmHg. Using a diagnostic cut off point of 40 mmHg, the investigation failed to recognize 26% of acute rejection episodes--and, in the presence of acute tubular necrosis, it wrongly categorized 21% of nonrejectors. While its predictive capacity was limited, the test may occasionally be helpful in the differentiation of cyclosporine toxicity and rejection in functioning kidneys.

Dunnigan-Kobberling syndrome: an autosomal dominant form of partial lipodystrophy.

Dunnigan-Kobberling syndrome is a form of partial lipodystrophy characterized by sparing of the face. Despite descriptions of six families since 1974, details of total body adipose tissue distribution and studies of carbohydrate and fat metabolism are lacking. The mode of inheritance also remains unclear, with most authors favouring an X-linked dominant transmission lethal in the hemizygous male. We examined 23 members of a family, of whom at least eight had partial lipodystrophy. Auxological evaluation and cross-sectional imaging showed absence of subcutaneous fat, presence of adipose tissue inside the body cavities, and skeletal muscle hypertrophy. Biochemical evaluation identified insulin resistance but revealed inadequate suppression of non-esterified fatty acids. In this family, male-to-male transmission supports an autosomal dominant mode of inheritance for Dunnigan-Kobberling syndrome.

Can abnormalities of ventricular repolarisation identify insulin dependent diabetic patients at risk of sudden cardiac death?

OBJECTIVE: To study the possible association or QT dispersion and mean QTc intervals, as measured from standard 12 lead electrocardiograms, with baroreceptor-cardiac reflex sensitivity (BRS) in insulin dependent diabetic patients. DESIGN: Comparative study of non-invasive assessment of BRS, QT interval, and QT dispersion. SETTING: Large teaching hospital. SUBJECTS: 31 young asymptomatic, normotensive, insulin dependent diabetic patients, aged 20-55 years with normal clinical autonomic function. METHODS: QT intervals and QT dispersion were measured by a single observer blinded to other data about the patients. BRS was measured after activating the baroreflex with a Valsalva manoeuvre, and the rate in change of R-R interval to increasing systolic pressure during phase 4 was measured; in addition sequence analysis of resting systolic blood pressure and heart rate was performed during standing. The alpha coefficient--an index of the overall gain of the baroreflex mechanisms--was estimated from spectral analysis data of systolic blood pressure and pulse interval variability. RESULTS: Mean (SD) QTc interval was 406 (23) ms, QT dispersion was 44 (13) ms. There was no association between QT dispersion and any measurement of BRS. There was a negative correlation between mean QTc intervals and sequence analysis BRS (r = -0.355, P = 0.049), but no association with Valsalva BRS. The alpha coefficient, showed a significant negative correlation with mean QTc (r = -0.42, P = 0.008). CONCLUSIONS: Abnormal BRS may be reflected in the heart by global prolongation of ventricular repolarisation, but not by dispersion of ventricular repolarisation. This may, in part, explain the increase in sudden cardiac death seen in IDDM patients.

The effect of short chain fatty acid supplementation on membrane electrolyte transport and blood pressure.

Eleven normotensive subjects with no family history of essential hypertension took part in a double-blind randomized placebo-controlled crossover study to examine the effects of supplementing a normal omnivore diet with miglyol. This resulted in a fall in diastolic blood pressure in both the supine and standing positions, achieving statistical significance for the standing diastolic pressures, following miglyol treatment. Miglyol is rich in caprylic (8:0) and capric acids (10:0), both short chain saturated fatty acids, and supplementation with this produced a significant fall in erythrocyte membrane oleic and linoleic acid (P less than 0.01 compared to placebo for each fatty acid), as well as a fall in the saturated fat palmitic acid (16:0) (P less than 0.01). These changes were not associated with any alterations in total erythrocyte sodium influx, bumetanide sensitive influx or sodium red cell intracellular or potassium content. In addition, body weight and urinary excretion of sodium and potassium did not change. These data indicate that this dietetic manipulation with an oil rich in short chain saturated fatty acids lowers diastolic blood pressure but not as a result of changes in membrane sodium handling. It is possible that the short chain fats displace the longer carbon chain fatty acids which are metabolically important to cellular integrity and it is in this way that blood pressure falls.

Evidence of defective cardiovascular regulation in insulin-dependent diabetic patients without clinical autonomic dysfunction.

(1) Autonomic dysfunction is a well recognised complication of diabetes mellitus and early detection may allow therapeutic manoeuvres to reduce the associated mortality and morbidity. We sought to identify early cardiovascular autonomic neuropathy using spectral analysis of heart rate and systolic blood pressure variability. (2) Thirty patients with Type 1 (insulin-dependent) diabetes mellitus (DM) and 30 matched control subjects were studied. In addition to standard tests of autonomic function, heart rate and systolic blood pressure variability were assessed using power spectral analysis. From the frequency domain analysis of systolic blood pressure and R-R interval, the overall gain of baroreflex mechanisms was assessed. (3) Standard tests of autonomic function were normal in both groups. Total spectral power of R-R interval was reduced in the Type 1 DM group for low-frequency (473 +/- 63 vs. 747 +/- 78 ms2, mean +/- S.E.M., P = 0.002) and high-frequency bands (125 +/- 13 vs. 459+/-90 ms2, P < 0.0001). Systolic blood pressure low-frequency power was increased in the diabetic group (9.3 +/- 1.2 vs. 6.6+/-0.7 mmHg2, P < 0.05). The low frequency/high frequency ratio for heart rate variability was significantly higher in the Type 1 DM patients (4.6+/-0.5 vs. 2.9+/-0.5, P = 0.002), implying a relative sympathetic predominance. When absolute powers were expressed in normalised units, these differences persisted. There were significant reductions in baroreceptor-cardiac reflex sensitivity in Type 1 DM patients compared to controls while supine (9.7+/-0.7 vs. 18.5 +/- 1.7 ms/mmHg, P < 0.0001) and standing (2.9+/-0.9 vs. 7.18+/-1.9 ms/mmHg, P < 0.001). (4) Spectral analysis of cardiovascular variability detects autonomic dysfunction more frequently in Type 1 DM patients than conventional tests, and is suggestive of an abnormality of parasympathetic function. The abnormality of baroreceptor-cardiac reflex sensitivity could be explained by this impairment of parasympathetic function and this may predispose to the development of hypertension and increase the risk of sudden cardiac death. Using spectral analysis methods may allow detection of early diabetic cardiac autonomic neuropathy and allow therapeutic intervention to slow the progression.

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.

Ectopic prolactin secretion secondary to an ovarian tumour.

UNLABELLED: Ectopic hormone secretion is a well-recognised phenomenon; however, ectopic prolactin secretion is exceptionally rare. Hoffman and colleagues reported the first ever well-documented case of ectopic prolactin secretion secondary to a gonadoblastoma. We report a lady who presented with galactorrhoea and a large ovarian tumour that was found to secrete high levels of prolactin. LEARNING POINTS: Aim of this case report is to highlight the occurrence of this condition.Lack of awareness can often lead to a diagnostic conundrum.

Multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: the Microalbuminuria Education and Medication Optimisation (MEMO) study.

AIMS: To determine whether tighter cardiovascular risk factor control with structured education in individuals with type 2 diabetes (T2DM) and microalbuminuria benefits cardiovascular risk factors. METHODS: Participants from a multiethnic population, recruited from primary care and specialist clinics were randomised to intensive intervention with structured patient (DESMOND model) education (n=94) or usual care by own health professional (n=95). PRIMARY OUTCOME: change in HbA1c at 18months. SECONDARY OUTCOMES: changes in blood pressure (BP), cholesterol, albuminuria, proportion reaching risk factor targets, modelled cardiovascular risk scores. RESULTS: Mean (SD) age and diabetes duration of participants were 61.5 (10.5) and 11.5 (9.3) years, respectively. At 18months, intensive intervention showed significant improvements in HbA1c (7.1(1.0) vs. 7.8(1.4)%, p<0.0001), systolic BP (129(16) vs. 139(17) mmHg, p<0.0001), diastolic BP (70(11) vs. 76(12) mmHg, p<0.001), total cholesterol (3.7(0.8) vs. 4.1(0.9) mmol/l, p=0.001). Moderate and severe hypoglycaemia was 11.2 vs. 29.0%; p=0.001 and 0 vs. 6.3%; p=0.07, respectively. More intensive participants achieved ≥3 risk factor targets with greater reductions in cardiovascular risk scores. CONCLUSIONS: Intensive intervention showed greater improvements in metabolic control and cardiovascular risk profile with lower rates of moderate and severe hypoglycaemia. Intensive glycaemic interventions should be underpinned by structured education promoting self-management in T2DM.

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.

A randomized controlled trial examining combinations of repaglinide, metformin and NPH insulin.

AIMS: To compare combination use of repaglinide, metformin and bedtime Neutral Protamine Hagedorn (NPH) insulin with conventional approaches of insulin initiation in patients with Type 2 diabetes (T2DM). METHODS: Eighty-two patients with T2DM with suboptimal glycaemic control on oral glucose-lowering agents were randomized to one of three treatment regimens for 4 months. Group 1 received metformin and twice daily biphasic 30/70 human insulin mixture (n = 27), group 2 metformin and bedtime NPH insulin (n = 26) and group 3 metformin, bedtime NPH insulin and mealtime repaglinide (n = 25). RESULTS: Seventy-five patients completed the study. Baseline and end-point mean HbA1c levels fell from 9.0 +/- 1.1 to 7.9 +/- 1.1% in group 1, 10.0 +/- 2.2 to 9.2 +/- 1.4% group 2 and 10.0 +/- 1.7 to 8.1 +/- 1.5% in group 3, respectively. All groups showed improvements in HbA1c. There was no significant difference between groups in the proportions of patients experiencing hypoglycaemia (29.6, 25.0 and 16.7%, respectively; P = 0.55) or in mean weight gain (2.9, 0.7 and 2.2 kg, respectively; P = 0.06). By 4 months, insulin doses were 0.63 +/- 0.32 IU/kg in group 1, 0.58 +/- 0.21 IU/kg in group 2 and 0.37 +/- 0.22 IU/kg in group 3 (group 3 vs. groups 1 and 2: P < 0.002). CONCLUSIONS: The approach using repaglinide, metformin and NPH insulin improved glycaemic control with a similar safety profile to conventional insulin initiation in T2DM and produced final glycaemic control similar to metformin and a twice daily biphasic insulin mixture.

Metabolic alkalosis and myoclonus.

This is the first case reported of vomiting-induced metabolic alkalosis associated with myoclonus. The report describes an unusual presentation of myoclonus secondary to acid-base disturbance caused by recreational drug-induced vomiting. The severe derangement of hyponatraemia, hypokalaemia, and alkalosis appears to have been reasonably well tolerated due to the gradual onset and relatively long history. The causes, mechanism, and management of metabolic alkalosis are discussed.

Cow's milk and type 1 childhood diabetes: no increase in risk.

A retrospective case-control study was undertaken to investigate the relationship between the early introduction of cow's milk and the subsequent risk of developing Type 1 diabetes (< 15 years at diagnosis). A total of 268 children who developed diabetes during the period 1980-1990 (11 years inclusive) in Leicestershire were identified. Age-, sex-, and race-matched controls were identified using the Leicestershire population register. Parents of children with diabetes and their controls completed a structured questionnaire on infant feeding habits from birth. A total of 184 questionnaires (67%) were analysed. There was no difference between the diabetic and control children with respect to the introduction of cow's milk at an early age and the risk of developing diabetes (odds ratio: 0.98 (0.65-1.47)). In addition, short duration of breast-feeding (< 3 months) had no influence on the incidence of diabetes (1.05 (0.64-1.75)). This study does not support the hypothesis that the early introduction of cow's milk or a short duration of breast-feeding increases the risk of developing Type 1 diabetes.